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Current Stem Cell Research & Therapy

Mesenchymal Stem Cells as a Source of Dopaminergic Neurons: A Potential Cell Based Therapy for Parkinson’s Disease BENTHAM SCIENCE

Katari Venkatesh1,*,# and Dwaipayan Sen1,*,# 1

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Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT) University, Vellore 632014, Tamil Nadu, India

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DOI: 10.2174/1574888X12666161114122 059

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Received: June 22, 2016 Revised: October 5, 2016 Accepted: November 1, 2016

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ARTICLE HISTORY

Abstract: Cell repair/replacing strategies for neurodegenerative diseases such as Parkinson’s disease depend on well-characterized dopaminergic neuronal candidates that are healthy and show promising effect on the rejuvenation of degenerated area of the brain. Therefore, it is imperative to develop innovative therapeutic strategies that replace damaged neurons with new/functional dopaminergic neurons. Although several research groups have reported the generation of neural precursors/neurons from human/mouse embryonic stem cells and mesenchymal stem cells, the latter is considered to be an attractive therapeutic candidate because of its high capacity for self-renewable, no adverse effect to allogeneic versus autologous transplants, high ethical acceptance and no teratoma formation. Therefore, mesenchymal stem cells can be considered as an ideal source for replacing lost cells in degenerative diseases like Parkinson’s. Hence, the use of these cells in the differentiation of dopaminergic neurons becomes significant and thrives as a therapeutic approach to treat Parkinson’s disease. Here we highlight the basic biology of mesenchymal stem cells, their differentiation potential into dopaminergic neurons and potential use in the clinics.

are of several types based on its location in the human body which includes hematopoietic stem cells (HSCs) [5-8], neural stem cells [9], mammary stem cells, cardiac stem cells, and limbal stem cells [10]. Mesenchymal stem cells (MSCs) are the most abundant multipotent stem cells present in almost every tissue including adipose tissue [11, 12], bone marrow [13], placenta [14], umbilical cord blood [15, 16], amniotic fluid [17], synovium [18], cartilage [19], exfoliated deciduous teeth [20], skin [21] and muscle [22]. Due to ethical and safety concerns in using embryonic stem cells (ESCs) [23] and induced pluripotent stem cells (iPSCs) [24, 25] in the clinics, great interest has been developed in MSCs, which are of free from both ethical concerns and tumor formation [26]. This is evident from the huge increase in the number of clinical trials that have used MSCs since the past decade. Although the continuing “gold rush” to use MSCs in clinical settings is encouraging, we should also be mindful of some of the associated challenges including poor survivability post-transplantation and effective delivery systems [2729]. Numerous scientific issues still remain to be resolved before establishment of clinical standards in the use of MSCs [30-32].

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1. INTRODUCTION

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Keywords: Mesenchymal stem cells, MSC-derived dopaminergic neurons, Parkinson’s disease, clinical trials, cell-based transplantation therapy.

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Stem cells are defined as immature cells capable of selfrenewal and regenerating any cell type within the human body. Stem cells have three major properties, namely i. Unspecialization: ability to remain quiescent without any specialized functions, ii. Differentiation: ability to give rise to various cell types of the body and iii. Self-renewal: ability to divide asymmetrically and produce daughter cells having the same potency (Table 1) [1-3]. Organs of adult human body also possess undifferentiated naive stem cells in very low population residing in specialized microenvironment known as “stem cells niche” [4]. Although adult cells slowly die due to normal ageing process, the tissue remains functional because of these multipotent endogenous stem cells which help in replenishing the dead cells with a new wave of specialized cells during the lifetime. Therefore, these stem cells are being used to repair and regenerate the cells to restore impaired function thus making them extremely important in regenerative medicine and tissue engineering. Multipotent stem cells

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*Address correspondence to this author at the Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology (VIT) University, Vellore 632014, Tamil Nadu, India; Tel: +91-416-220-2141/2151; +91-9177759050; E-mails: [email protected]; [email protected]l.com # Both authors contributed equally to this article. 2212-3946/17 $58.00+.00

Dopaminergic (DA) neurons which constitute less than 1% of the total number of neurons in the brain play a very significant role in regulating several aspects of its functions. © 2017 Bentham Science Publishers

MSC-Derived Dopamine Cells in the Treatment of PD

Table 1.

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

327

Classification of stem cells based on their potency.

S. No.

Type of Potency

Location

Key Property

1

Totipotent

Zygote and cells upto Morula stage during embryonic development.

Can differentiate into all cells in an organism including extraembryonic, or placental, cells.

2

Pluripotent

Inner cell mass of Blastocyst

Can differentiate into all cell types of an organism except the placental cells.

3

Multipotent

Every organ of adult human body

Can differentiate into multiple, but limited cell types.

4

Unipotent

Lineage committed Precursor cells

Can differentiate into only one cell type.

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cells. For example, tissues like hematopoietic [47], skeletal [48], cardiac [49], pancreatic [50], epithelial [51], corneal [51], hepatic [52], renal [53], testicular [54], ovarian [55], hair follicle [56] etc., have their own stem cell niches. These endogenous stem cell niches are thought to aid in repairing or restoring impaired function and maintain normal cellular turnover [13, 57]. The frequency of MSCs also varies greatly between different tissues. For example, in bone marrow they are 1-10 in number for every 105 mononuclear cells whereas, in the adipose tissue they are 1-10 in number for every 102 stromal vascular fractions. On the other hand, in peripheral blood, the presence of MSCs is quite low when compared to either bone marrow or adipose tissue [58, 59]. However, the availability of MSCs from multiple tissue sources is high and ethical concerns are less compared with ESCs. Moreover MSCs are non-tumorogenic compared to either ESCs or iPSCs. MSCs also secrete variety of trophic factors for paracrine signalling and have the ability to differentiate into a wide range of cell types. Due to such advantageous traits of MSCs, it makes them an attractive choice for treating various diseases [9, 60, 61].

2. CHARACTERISTIC FEATURES OF HUMAN MSCs MSCs were first isolated by Friedenstein et al., in 1967 from bone marrow and were described as colony-forming unit-fibroblasts [41-45]. These colony-forming fibroblasts were later named as “mesenchymal stem cells” by Caplan [46]. In adult human body, all tissues have specific stem cell niches with multi-lineage capacity. Tissue specific stem cellniche helps to maintain the homeostasis of endogenous stem

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These DA neurons are the major source for production of the neurotransmitter called dopamine. Dopamine can control motor functions and can regulate the release of various hormones thus directing both mental and physical health of a human brain. Dopamine increases heart rate and cardiac contractility by producing inotropic and chronotropic effects on the myocardium and can also act as a vasodilator. It increases renal blood flow and can regulate natriuretic response in the kidneys [33]. It reduces gut motility and modulates intestinal mucosal blood flow in the digestive system [34]. Thus, dopamine not only functions in the brain but can also work in other parts of the nervous system where it acts as a chemical messenger. Hence, dysfunctioning of dopamine production shows profound effect on several parts of human body. Parkinson’s disease (PD) is one of such disorder and it is considered as second most common neurodegenerative condition after Alzheimer’s disease [35, 36]. PD is characterized by the loss of nigrostriatal DA neurons causing tremor and motor impairments. The current gold standard clinical treatment for PD which involves L-Dopa administration has several side effects like nausea, hypotension, arrhythmias, hair loss, disorientation, vivid dreams, auditory hallucinations, somnolence etc thus failing to improve the quality of life [37, 38]. Therefore it is essential to develop new therapeutic strategies to replace damaged neurons in PD patients. Cell therapy has been seen as an emerging therapeutic to slow down PD symptom by replacing the lost neuronal cells. Till date there is only one clinical report (NCT02538315) from the University of Saskatchewan, Canada stating that transplantation of DA neurons might be a potential therapeutic way to improve PD pathogenesis [39]. Therefore, the use of MSCs in differentiation to DA neurons becomes significant and thrives as a therapeutic approach for PD [40]. In this article, we review the biological properties of MSCs and factors that affect their differentiation process to DA neurons and their potential in cell-based transplantation therapy for PD.

2.1. Markers and Receptors of Human MSCs Although MCSs can express a large number of surface antigens/growth factor proteins, till date no particular surface antigen(s) have been isolated in the literature as the best marker(s) for their identification and characterization [62, 63]. Moreover majority of the reported markers are based on study conducted in in vitro expanded cells. Several antibodies have been raised against different surface markers. For instance, Stro-1 recognizes the subpopulation of MSCs that are capable of osteogenic differentiation [64, 65]. CD73 monoclonal antibodies produced against ecto-5’nucleotisidase [66, 67], CD90 for Thy-1 [68], CD105 for Endoglin [69] and CD166 for activated leukocyte cell adhesion molecule [70, 71] were reported to characterize pure population of MSCs. MSCs can express specific molecular proteins that includes adhesion molecules, extracellular surface proteins, growth factor receptors that are responsible for interactions with the microenvironment of bone marrow. However, all these surface antigens can be differently expressed depending of the source of MSCs (Tables 2 and 3). For example Stro-1 antigen is expressed in bone marrow derived MSCs but not in adipose tissue-derived MSCs. Also, MSCs do not express hematopoietic and endothelial markers like CD34, CD45, CD133, CD11 and CD33 [62, 72, 73].

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Table 2.

Venkatesh and Sen

List of reported cell surface markers of human MSCs. Tissue Source

Positive Markers

Negative Markers

Reference

1

Adipose tissue

CD73, CD90, CD29, CD44, CD71, CD105, CD13, CD166, STRO-1

CD14, CD31, CD34, CD45

[249, 250]

2

Amniotic fluid

CD29, CD44, CD90, CD105, CD, SH2, SH3, HLA-DR

CD10, CD14, CD34, HLA-DR

[251, 252]

3

Bone marrow

CD73, CD90, CD105, STRO-1

CD14, CD34, CD45, HLA-DR

[253, 254]

4

Dental tissues

CD29, CD44, CD90, CD105

CD14, CD34, CD45

[255, 256]

5

Endometrium

CD73, CD90, CD105, CD146

CD34, CD45

[187, 257]

6

Limb bud

CD13, CD29, CD90, CD105, CD106

CD3, CD4, CD14, CD15, CD34, CD45, HLA-DR

[258]

7

Peripheral blood

CD44, CD90, CD105, HLA-ABC

CD45, CD133

[259]

8

Placenta

CD29, CD73, CD90, CD105

CD34, CD45

[260]

9

Salivary gland

CD13, CD29, CD44, CD90, STRO-1

CD34, CD45

[261]

10

Skin and foreskin

CD44, CD73, CD90, CD105, CD166, SSEA-4, Vimentin

CD34, CD45, HLA-DR

[262, 263]

11

Umbilical cord lining membrane

CD29, CD44, CD73, CD90, CD105

CD34, CD45

[264]

12

Synovial fluid

CD44, CD90, CD105, CD147, STRO-1

CD31, CD34, CD45, CD106

[264]

13

Wharton's jelly

CD14, CD34, CD45, CD79, HLA-DR

[265]

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Cell surface receptors of MSCs and their biological functions. Name of Receptor

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Type of Receptors

Biological Function

EGFR, bFGFR, IGFR, PDGFR, TGFRI and RII

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Self-renewal and differentiation

References [266]

Hepatocyte growth factor receptor (HGFR)

Exerts a very strong chemotactic stimulus on MSCs

[158, 267, 268]

Receptor tyrosine kinases (RTKs)

Regulates the downstream signaling with TGF

[267]

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Growth Factor Receptors

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Table 3.

CD73, CD90, CD105

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S. No.

CCR1, CCR2, CCR4, CCR6, CCR7, CCR9, CCR10, CXCR1, CXCR2, CXCR4, CXCR5, CXCR6 and CX3CR1

Helps in homing, migration and engraftment of MSCs to sites of injury as well as neoplasia

IL-1R, IL-3R, IL4R, IL-6R, IL-7R, IFNR, TNFI and IIR

Recognizes interleukins belonging to type I and type II cytokine receptor families and have the ability to respond to local signals to access damaged tissue

[270]

Cytokine Receptors

Role in homing to injury sites

[271]

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Cell-Matrix Receptors

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Chemokine Receptors

Integrins

Mediate cell-matrix and cell-cell adhesion and affect many cellular processes like cell attachment motility, proliferation and differentiation.

CD44

Involved in cell-matrix interactions

Notch receptors

Activation of Notch, by its ligands (Jagged-1, DLL-1, DLL-3 and DLL-4) triggers proteolytic cleavage and release of the Notch intracellular domain, which then enters the cell nucleus and alters gene expression.

Cell-Cell Receptors

Immuno Modulating Receptors

ICAM-1, 2VCAM-1 and ALCAM

Hematopoietic and immune functions

Toll-like receptors (TLRs 1-6 and 9)

Specifically drive the recruitment , migration and immuno-modulating functions of MSCs at injured sites

[269]

[272]

[273]

MSC-Derived Dopamine Cells in the Treatment of PD

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

Thus, it becomes highly difficult in not having a specific marker for better identification of all the sub population of MSCs. In this respect, the International Society of Cellular Therapy (ISCT) has proposed the minimal criteria to phenotypically define human MSCs based on their cellular properties: According to the guideline, for cells to qualify as MSCs they (1) must be adherent to plastic in standard culture conditions, (2) must have positive expression for CD105, CD73, and CD90 and negative expression for CD45, CD34, CD14/CD11b, CD79/CD19, and HLA-DR class II, and (3) must differentiate into osteocyte, adipocyte, and chondrocyte lineages in vitro [74].

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Secondly, several studies indicated that MSCs can also suppress T-lymophocyte (naive and memory) activation and proliferation when induced with mitogens [86, 87], alloantigens [88], CD28 and CD3 antibodies [88, 89]. These data suggests that MSCs can suppress our immune cells (innate and adaptive) such that the immune system is switched from a pro-inflammatory state to an anti-inflammatory state [17, 90]. Such immune-suppressive property of MSCs is extremely beneficial as it leads to higher graft survival and further highlights the potential clinical use of MSCs in cell therapy and tissue regeneration studies [72, 91, 92]. 4. MSC-MEDIATED TISSUE REPAIR

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Immunomodulatory property of MSCs makes them a very potent candidate for use in cell transplantation therapy [75-77]. Immune-suppressive effects of MSCs act both on the innate as well as adaptive immune cells of the human body. The neutrophils, nature killer (NK) cells and dendritic cells are main players responsible for exerting innate (nonspecific) immunity. MSCs produce IL-6 that can prevent the release of reactive oxygen species and hydrogen peroxide by neutrophils [78]. MSCs also inhibit differentiation of immature monocytes into dendritic cells, thus preventing them to present foreign antigens to naive T cells and prevent T cell activation [79]. MSCs are capable to reduce the productions of IL-2 and IFN which are required for proper activation and functioning of NK cells [80-83]. They can also inhibit the proliferation of T cells by releasing soluble factors like TGF and hepatocyte growth factor [84] (Fig. 1). Tse et al. showed that there was no T-cell proliferative response even after co-treatment with IFN- and anti-CD28 antibody [85].

MSCs have been used clinically for treating various diseases which involves tissue damage [93, 94] and wound healing [95] including cardiomyopathy [96, 97] and liver cirrhosis [98, 99]. MSCs also help in many cellular functions including regulation of neuronal growth and differentiation [100], inhibition of T and B cell proliferation and NK cell functioning (immunosupression) [101], reduction in apoptotic cell death [102], increased myelofibroblast differentiation to heal wounds [103], enhanced axonal remyelination process [104] and promotion of haematopoietic stem cell (HSC) survival and engraftment (Fig. 1). MSCs mediate these therapeutic effects primarily via four mechanisms of action which includes differentiation, paracrine effects, immune-modulation and antiinflammatory effects. MSCs have been shown to secrete a variety of trophic factors that may help in repair and regeneration of the damaged tissues. Both differentiation and paracrine signaling have been shown to be the key mechanisms by which MSCs can repair damaged tissues [105]. However, due to a variety of negative signals like increased reactive oxygen species, inflammation and anoikis, MSCs can find it difficult

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3. IMMUNOMODULATORY PROPERTY OF HUMAN MSCs

Fig. (1). Key cellular functions of human mesenchymal stem cells (MSCs). Human MSCs have immunomodulatory properties to reduce inflammation and secrete various neurotrophic and angiogenic factors during tissue mediated repair. MSCs also regulate hematopoietic stem cell (HSC) survival, differentiation and reduce apoptotic cell death. MSCs have been used in various clinical trials due to its multipotent nature that aids in tissue regeneration process.

330 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

Venkatesh and Sen

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known as a neurological disorder with four major cardinal manifestations: tremor (shaking), bradykinesia (slowness of movement), rigidity and postural instability. In addition to motor symptoms, it also shows non-motor symptoms (features affecting mood, sleep, cognition, and autonomic function) which then worsen the executive (such as attention, recognition, working memory, and problem solving) and psychiatric functions (dementia, hallucinations, anxiety, bradyphrenia and depression) [124, 125]. These motor, cognitive and psychiatric symptoms are severe enough to reduce a patient’s quality-of-life to approximately 50 to 60% [126]. The progression of PD is due to collective effects of several mechanisms that include oxidative stress, mitochondrial dysfunctioning, protein misfolding, protein aggregation, inflammation, excitotoxicity, apoptosis and lowered trophic support [127]. These cascades of mechanism cause the loss of nigrostriatal DA neurons, which is accompanied by the accumulation of -synuclein containing cytoplasmic inclusions (Lewy bodies) [128, 129]. Midbrain DA (mDA) neurons are the selective subgroup of neurons and are critical for the regulation of motor and cognitive functions. These mDA neurons are located in three distinct regions of the brain: the substantia nigra pars compacta (SNc, also known as A9 group) the ventral tegmental area (VTA, or A10 group) and the retrorubral field (RrF, or A8 group) [130]. VTA and RrF DA neurons control emotional behaviour, natural motivation and cognitive functions [131] while SNc DA neurons primarily regulate motor function. These mDA neurons constitute major source for the production of dopamine in the CNS. Dopamine is a well-known neurotransmitter which transmits neural information between the substantia nigra (SN) and other parts of the brain thus controlling voluntary movements of the human body. However, the complete molecular mechanism and their underlying role in the progression of PD have not been fully elucidated. The researchers also reviewed the pathophysiological features of various monogenic forms of PD caused by mutations in the Synuclein alpha (SNCA), Leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1), deglycase (DJ-1) and Probable cation-transporting ATPase (ATP13A2) genes [132]. These monogenic variant are significant tools in identifying cellular/molecular pathways that shed light on the pathogenesis of PD [133]. The identification of the mutations in these genes till date, have not provided any significant progress in the treatment of PD. However, if we know the complete genetic makeup of PD it could allow researchers to design new treatments that could alter the course of the disease [134].

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to differentiate at the injured site. Hence, under these conditions the repair mechanism will depend heavily on the paracrine signalling ability of MSCs. Upon delivering these MSCs at injured site it may provide a therapeutic benefit through localized secretion of certain growth factors and cytokines that act in a paracrine manner. The paracrine effects of MSCs are also exemplified in multiple animal disease models like spinal cord injury, disease of central nervous system and myocardial infarction [106, 107]. Other researchers also reported that MSCs can promote neurogenesis in an animal model of Huntington’s disease and showed functional recovery from the neurodegenerative condition [108, 109]. In this disease condition, MSCs were tightly associated with immature astrocytes and bundles of cells that bridged the injury. MSCs may also mediate the release of neurotrophic factors that can regulate the therapeutic efficacy in CNS related disease models. The neurotrophic factors that are secreted by MSCs can arbitrate neuronal cell survival, trigger proliferation of neural stem cells and promote the regeneration of nerve fibres [110, 111]. Thus, paracrine factors released by MSCs may account for the beneficial effects of MSC transplants on CNS injury models. Several other studies have demonstrated significant improvement in the left ventricular ejection fraction of heart following transplantation of MSCs in myocardial infracted animal models [112-114]. This is due to the upregulation of myogenesis genes including vascular endothelial growth factor, fibroblast growth factor-2, various interleukins, and macrophage colony-stimulating factor [115-117]. In contrast, MSCs also have been reported to differentiate into epidermal keratinocytes, endothelial cells and pericytes in cutaneous wound [118]. It is very well documented that MSCs have an ability to differentiate into multiple cell types including adipocytes, osteocytes, chondrocytes, neurons and myoblasts in response to various initiation factors (growth factors, small chemical inducers) supplemented in the culture medium [119, 120]. These findings clearly suggest that in addition to paracrine signalling, differentiation is also necessary to show its therapeutic effects. In addition MSCs might also provide antioxidants, free radical scavengers and chaperone proteins at an ischemic site. Due to this the toxic substances that were released in the local environment can be removed thus increasing the survival rate of the cells [121]. Taken together these data indicate the immense therapeutic potential of MSCs in tissue repair. In the clinical situation, MSCs are being explored in the treatment of various disease conditions, including liver cirrhosis, multiple sclerosis, retinal degeneration, respiratory distress syndrome, cardiomyopathy, spinal cord injury, critical limb ischemia, ovarian cancer and prostate cancer. So far, hundreds of clinical trials using MSCs have been registered in the clinical trial-database maintained by the National institutes of Health (NIH), the United States of America (https: //clinicaltrials.gov/). Some of the important clinical trials using MSC transplantation have been summarized and listed in Supplementary Table 1. 5. SPECIAL NOTE ON MSCs-PD RECOVERY 5.1. Pathophysiology of PD PD is the second most common chronic neurodegenerative disease and currently incurable [122]. It affects about 1% of the populace by the age of 65 years, and 4-5% of the population by the age of 85 years [123]. Clinically, PD is

The current managements for PD fail to show any significant improvements. Pharmacological treatment with dopamine analogues (levadopa) have limited clinical success due to severe long term side effects [37]. In PD patients treated with deep brain stimulation (DBS), electrical impulses are delivered using implantable pulse generator (electrodes) to specific regions in the brain which blocks the abnormal neuronal signals [135-137]. However this medical technique has certain limitations. For example, this surgical procedure cannot be used in patients showing signs of dementia. Additionally, although DBS can change the brain firing pattern but in most cases is unable to halt/slow down the progression of PD symptoms [138]. However, there are

MSC-Derived Dopamine Cells in the Treatment of PD

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

6. SIGNALING MECHANISMS INVOLVED IN DIFFERENTIATION OF DA NEURONS

6.1. cAMP and PKA Signaling Pathway cAMP is a well-known secondary messenger which is formed by the action of an enzyme known as adenylyl cyclase on adenosine-triphosphate (ATP). In the cytoplasm, the released cAMP effectively activates protein kinase A (PKA) which in turn phosphorylates the transcription factor cAMP responsive element binding protein (CREB protein) [172, 173]. The phosphorylated CREB protein then binds to CREB-binding protein (CBP) with the help of co-factors and specific DNA sequences and regulates the expression of various genes like tyrosine hydroxylase (TH), FOXA2 and BDNF [174]. Furthermore, the destruction of intra-cellular cAMP is mediated by phosphodiesterases (PDE), which converts cAMP to AMP, thus regulating cAMP levels in the cytoplasm [175]. In the various in vitro assays, cAMP or other molecules which increases cAMP levels in the cytoplasm are frequently being used in the culture media to differentiate MSCs into neural cell types [176]. For example, forskolin activates adenylyl cyclase, dibutyryl-cAMP and IBMX both act as inhibitors of PDE [177] and 8-bromocAMP induces PKA to complete differentiation of MSCs into neuronal cell types [171]. Lepski et al. demonstrated the differentiation of human bone marrow MSCs to neuronal cell types through the PKA pathway by using the PDE inhibitorIBMX. Moreover, MSC-derived neuronal cells also showed

Umbilical cord

Bone marrow

3

4

5

Adipose tissue

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cAMP-PKA

NF, GFAP

[176]

EGF,bFGF, cAMP, IBMX, BDNF

cAMP-PKA, NT

NeuroD, NeuN, GABA, NF-200

[178]

GM-CSF

cAMP-PKA

Nestin, NSE, GFAP

[274]

SHH, FGF8, GDNF, RA

SHH, NT

III-tubulin, DAT, FoXA2, Girk2, TH

[212, 275]

Forskolin, IBMX, cAMP and TPA

cAMP-PKA

III-tubulin, DAT, FoXA2, Girk2, TH

[147, 276]

Forskolin, IBMX

cAMP-PKA

III-tubulin, GFAP, NSE

[277]

Forskolin/8-brmo-cAMP

cAMP

III-tubulin

[278]

SHH, FGF8, bFGF+BDNF

NT, SHH

NeuN, TH, III-tubulin, DAT

[163, 181]

Forskolin, SHH/RA

cAMP, RA, SHH, NT

GATA3, Sox10, NeuN, III-tubulin

[279]

bFGF, IBMX, SHH, RA, BDNF, GDNF

cAMP, NT, RA, SHH

III-tubulin, Nkx2.2, Pax6, Olig2

[147, 280, 281]

bFGF, EGF, BDNF, IBMX

cAMP-NT

III-tubulin, GFAP

[147, 282]

EGF, bFGF+RA

RA

Nestin, III-tubulin, NF-M, NCAM

[283, 284]

Forskolin, SHH, FGF8, GDNF

cAMP-PKA, SHHNT

III-tubulin, DAT, FoXA2, Girk2, TH

[285]

SHH, FGF8+ brian conditioned medium

SHH, NT

III-tubulin, DAT, FoXA2, Girk2, TH

[286]

Dental pulp

Wharton's jelly

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References

Forskolin

Signaling Pathway

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Neural Markers

N

2

Induction Molecules

Fo

1

MSCs Derived From

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List of signaling molecules that are used for neuronal induction of MSCs.

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Table 4.

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There is a wide range of signaling molecules which give rise to neural differentiation that includes growth factors like epidermal growth factor (EGF), basic fibroblast growth factor (bFGF/FGF8) [158, 159], cerebral dopamine neurotrophic factor [160, 161], sonic hedgehog (SHH) [162], brainderived neurotrophic factor, (BDNF) [163, 164], glial cell derived neurotrophic factor (GDNF) [139, 165, 166], nerve growth factor (NGF) and neurotrophin (NT) [167, 168]. Small molecules like cyclic-adenosine-monophosphate (cAMP), 3-isobutyl-1-methyxanthine (IBMX) and retinoic acid (RA) [169-171] are also known to induce neuronal dif-

ferentiation (Fig. 2A). In all cases there is an activation or deactivation of several intracellular signaling pathways which decides neuronal fate (Table 4) (Fig. 2A).

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various other studies where directly transplanted MSCs showed improved pathophysiology of neurodegenerative diseases including PD [139-149]. Even as there are no treatments to cure PD, DA neuron replacement therapies have been shown to improve motor functions [150-152]. Thus, this review mainly focuses on the derivation of DA neurons from MSCs to reverse the motor deficits and improve on the PD phenotype. These derived functional neurons have also been shown to suppress side effects like tumorogenesis; graft versus host diseases etc., and thus have great potential for treating PD [153-155]. Therefore, a keen interest has been increasing in the development of novel therapeutic strategies to generate DA neurons, that actually repair the fundamental disease process or even slow down its progression [156, 157].

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332 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

6.2. Sonic Hedgehog Signaling Pathway

6.4. Neurotrophic Factors-Related Signaling Pathways

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The hedgehog mediated signaling involves a key ligand molecule known as sonic hedgehog (SHH), which plays a prominent role in the organization and patterning of nervous system. SHH binding to Patched1 (Ptc) receptor reduces Ptcmediated inhibition of a second receptor called smoothened (Smo). Smo then accumulates and triggers the activation of Gli family of transcription factors (Gli1, Gli2 and Gli3) [179, 180] and regulate the expression of DA neuron-specific genes. Trzaska et al. demonstrated the differentiation of bone marrow derived MSCs into DA neurons upon supplementation with SHH coupled with FGF8 and bFGF. The treatment was shown to trigger a good number of putative DA neurons which showed TH expression along with electrophysiological features [163, 181].

ditional medium supplemented with SHH coupled with RA showed expression of neuronal markers like TH and Nurr1 which were then assessed for their dopaminergic profile [171].

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electrophysiological property (Na+, K+ and Ca2+ currents) [178].

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Fig. (2). Mesenchymal stem cells (MSCs) - based strategies for the treatment of Parkinson’s disease (PD). A. Differentiation of human MSCs into dopaminergic (DA) neurons through the induction of various signaling molecules and its respective signaling pathways (for details please refer to the text). B. Therapeutic application of in vitro developed DA neurons to treat PD patients and screening of small molecules in the MSC-derived DA neuronal cell model.

6.3. RA Signaling Pathway

RA is bound by cellular retinoic acid binding protein (CRABP) and forms a complex known as CRABP-RA complex which translocates into the nucleus to bind to specific receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs) [182]. These receptor complexes heterodimerize and bind to specific DNA sequences known as RAresponsive elements (RARES) which leads to activation of target genes [183]. In adult neurogenesis, RA regulates the expression of Hox genes and has an important role in the development of anterio-posterio axis of the nervous system [182]. Umbilical cord derived MSCs cultured in neural con-

Neurotrophins are secreted growth factors and are comprised of NGF, BDNF, glial derived neurotrophic factor (GDNF) and neurotrophins (NT-) 3, 4/5 and 6 [142, 184, 185]. This protein family is involved in the regulation of development, survival and functionality of neurons in the nervous system [186, 187]. These neurotrophins activate high affinity tyrosine kinase (Trk) receptors including TrkA, TrkB and TrkC and induce events like neurite formation [188, 189]. Lim et al. reported the role of BDNF in the differentiation of human umbilical cord-derived MSCs into neural cell types via activation of Raf1 and ERK pathway. The differentiated cells were shown to express neuronal markers like III-tubulin and NeuN [190]. Zhang et al. reported that neuronal survival and differentiation were significantly improved when treated with NT-3 after RA induction and these signaling effects were confirmed by the addition of Trk receptor inhibitor K252a in the culture media [191]. GDNF is also known to promote the differentiation of MSCs into DA neurons and motor neurons and is considered as a therapeutic agent in the management of neurological diseases such as PD [192, 193]. Combination of the three main neurotrophins (BDNF, NT-3 and NGF) was also used in the differentiation of marrow derived adult multilineage inducible cells to neuronal cells. These differentiated cells showed expressions of several neural markers such as NF-L and NeuN [194].

MSC-Derived Dopamine Cells in the Treatment of PD

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Studies on the generation of DA neurons from stem cells were started in the mid-nineties [195]. Several research groups have reported the generation of DA neurons from various stem cell sources like; ESCs [151, 196], iPSCs [197199] , NSCs [200, 201] and MSCs [163, 181]. The direct use of these stem cells (especially ESCs and iPSCs) in clinical settings is limited due to its unavailability and their propensity to form tumours. Also, isolation of ESCs for transplantation therapies is considered unethical. Roy et al., reported that ESC-derived DA neurons when implanted in the nigrostriatum of 6-hydroxydopamine-lesioned PD rats, showed significant recovery in motor functions. However, transplanted TH-positive grafts exhibited neuroblastic undifferentiated phenotype with tumorigenic property [202]. In another study, iPSCs were generated and differentiated into DA neurons, and transplanted into rats with striatal lesions following which significant motor improvements were observed. However, it was also accompanied by tumor formation [203]. Unlike ESCs and iPSCs, neural stem cells (NSCs) are considered to be less tumorogenic but their use is hampered by poor survival rate, lack of proper source and obtaining enough numbers for transplantation [204, 205]. With respective to these clinical aspects, the use of MSCs has been considered as an ideal source for producing DA neurons primarily due to its high ethical acceptance, widespread availability, ease of isolation and ability to be readily expanded without forming teratomas. Various reports have shown the differentiation of MSCs into authentic nigral DA neurons for the treatment of PD [139, 206, 207]. This differentiation capacity of MSCs can give us a potentially unlimited source of DA neurons that can be used to screen number of drugs without needing to test them on preclinical models (PD-drug discovery). In this way we might also be able to minimize the use of animals on our way forward in finding a cure for PD (Fig. 2B). Cova et al. demonstrated that the use of human MSCs could propel local microenvironmental signals to sustain active endeavors for substitution of damaged neurons. Upon implantation of naive human MSCs into the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), the animals survived for 23 days more and regionally sustained the survival of striatal/nigral dopaminergic terminals with enhanced neurogenesis in the subventricular zone (SVZ), when compared with lesioned and PBS grafted animal groups [208-210]. The number of proliferative cells (Ki67/Proliferating Cell Nuclear Antigen) as well as neuroblasts migration was significantly augmented in the lesioned striatum of transplanted animals compared to controls providing remarkable cues of MSCs potential in promoting endogenous reparative mechanisms that may prove beneficial for PD treatment [208]. The bone marrow stromal cells (BMSCs) have also been considered as an ideal source for producing DA neurons and are ethically acceptable and readily expanded. In a study the authors employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs by exposing the cells to pre-induction and neuronal induction steps to regenerate functional neurons [211]. Khoo et al. reported that bone marrow-derived human MSCs have shown promise in in vitro neuronal differentiation and in cellular therapy for neu-

rodegenerative disorders, including PD. Neuronal differentiation was based on several growth factors (EGF/FGF2/SHH/FGF-8/GDNF/PDGF) and all were found to be capable of eliciting an immature neural phenotype [212]. Despite the reported immunosuppressive properties of MSCs and cyclosporine based immunosuppression, transplantation of these undifferentiated and neuronal-primed human MSCs into the striatum and substantia nigra of 6-OHDA-lesioned hemiparkinsonian rats only revealed transient graft survival for 7 days [212]. The efficacy in restoration of motor function was found to be comparable to that seen with human fetal DA neurons [212-214]. The long-term survival and functionality of DA neurons differentiated from MSCs has also been identified with the use of MRI and PET imaging techniques [215]. Furthermore, the study also reported that human ESC-derived DA neurons can project sufficiently long distances, fully regenerate midbrain-to-forebrain projections and innervate correct target structures [215]. There is preclinical evidence that human ESC-derived dopamine neurons are functionally equivalent to those derived from fetal tissue which supports the usefulness of cell replacement therapy for PD [215-218]. Human pluripotent stem cells have also been used to differentiate into spinal motor neurons 11 days after exposing them to small molecule activators of SHH and canonical WNT signalling. These developed DA neurons were obtained by day 25 and maintained for several months. The developed neurons positive for FOXA2+/TH+ expression were transplanted in 6-OHDAlesioned mice following which the animals’ demonstrated robust survival of midbrain DA neurons [196]. In another study, Lenka and Ramasamy, demonstrated the generation of TH+ dopaminergic neurons using murine ES cells. The authors demonstrated in vitro differentiation of ES cells into TH+ dopaminergic neurons in the absence of any signaling molecules [219]. In a separate study, the authors were able to differentiate MSCs derived from Wharton's jelly of the umbilical cord into DA neurons upon exposure to signaling cues such as SHH, fibroblast growth factor 8 and basic fibroblast growth factor. Kanafi et al. reported an upregulation of DA neuron-specific transcription factors like nuclear receptor related protein 1, engrailed 1 and paired-like homeodomain transcription factor 3 in dental pulp MSCs following exposure to midbrain-cues such as SHH, fibroblast growth factor 8 and basic fibroblast growth factor [220]. Taken together these data indicate a very strong potential of cell based therapy for neurodegenerative disease like PD (Fig. 2B). Also due to ethical issues and immune responses associated with the use of ESCs and pluripotent stem cells, MSCs demand higher acceptance in cell based therapy and has encouraged scientists and clinicians to seek suitable protocols to apply these cells to treat PD.

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7. MSCs TO DA NEURONS: PRE-CLINICAL STUDIES

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8. CLINICAL TRIALS USING NEURAL TISSUES AND CELLS – A PROMISE TO USE MSC DERIVED DA NEURONS FOR TRANSPLANTATION The treatment options for PD have expanded from conventional drugs (L-dopa) [221] to direct transplantation of neural tissue [222]. The underlying confidence of this advanced clinical technology stems from the understanding that the implanted neural tissues will be able to provide dopamine support and along with neurotrophic hold can reconnect and

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processing to avoid contaminants (for example, cells derived from feeder layers, residual stem cells during isolation etc.,). In addition, knowing the physiology of the biological product will be crucial to predict likely contaminants. The challenging part here is assessing the potency of the biological product in vivo after transplantation; therefore the research reports on animal models probably will be more important for analysis. Previous pre-clinical reports on transplanted grafts (stem cell-derived products) should clearly explain their safety and efficacy that must be filed with the FDA.

4.

For allogenic transplantations, it is required to screen and/or test for communicable diseases and assess the risk of contamination. Therefore, current good tissue/cell practice is required to prevent such transmission of communicable disease.

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3.

5.

In vitro expansion of stem cells requires the use of fetal bovine/calf serum which may be a possible source of contamination. Hence, the FDA also specifies that serum should come from a source that is certified to be free of contaminations.

8.1. Safety in Cell/Tissue Transplantation

N

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In the interest of public safety, the Food and Drug Administration (FDA) has given certain guidelines over the generation and marketing of any cell-based products involving the transplantation of human cell into patients. Stem cell based therapies have existed since the first successful bone marrow transplantations in 1968 [236]. The highlights of the regulations applicable to stem cell-based products are described by the governing statute in the Public health safety act, section 361 as follows. 1.

Any stem cell-based product that includes cells or tissues or non-tissue components that are “highly processed” and that are used for metabolic improvement or tissue regeneration purpose will be considered as a biological product. Fluorescence-activated cell sorting and immunological techniques will be used to characterize the isolated cells through cell-surface expression profile.

2.

The manufacturer should demonstrate the graft’s (for example, stem cells or stem cell-derived cells) “safety, purity, and potency.” If the biological product is derived from cultures then it is essential to be careful during

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Overall, safety remains one of the main concerns in cell therapy. Therefore, any biological product (stem cells, stem cell-derived cells) needs critical quality control procedures and must be assured for safety and efficacy before its clinical application.

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9. CHALLENGES AND FUTURE PERSPECTIVES

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The current gold standard treatment for PD with L-dopa has recurrent side effects including nausea, vomiting, dyskinesia, restless legs syndrome and dementia [237]. Long-term use of levadopa has also been shown to be associated with ventricular arrthymias [238]. Cell therapy has thus been emerging as a potential alternate strategy for PD treatment [231, 239, 240]. For example, a clinical study reported that following transplantation of human fetal dopamine cells isolated from a 7-week human embryo into the caudate and putamen of a 52-year-old non-immuno-suppressed PD patient [225] there was an improvement in the movements of the left-hand, right-hand as well as walking by 42%, 15% and 33% respectively. Such encouraging data suggests that direct cell transplantation could provide long-term clinical benefit to patients with advanced PD [224, 225]. However further trials and validations are required to establish the efficiency and side effects of these methods. For example, in the first randomized placebo-controlled trial by Freed et al. in 2001, the recipients of bilateral putamen DA grafts experienced abnormal dyskinesia during the first and second postoperative years [231]. Due to difficulty in obtaining primary grafts, we also need to explore the idea of transplanting neuronal cells generated in vitro through differentiation of stem cells. Till date, there are a number of reports holding the promise of ESCs and pluripotent stem cells as cellular therapeutics to treat PD [215, 231, 241]. However, beyond their differentiating capacity they also have tumorigenic potential [242, 243] thus posing a big risk in their clinical applications. In this regard MSCs becomes a very attractive

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regenerate the damaged neuronal circuits [223]. In the early 1990’s, various clinical studies have been conducted to assess the safety and efficacy of embryonic/fetal-derived dopaminergic neural cells for patients with advanced PD [224229] (Table 5). Fetal/embryonic cell transplantation offers a prospect to replace the damaged neural tissue and able to restore physiological dopamine release in the brain. Although dopamine replacement therapy have shown improvements in the scores of Unified Parkinson's Disease Rating Scale (UPDRS) and Schwab-England disability in the implanted patients, however the number of patients who developed abnormal involuntary movements and postures was about 56.5% [230]. In a clinical report, persistent dyskinesia was seen in 15% of patients who received bilateral putamen dopamine grafts in the first randomized placebo-controlled trial [231]. One of the prime challenges in neural cell implantation is to control the unbalanced increase in regional dopaminergic function within the striatum [232-234]. Indeed, another report disclosed worsening dyskinesia in implanted patients during withdrawal of long-term immunosuppression over a mean period of 29 months postoperatively [235]. Due to allogenic nature of such transplantations, immunosuppressive drugs are required to allow for better graft survival. However, immunosuppression is not always advisable, especially if the concerned host is predisposed to infections or has a weak immune system. Long term immunosuppression also makes a healthy individual susceptible to severe infections if proper care is not taken. Hence it is desirable to have patient specific cell therapy (autologous) where patients own cells can be used for transplantation (autologous) thus avoiding continuous immune-suppression and graft rejection. To this end, autologous MSC derived DA neurons pose a great advantage as the cells (MSCs) can be easily isolated, maintained and expanded invitro prior to differentiation. Thus it is highly tempting to think of the possibility of being able to create neuronal cells from a potentially unlimited source of autologous cells i.e. MSCs.

MSC-Derived Dopamine Cells in the Treatment of PD

Table 5. S. No.

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

335

Clinical trials of Parkinson’s disease using “neural tissue and or cells” as a therapeutic target. Cell/Tissue Type Used

Graft Type

Implanted Area

No. of Patients

Clinical Outcome

Adverse Effects/Challenges

8

• After 12 months significant signal changes in the grafted region was reported with dopamine production.

• Adverse events like urinary retention, hypomania shortness of breath, superficial cellulitis, cough and headache are reported after one month of postsurgery.

References

Tissue

1

Peripheral nerve tissue

Autologous

Substantia nigra

Postcommissural putamen

34

• Inadequate graft survival due to dyskinesia with low levels of dopamine. • Unanticipated and potentially disabling off-medication dyskinesias developed in greater than 50% of patients.

• This study is not recommending fetal nigral transplantation due to raising dyskinesia more than 50 % of implanted patients as a therapy for PD.

• Significantly greater improvement in UPDRS scores.

• Noticed subdural hematoma.

Fetal ventral mesencephalic tissue

Fetal nigral tissue

Allogenic

Substantia nigra

Allogenic

Ventral and dorsal regions of putamen

tri

• Tremor did not improved.

[230]

[288]

• Motor sub-scores and in the timed motor tests were not statistically significant.

[226]

2

• Shown recovery of motor function and dopaminergic innervation in the grafted region was increased by 230%.

• Occurrence of off-phase graftinduced dyskinesias.

[289]

14

• 11 years after grafting, abnormal involuntary movements and postures increased during postoperative off phases, (mild to moderate).

34

• Patients who experienced off-medication dyskinesia had greater improvement in UPDRS motor score (including tremor, rigidity, bradykinesia, posture and postural stability) at 6 months following transplantation.

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• There was substantial benefit in the timed motor tasks, UPDRS motor scores and Hoehn & Yahr ‘‘off’’ scores in three of the five patients.

5

Fo

Allogenic

Putamen or caudate nucleus

• Increased dopamine levels in putamen.

is

U 7

Autologous

Right caudate nucleus and putamen

40

ot

6

Fetal ventral mesencephalic tissue

Posterior tip of the putamen

N

5

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4

Mixture of intercostal nerve segments and adrenal medullary tissue

Allogenic

Pe rs

3

Embryonic mesencephalic tissue

• Many self-reported adverse events noticed including; Dyskinesia, Insomnia, Depression, Constipation Increased blood urea nitrogen, confusion, Diarrhea, tingling skin, incisional pain, leg edema etc,.

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Allogenic

O

Fetal mesencephalic tissue

se

2

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• Although there was an increase in striatal dopamine uptake on PET was observed still the levels are below the lower limits of normal.

[287]

• Severe dyskinesia. • Overgrowth of grafted dopamine neurons.

• 13 out of 34 transplanted patients developed off-medication dyskinesia.

[290]

[291]

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Table (5) contd….

S. No.

8

Cell/Tissue Type Used

Fetal ventral mesencephalon tissue

Graft Type

Allogenic

Implanted Area

No. of Patients

Right and left postcommissural putamen

1

Clinical Outcome • Eighteen months follow-up showed clinical improvement in motor function during “off” stages, reduced motor fluctuations, reduced dyskinesias, progressive increase in striatal dopamine and TH+ fiber innervation within the putamen was determined.

Adverse Effects/Challenges

References

• There was no evidence that the implants induced sprouting of host TH-ir systems.

[229]

• One patient was died after two years 4 months and another patient was died after four years four months after transplantation with unrelated causes like myocardial infarct and acute renal failure respectively.

[292]

• The improvement gained from adrenal transplants was not sufficient to improve but suggested that use of other dopamine tissues for future use.

[293]

Allogenic

12

Adrenal medulla

Autologous

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Adrenal medulla

4

Putamen

61

• Global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the UPDRS, occurred in 32% of the patients at 2 years after surgery. • At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline.

N

11

Right Caudate

• In addition, patients who reported marginal improvement in symptoms, overall well being, facial expression, gait and reduction in freezing episodes which never got benefited from traditional modes.

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Autologous

• Improvement showed in UPDRS in “off” and ‘‘on’’ periods.

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Adrenal tissue

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10

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• Marked increase of dopamine levels in the right putamen and never experienced offperiod dyskinesia.

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Allogenic

Postcommissural putamen

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Fetal ventral midbrain tissue

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• Grafts reinnervated 53% and 28% at the post-commissural putamen.

Intracerebrum

1

• A few tyrosine hydroxylaseimmune reactive cells were found within the graft, providing the first evidence that adrenal medullary cells may be viable and produce catecholamines following human transplantation.

• A serious level of mortality and morbidity. • Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery.

• Poor survival rate

[294, 295]

[228]

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Table (5) contd….

Intrastriatal Adrenal

Graft Type

Autologous

Implanted Area

No. of Patients

Clinical Outcome

Adverse Effects/Challenges

References

3

• The post-op UPDRS motor scores in the "off’ state changed as follows: after 3 months increased 23%, 6 months decreased 14%, 9 months decreased 25%.

• 3 patients developed a mild increase of dyskinesias.

[296]

Intra striatal

Allogenic

Posterior section of the putamen

13

• Showed significant improvement over presurgical baseline scores on all major parameters.

Allogenic

17

18

Fetal dopaminergic neuronal tissue

Fetal ventral mesencephalon tissue

Allogenic

Allogenic

• Unanswered questions are still remain like: the optimal amount of tissue that grafted in the targeted area, how the distribution of the grafts will happen, and the preparation of the tissue (grafts), as well as the effects of various patient predisposing factors including age and premorbid level of PD, are all poorly understood clinical issues.

[227]

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is

• Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right and 33% on the left.

• Variations of fetal graft volume also have an impact on clinical outcome.

• One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations.

[297]

• Heavy dyskinesias.

[217]

• In one patient, some motor functions continued the steady decline seen before surgery.

[298]

• No serious complications.

[299]

• Increase in 18F-dopa uptake at the grafted site.

Intrastriatal

2

ot

Fetal ventral mesencephalic tissue

4

N

16

Postcommissural putamen

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Allogenic

• Significant improvement was detected in total UPDRS score and Schwab-England disability score during the "off" state.

Fo

Fetal nigral tissue

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15

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16

Mesencephalic fetal tissue

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Medulla

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13

Cell/Tissue Type Used

O

S. No.

Right caudate

Intra cerebral

• The quality of movements improved almost exclusively on the side contralateral to the graft. • Persistent improvement in the rigidity, bradykinesia and gait.

4

• Cognitive-fucntion testing showed 14-point increase in his performance IQ. • Sustained improvement in motor function and became much more independent.

2

• Striatal uptake of fluorodopa was increased at 12 to 13 and 22 to 24 months.

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Table (5) contd….

S. No.

19

Cell/Tissue Type Used

Fetal mesencephalic tissue

Graft Type

Allogenic

Implanted Area

No. of Patients

Clinical Outcome

Adverse Effects/Challenges

References

2

• In both patients F-dopa uptake increased within the operated putamen but a progressive decrease in in unoperated striatal structures.

• The disease progression in the unoperated striatum is actually explains why clinical improvement reached a plateau within months after surgery.

[216]

Putamen

• There was a worsening on the ipsilateral side of putamen.

Putamen

2

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Allogenic

• After 3 years grafting the patients still exhibited increased f-dopa uptake in the grafted putamen.

Allogenic

Intrastriatal

Autologous

Subventricular zone

24

Embryonic dopamine cells

Allogenic

Caudate and putamen

• 16.8% of the cases did not show any improvement from the basal score.

• No parenchymal changes or evidence of tumor formation at the end of the follow-up period.

• Following stem cell injection his rigidity had reduced and speech had improved.

• PD plus patients did not show improvement.

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[301]

• No inflammatory reactions are noted.

• Improvement showed in UPDRS in ‘‘off’’ and ‘‘on’’ periods. In addition, patients who reported marginal improvement in symptoms, overall well being, facial expression, gait and reduction in freezing episodes which never got benefited from traditional modes of therapy.

is

[300]

[154]

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7

12

ot

Bone marrow mesenchymal stem cells

Lateral ventricles of the left/right cerebral hemisphere

• Stiffness and tremors are very minimal. • Rigidity and stiffness has reduced.

N

23

• 58.3% improvement in the bradykinesia scoring from the pre-transplant level.

Fo

Auotlogous

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Bone marrow mesenchymal stem cells

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Cells

22

12

• Overall improvement indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery within the parkinsonian brain.

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Fetal cortical brain tissue

U

21

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O

20

Embryonic dopamine-rich mesencephalic tissue

7

• Overall all patients receovered their hand functions and in computer testing to determine the finger speed.

• PD plus patients could not be rated using the UPDRS scoring system after stem cell transplantation due to the severity and progression of the disease.

• Improvement in the speaking ability.

• Implantation at putamen site has more symmetric innervations, with improving axial functions such as walking than the transplantation at the caudate region.

• Reduction in urinary urgency.

• No evidence of hemorrhage.

[302]

[224]

MSC-Derived Dopamine Cells in the Treatment of PD

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Table (5) contd….

25

Cell/Tissue Type Used

Embryonic dopamine cell

Graft Type

Implanted Area

No. of Patients

Clinical Outcome • Significant increases in putamen 18F-FDOPA uptake were evident at all posttransplantation time points.

Allogenic

Putamen

33

• Posttransplantation changes in putamen PET signal and clinical outcome were significantly intercorrelated

References

• Clinical benefit and graft viability are sustained up to 4 y after transplantation.

[303]

technology, patient-specific cell therapy is also potentially possible without any problem of graft rejection. In future, it will be obligatory to perform well-designed and controlled clinical trials to substantiate these regenerative/replacement effects of MSC derived DA neurons. Nevertheless, such MSC derived DA neurons will be useful in understanding the basic differentiation mechanism(s), high-throughput drug discovery as well as PD modelling—a major step on the road towards designing novel patient-specific cell based therapy (“personalized-cell medicine”) (Fig. 2B) for PD.

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LIST OF ABBREVIATIONS ESCs

= Embryonic stem cells

= Hematopoietic stem cells

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HSCs

= Mesenchymal stem cells

iPSCs

= Induced pluripotent stem cells

PD

= Parkinson’s disease

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MSCs

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candidate for reasons elucidated throughout this article. There is a need to develop proper sustainable protocols to make neuronal cells from adult stem cells like MSCs which can easily bypass the ethical barrier related to the use of cells from fetal tissue [230, 244]. There are many clinical trials that have used direct transplantation of MSCs to treat various diseases; however none of them show long-term survivability and permanent recovery. Transplanted cells/tissues face several obstacles including maintenance of self-renewal property. Often poor survivability is seen which is attributed to the negative/inflammatory surrounding environment (due to presence of apoptotic and/or necrotic tissue at the site of administration) [245]. Hence, there is an urgent need for developing biomaterials that can help in long-term cell retention and functional recovery of the damaged site [246]. There are several biomaterials (both natural and synthetic) which mimic the in vivo microenvironment. This microenvironment plays an important role in cell proliferation and maintenance of long term-term survivability. Blocki et al., reported that use of injectable microcapsules (comprising low concentration of agarose supplemented with ECM proteins like collagen and fibrin) at infracted myocardium could solve the current limitation of poor cell retention in cardiac cell-based therapy [247, 248]. This idea can potentially be applied in case of neural transplantation as well. It is also important to investigate the role of trophic agents such as neurotrophic factors in enhancing graft viability and integrity. Lastly, to successfully overcome these challenges, apart from in-depth clinical and/or basic research, studies should also focus on developing improved imaging techniques which could help in efficient tracking of the grafts and assessment of its outcome.

Adverse Effects/Challenges

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S. No.

= Dopaminergic

ISCT

= International Society of Cellular Therapy

EGFR

= Epidermal growth factor receptor

IGFR

= Insulin growth factor receptor

TGFR

= Transforming growth factor receptor

HGFR

= Hepatocyte growth factor receptor

RTKs

= Receptor tyrosine kinases

CXCR2

= Chemokine (C-X-C Motif) Receptor 2

IL-6

= Interleukin-6

CONCLUSION

TNF

= Tumor necrosis factor

Cell replacement therapy is one of the most encouraged therapies for the treatment of PD. Stem cells, which have potential to differentiate into DA neurons without inducing tumor condition, will always be clinically more acceptable for treating the disease. MSCs are such cells which along with the ability to differentiate into DA neurons are considered quite safe due to their lack of tumorigenicity and immunogenicity. The future hope of using MSC-derived DA neurons to treat PD patients will however strongly depend on a thorough understanding of the exact signaling mechanisms which leads to DA neuronal development. Through this

TLRs

= Toll-like receptors

ECM

= Extra cellular matrix

PPAR

= Peroxisome proliferator activated receptor 

ICAM1

= Intercellular Adhesion Molecule 1

IBMX

= 3-isobutyl-1-methylxanthine

BMPs

= Bone morphogenic proteins

ALS

= Amyotrophic lateral sclerosis

MS

= Multiple sclerosis

N

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DA

340 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

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CRP

= C-reactive protein

SUPPLEMENTARY MATERIAL

BNPs

= Brain natriuretic peptides

DMEM

= Dulbecco's Modified Eagle Medium

Supplementary material is available on the publisher's website along with the published article.

RA

= Retinoic acid

REFERENCES

cAMP

= Cyclic-adenosine-monophosphate

[1]

PKA

= Protein kinase A

[2]

GFAP

= Glial fibrillary acidic protein

[3] [4]

BDNF

= Brain derived neurotrophic factor

[5]

GDNF

= Glial derived neurotrophic factor

ATP

= Adenosine-triphosphate

CREB

= cAMP responsive element binding

CBP

= CREB-binding protein

RARs

= Retinoic acid receptors

RXRs

= Retinoid X receptors

RAREs

= RA-responsive elements

Trk

= Tyrosine kinase

SVZ

= Subventricular zone

BMSCs

= Bone marrow stromal cells

UPDRS

= Unified Parkinson's Disease Rating Scale

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GM-CSF = Granulocyte macrophage colony-stimulating factor

[6]

se

[8]



tri

[12]

[13]

[14]

Cell-based therapy is an emerging strategy to treat PD.

[15]

Neuronal grafts are functionally active and able to reactivate neuronal circuits.

[16]

Fo



Conventional treatments for PD have several long term severe side effects.

Transplantation of MSCs-derived DA neurons can become a hopeful advancement in treating PD.

N

CONFLICT OF INTEREST

ot



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[11]

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KV wrote the manuscript. DS conceptualized and wrote the manuscript.

[10]

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[9]

[17] [18]

The authors confirm that this article content has no conflict of interest.

[19]

ACKNOWLEDGEMENTS

[20]

DS is supported by a ‘Fast Track Young Scientist’ grant (YSS/2014/000027) from SERB, Department of Science and Technology (DST), Government of India and an investigator initiated grant (H15-27983) from Baxalta, USA. The funding sources did not play any role in the research and/or preparation of the article, study design, data collection, analysis/interpretation of data, writing of the report and decision to submit the article for publication.

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[7]

AUTHORS’ CONTRIBUTION

HIGHLIGHTS

Condic ML. Totipotency: what it is and what it is not. Stem Cells Dev 2014; 23: 796-812. Gardner RL. Stem cells: potency, plasticity and public perception*. J Anat 2002; 200: 277-82. Mitalipov S, Wolf D. Totipotency, pluripotency and nuclear reprogramming. Adv Biochem Eng Biotechnol 2009; 114: 185-99. Kfoury Y, Scadden DT. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 2015; 16: 239-53. Venkatesh K, Srikanth L, Vengamma B, et al. In vitro transdifferentiation of human cultured CD34+ stem cells into oligodendrocyte precursors using thyroid hormones. Neurosci Lett 2015; 588: 3641. Venkatesh K, Srikanth L, Vengamma B, et al. In vitro differentiation of cultured human CD34+ cells into astrocytes. Neurol India 2013; 61(4): 383-8. Srikanth L, Sunitha MM, Kumar PS, et al. Gel based in vitro 3D model exploring the osteocytic potentiality of human CD34+ stem cells. Mol Biol Rep 2016; 43(11): 1233-42. Srikanth L, Venkatesh K, Sunitha MM, et al. In vitro generation of type-II pneumocytes can be initiated in human CD34(+) stem cells. Biotechnol Lett 2016; 38(2): 237-42. Guo W, Patzlaff NE, Jobe EM, Zhao X. Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nat Protoc 2012; 7(11): 2005-12. Via AG, Frizziero A, Oliva F. Biological properties of mesenchymal Stem Cells from different sources. Muscles Ligaments Tendons J 2012; 2: 154-62. Izadpanah R, Trygg C, Patel B, et al. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem 2006; 99(5): 1285-97. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001; 7(2): 211-28. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7. Zhang Y, Li C, Jiang X, et al. Human placenta-derived mesenchymal progenitor cells support culture expansion of long-term culture-initiating cells from cord blood CD34+ cells. Exp Hematol 2004; 32(7): 657-64. Bieback K, Kern S, Kluter H, Eichler H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22(4): 625-34. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109(1): 235-42. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 2011; 109: 923-40. De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001; 44(8): 1928-42. Hiraoka K, Grogan S, Olee T, Lotz M. Mesenchymal progenitor cells in adult human articular cartilage. Biorheology 2006; 43(3-4): 447-54. Vishwanath VR, Nadig RR, Nadig R, et al. Differentiation of isolated and characterized human dental pulp stem cells and stem cells from human exfoliated deciduous teeth: An in vitro study. J Conserv Dent 2013; 16: 423-8. Orciani M, Di Primio R. Skin-derived mesenchymal stem cells: isolation, culture, and characterization. Methods Mol Biol 2013; 989: 275-83. Asakura A, Komaki M, Rudnicki M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 2001; 68: 245-53. Sugarman J. Human stem cell ethics: beyond the embryo. Cell Stem Cell 2008; 2(6): 529-33.

[21]

[22] [23]

MSC-Derived Dopamine Cells in the Treatment of PD

[35] [36]

[37] [38]

[39] [40]

[41] [42]

[43] [44]

[45] [46] [47] [48] [49]

[54] [55] [56] [57]

nl y

[58] [59]

O

[60]

[61]

[62] [63]

[64]

bu tio n

[34]

[53]

tri

[33]

[52]

[65]

[66]

[67]

[68]

[69]

[70] [71]

[72]

[73] [74]

341

Venkatesan V, Gopurappilly R, Goteti SK, Dorisetty RK, Bhonde RR. Pancreatic progenitors: The shortest route to restore islet cell mass. Islets 2011; 3(6): 295-301. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science 2004; 303(5656): 359-63. Kordes C, Haussinger D. Hepatic stem cell niches. J Clin Invest 2013; 123(5): 1874-80. Al-Awqati Q, Oliver JA. The kidney papilla is a stem cells niche. Stem Cell Rev 2006; 2(3): 181-4. Oatley JM, Brinster RL. The germline stem cell niche unit in mammalian testes. Physiol Rev 2012; 92(2): 577-95. Bukovsky A. Ovarian stem cell niche and follicular renewal in mammals. Anat Rec (Hoboken) 2011; 294(8): 1284-306. Rompolas P, Greco V. Stem cell dynamics in the hair follicle niche. Semin Cell Dev Biol 2014; 25-26: 34-42. Minguell JJ, Erices A, Conget P. Mesenchymal stem cells. Exp Biol Med (Maywood) 2001; 226(6): 507-20. Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int 2012; 2012: 812693. Bourin P, Gadelorge M, Peyrafitte J-A, et al. Mesenchymal Progenitor Cells: Tissue Origin, Isolation and Culture. Transfus Med Hemother 2008; 35: 160-7. Zhu XY, Lerman A, Lerman LO. Concise review: mesenchymal stem cell treatment for ischemic kidney disease. Stem Cells 2013; 31(9): 1731-6. Bharti D, Shivakumar SB, Subbarao RB, Rho GJ. Research Advancements in Porcine Derived Mesenchymal Stem Cells. Curr Stem Cell Res Ther 2016; 11(1): 78-93. Lin C-S, Xin Z-C, Dai J, Lue TF. Commonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges. Histol Histopathol 2013; 28: 1109-16. Penny J, Harris P, Shakesheff KM, Mobasheri A. The biology of equine mesenchymal stem cells: phenotypic characterization, cell surface markers and multilineage differentiation. Frontiers in bioscience (Landmark edition) 2012; 17: 892-908. Bensidhoum M, Chapel A, Francois S, et al. Homing of in vitro expanded Stro-1- or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment. Blood 2004; 103: 3313-9. Xu J, Wang W, Kapila Y, Lotz J, Kapila S. Multiple differentiation capacity of STRO-1+/CD146+ PDL mesenchymal progenitor cells. Stem Cells Dev 2009; 18: 487-96. Barry F, Boynton R, Murphy M, Haynesworth S, Zaia J. The SH-3 and SH-4 antibodies recognize distinct epitopes on CD73 from human mesenchymal stem cells. Biochem Biophys Res Commun 2001; 289: 519-24. Ode A, Schoon J, Kurtz A, et al. CD73/5'-ecto-nucleotidase acts as a regulatory factor in osteo-/chondrogenic differentiation of mechanically stimulated mesenchymal stromal cells. European cells & materials 2013; 25: 37-47. Campioni D, Rizzo R, Stignani M, et al. A decreased positivity for CD90 on human mesenchymal stromal cells (MSCs) is associated with a loss of immunosuppressive activity by MSCs. Cytometry. Part B, Clinical cytometry 2009; 76: 225-30. Anderson P, Carrillo-Gálvez AB, García-Pérez A, Cobo M, Martín F. CD105 (endoglin)-negative murine mesenchymal stromal cells define a new multipotent subpopulation with distinct differentiation and immunomodulatory capacities. PloS one 2013; 8: e76979. Maleki M, Ghanbarvand F, Behvarz MR, Ejtemaei M, Ghadirkhomi E. Comparison of Mesenchymal Stem Cell Markers in Multiple Human Adult Stem Cells. Int J Stem Cells 2014; 7: 118-26. Lin CS, Xin ZC, Dai J, Lue TF. Commonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges. Histol Histopathol 2013; 28(9): 1109-16. Bianchi G, Borgonovo G, Pistoia V, Raffaghello L. Immunosuppressive cells and tumour microenvironment: focus on mesenchymal stem cells and myeloid derived suppressor cells. Histol Histopathol 2011; 26(7): 941-51. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997; 276(5309): 71-4. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.

is

[32]

[51]

se

[31]

[50]

rD

[30]

U

[29]

Fo

[28]

ot

[27]

on al

[26]

N

[25]

Kato K, Kimmelman J, Robert J, Sipp D, Sugarman J. Ethical and policy issues in the clinical translation of stem cells: report of a focus session at the ISSCR Tenth Annual Meeting. Cell Stem Cell 2012; 11(6): 765-7. London AJ, Kimmelman J, Emborg ME. Research ethics. Beyond access vs. protection in trials of innovative therapies. Science 2010; 328(5980): 829-30. Aldahmash A, Atteya M, Elsafadi M, et al. Teratoma formation in immunocompetent mice after syngeneic and allogeneic implantation of germline capable mouse embryonic stem cells. Asian Pacific journal of cancer prevention : APJCP 2013; 14: 5705-11. Burst VR, Gillis M, Putsch F, et al. Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury. Nephron Exp Nephrol 2010; 114(3): e107-16. Li L, Chen X, Wang WE, Zeng C. How to Improve the Survival of Transplanted Mesenchymal Stem Cell in Ischemic Heart? Stem Cells Int 2016; 2016: 9682757. Rodrigues M, Griffith LG, Wells A. Growth factor regulation of proliferation and survival of multipotential stromal cells. Stem Cell Res Ther 2010; 1(4): 32. Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacologica Sinica 2013; 34: 747-54. Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010; 28(3): 585-96. Shen Y, Huang J, Liu L, et al. A Compendium of Preparation and Application of Stem Cells in Parkinson's Disease: Current Status and Future Prospects. Front Aging Neurosci 2016; 8: 117. Olsen NV. Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans. Dan Med Bull 1998; 45(3): 282-97. Eisenhofer G, Aneman A, Friberg P, et al. Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab 1997; 82(11): 3864-71. Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest 2005; 115: 1449-57. Alexander GE. Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Dialogues Clin Neurosci 2004; 6(3): 259-80. Thanvi B, Lo N, Robinson T. Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J 2007; 83: 384-8. Atlas D. DopAmide: Novel, Water-Soluble, Slow-Release ldihydroxyphenylalanine (l-DOPA) Precursor Moderates l-DOPA Conversion to Dopamine and Generates a Sustained Level of Dopamine at Dopaminergic Neurons. CNS Neurosci Ther 2016; 22(6): 461-7. Hallett PJ, Cooper O, Sadi D, et al. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell reports 2014; 7: 1755-61. Kitada M, Dezawa M. Parkinson's disease and mesenchymal stem cells: potential for cell-based therapy. Parkinson's disease 2012; 2012: 873706. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3(4): 393-403. Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2008; 2(4): 3139. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968; 6(2): 230-47. Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 1987; 20(3): 263-72. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, Simmons PJ. Mesenchymal stem cells. Arch Med Res 2003; 34(6): 565-71. Caplan AI. Mesenchymal stem cells. J Orthop Res 1991; 9(5): 64150. Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood 2015; 125(17): 2621-9. Bianco P, Robey PG. Skeletal stem cells. Development 2015; 142(6): 1023-7. Leri A, Rota M, Hosoda T, Goichberg P, Anversa P. Cardiac stem cell niches. Stem Cell Res 2014; 13(3 Pt B): 631-46.

Pe rs

[24]

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

342 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

[76]

[77] [78]

[79]

[80] [81] [82]

[100]

[101] [102]

[103]

[104]

[105]

Kim EY, Lee KB, Yu J, et al. Neuronal cell differentiation of mesenchymal stem cells originating from canine amniotic fluid. Hum Cell 2014; 27(2): 51-8. De Miguel MP, Fuentes-Julian S, Blazquez-Martinez A, et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 2012; 12(5): 574-91. Gu Y, Zhang Y, Bi Y, et al. Mesenchymal stem cells suppress neuronal apoptosis and decrease IL-10 release via the TLR2/NFkappaB pathway in rats with hypoxic-ischemic brain damage. Mol Brain 2015; 8(1): 65. Desai VD, Hsia HC, Schwarzbauer JE. Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. PLoS One 2014; 9(1): e86865. Cruz-Martinez P, Gonzalez-Granero S, Molina-Navarro MM, et al. Intraventricular injections of mesenchymal stem cells activate endogenous functional remyelination in a chronic demyelinating murine model. Cell Death Dis 2016; 7: e2223. Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010; 316(14): 2213-9. Dasari VR, Veeravalli KK, Dinh DH. Mesenchymal stem cells in the treatment of spinal cord injuries: A review. World J Stem Cells 2014; 6: 120-33. Joyce N, Annett G, Wirthlin L, et al. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 2010; 5: 933-46. Maltman DJ, Hardy SA, Przyborski SA. Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem Int 2011; 59: 347-56. Snyder BR, Chiu AM, Prockop DJ, Chan AWS. Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington's disease. PloS One 2010; 5: e9347. Bouchez G, Sensebé L, Vourc'h P, et al. Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease. Neurochem Int 2008; 52: 133242. Qiu X-C, Jin H, Zhang R-Y, et al. Donor mesenchymal stem cellderived neural-like cells transdifferentiate into myelin-forming cells and promote axon regeneration in rat spinal cord transection. Stem Cell Res Ther 2015; 6: 105. Berry MF, Engler AJ, Woo YJ, et al. Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am J Physiol Heart Circ Physiol 2006; 290: H2196-203. Bian S, Zhang L, Duan L, et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014; 92: 387-97. Fujimoto KL, Miki T, Liu LJ, et al. Naive rat amnion-derived cell transplantation improved left ventricular function and reduced myocardial scar of postinfarcted heart. Cell Transplant 2009; 18: 477-86. Boyle AJ, McNiece IK, Hare JM. Mesenchymal stem cell therapy for cardiac repair. Methods Mol Biol (Clifton, N.J.) 2010; 660: 6584. Nagaya N, Fujii T, Iwase T, et al. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 2004; 287: H2670-6. Tang J, Xie Q, Pan G, Wang J, Wang M. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardio-thorac Surg 2006; 30: 353-61. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007; 25(10): 2648-59. Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta 2014; 1840: 2506-19. Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 2014; 32: 795-803. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res 2007; 100: 1249-60. George JL, Mok S, Moses D, et al. Targeting the progression of Parkinson's disease. Current neuropharmacology 2009; 7: 9-36.

[106]

[107]

[90] [91] [92]

[93] [94] [95]

[96] [97]

[98]

[99]

se

[110]

tri

[111]

is

U

[109]

[112]

rD

[89]

Fo

[88]

ot

[87]

on al

[86]

N

[85]

Pe rs

[84]

[108]

bu tio n

O

[83]

Ma S, Xie N, Li W, et al. Immunobiology of mesenchymal stem cells. Cell Death Differ 2014; 21(2): 216-25. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res 2015; 2015: 394917. Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11(5): 321-34. Raffaghello L, Bianchi G, Bertolotto M, et al. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem cells (Dayton, Ohio) 2008; 26: 151-62. Jiang X-X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105: 4120-6. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nature reviews. Immunology 2008; 8: 726-36. Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L. What is a natural killer cell? Nat Immunol 2002; 3(1): 6-8. Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76(8): 1208-13. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006; 107(4): 1484-90. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838-43. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75(3): 389-97. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105(4): 181522. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99(10): 3838-43. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57(1): 11-20. Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigenspecific T cells to their cognate peptide. Blood 2003; 101(9): 37229. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499-506. Hoogduijn MJ, Popp F, Verbeek R, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. International immunopharmacology 2010; 10: 1496-500. Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 2009; 11(4): 377-91. Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue repair. Front Immunol 2013; 4: 201. Darkazalli A, Vied C, Badger CD, Levenson CW. Human mesenchymal stem cell treatment normalizes cortical gene expression after traumatic brain injury. J Neurotrauma 2017; 34(1): 204-12. Isakson M, de Blacam C, Whelan D, McArdle A, Clover AJP. Mesenchymal Stem Cells and Cutaneous Wound Healing: Current Evidence and Future Potential. Stem Cells Int 2015; 2015: 831095. Selem SM, Kaushal S, Hare JM. Stem cell therapy for pediatric dilated cardiomyopathy. Curr Cardiol Rep 2013; 15: 369. Cerri S, Greco R, Levandis G, et al. Intracarotid Infusion of Mesenchymal Stem Cells in an Animal Model of Parkinson's Disease, Focusing on Cell Distribution and Neuroprotective and Behavioral Effects. Stem Cells Transl Med 2015; 4(9): 1073-85. Berardis S, Dwisthi Sattwika P, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: current situation and future prospects. World J Gastroenterol 2015; 21: 742-58. Takami T, Terai S, Sakaida I. Stem cell therapy in chronic liver disease. Curr Opin Gastroenterol 2012; 28: 203-8.

nl y

[75]

Venkatesh and Sen

[113]

[114]

[115]

[116]

[117]

[118] [119]

[120] [121] [122]

MSC-Derived Dopamine Cells in the Treatment of PD

[134] [135]

[136]

[137]

[138] [139]

[140]

[141] [142]

[143]

[144]

[145]

nl y [150]

O

[151]

[152]

[153] [154]

[155]

bu tio n

[133]

[149]

tri

[132]

[148]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

[163]

[164]

[165]

343

hydroxydopamine-induced dopaminergic neurodegeneration and glial activation in rats. Neurosci Lett 2015; 584: 276-81. Danielyan L, Beer-Hammer S, Stolzing A, et al. Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease. Cell Transplant 2015; 23 Suppl 1: S123-39. Berg J, Roch M, Altschuler J, et al. Human adipose-derived mesenchymal stem cells improve motor functions and are neuroprotective in the 6-hydroxydopamine-rat model for Parkinson's disease when cultured in monolayer cultures but suppress hippocampal neurogenesis and hippocampal memory function when cultured in spheroids. Stem Cell Rev 2015; 11(1): 133-49. Shetty P, Thakur AM, Viswanathan C. Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson's disease rodent model. Cell Biol Int 2013; 37(2): 167-80. Qin X, Han W, Yu Z. Neuronal-like differentiation of bone marrow-derived mesenchymal stem cells induced by striatal extracts from a rat model of Parkinson's disease. Neural Regen Res 2012; 7(34): 2673-80. Glavaski-Joksimovic A, Bohn MC. Mesenchymal stem cells and neuroregeneration in Parkinson's disease. Exp Neurol 2013; 247: 25-38. Kim J-H, Auerbach JM, Rodríguez-Gómez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 2002; 418: 50-6. Park C-H, Minn Y-K, Lee J-Y, et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 2005; 92: 1265-76. Harrower TP, Barker RA. Is there a future for neural transplantation? BioDrugs 2004; 18: 141-53. Venkataramana NK, Kumar SK, Balaraju S, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Transl Res 2010; 155(2): 62-70. Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson's disease. Trends Pharmacol Sci 2009; 30(5): 260-7. Kingwell K. Parkinson disease: Overcoming hurdles to stem-cell transplantation for treatment of Parkinson disease. Nature reviews. Neurology 2013; 9: 60. Riecke J, Johns KM, Cai C, et al. A Meta-Analysis of Mesenchymal Stem Cells in Animal Models of Parkinson's Disease. Stem Cells Dev 2015; 24: 2082-90. Xiong N, Yang H, Liu L, et al. bFGF promotes the differentiation and effectiveness of human bone marrow mesenchymal stem cells in a rotenone model for Parkinson's disease. Environ Toxicol Pharmacol 2013; 36(2): 411-22. Jinfeng L, Yunliang W, Xinshan L, et al. The Effect of MSCs Derived from the Human Umbilical Cord Transduced by Fibroblast Growth Factor-20 on Parkinson's Disease. Stem Cells Int 2016; 2016: 5016768. Jiaming M, Niu C. Comparing neuroprotective effects of CDNFexpressing bone marrow derived mesenchymal stem cells via differing routes of administration utilizing an in vivo model of Parkinson's disease. Neurol Sci 2015; 36(2): 281-7. Ren X, Zhang T, Gong X, et al. AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in a 6-hydroxydopamine induced parkinsonian rat model. Exp Neurol 2013; 248: 148-56. Lau T, Adam S, Schloss P. Rapid and efficient differentiation of dopaminergic neurons from mouse embryonic stem cells. Neuroreport 2006; 17: 975-9. Trzaska KA, Rameshwar P. Dopaminergic neuronal differentiation protocol for human mesenchymal stem cells. Methods Mol Biol (Clifton, N.J.) 2011; 698: 295-303. Trzaska KA, King CC, Li KY, et al. Brain-derived neurotrophic factor facilitates maturation of mesenchymal stem cell-derived dopamine progenitors to functional neurons. J Neurochem 2009; 110(3): 1058-69. Hoban DB, Howard L, Dowd E. GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammationdriven rat model of Parkinson's disease. Neuroscience 2015; 303: 402-11.

is

[131]

[147]

se

[130]

[146]

rD

[129]

U

[128]

Fo

[127]

ot

[126]

on al

[125]

N

[124]

Dawson TM, Dawson VL. Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J Clin Invest 2003; 111(2): 14551. Svenningsson P, Westman E, Ballard C, Aarsland D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol 2012; 11(8): 697-707. Williams-Gray CH, Foltynie T, Lewis SJ, Barker RA. Cognitive deficits and psychosis in Parkinson's disease: a review of pathophysiology and therapeutic options. CNS Drugs 2006; 20(6): 477505. Solari N, Bonito-Oliva A, Fisone G, Brambilla R. Understanding cognitive deficits in Parkinson's disease: lessons from preclinical animal models. Learn Mem 2013; 20(10): 592-600. Shulman JM, De Jager PL, Feany MB. Parkinson's disease: genetics and pathogenesis. Annu Rev Pathol 2011; 6: 193-222. Varma D, Sen D. Role of the unfolded protein response in the pathogenesis of Parkinson's disease. Acta Neurobiol Exp 2015; 75: 1-26. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 2008; 14(5): 504-6. Dahlstroem A, Fuxe K. Evidence for the existence of monoaminecontaining neurons in the central nervous system. I. demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl 1964: SUPPL 232: 1-55. Hornykiewicz O. Psychopharmacological implications of dopamine and dopamine antagonists: a critical evaluation of current evidence. Neuroscience 1978; 3(9): 773-83. Tian JY, Guo JF, Wang L, et al. Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease. Neurosci Lett 2012; 516(2): 207-11. Xiromerisiou G, Dardiotis E, Tsimourtou V, et al. Genetic basis of Parkinson disease. Neurosurg Focus 2010; 28(1): E7. Spatola M, Wider C. Genetics of Parkinson's disease: the yield. Parkinsonism Relat Disord 2014; 20 Suppl 1: S35-8. Broeder S, Nackaerts E, Heremans E, et al. Transcranial direct current stimulation in Parkinson's disease: Neurophysiological mechanisms and behavioral effects. Neurosci Biobehav Rev 2015; 57: 105-17. Bronstein JM, Tagliati M, Alterman RL, et al. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 2011; 68: 165. Jiménez-Urbieta H, Gago B, de la Riva P, et al. Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches. Neurosci Biobehav Rev 2015; 56: 294-314. Massano J, Garrett C. Deep brain stimulation and cognitive decline in Parkinson's disease: a clinical review. Front Neurol 2012; 3: 66. Yang WH, Yang C, Xue YQ, et al. Regulated expression of lentivirus-mediated GDNF in human bone marrow-derived mesenchymal stem cells and its neuroprotection on dopaminergic cells in vitro. PLoS One 2013; 8(5): e64389. Tate CC, Chou VP, Campos C, et al. Mesenchymal stromal SB623 cell implantation mitigates nigrostriatal dopaminergic damage in a mouse model of Parkinson's disease. J Tissue Eng Regen Med 2015. [Epub ahead of print]. Riecke J, Johns KM, Cai C, et al. A Meta-analysis of mesenchymal stem cells in animal models of Parkinson's Disease. Stem Cells Dev 2015; 24(18): 2082-90. Daviaud N, Garbayo E, Sindji L, et al. Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease. Stem Cells Transl Med 2015; 4(6): 670-84. Park BN, Kim JH, Lee K, Park SH, An YS. Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson's disease: small animal positron emission tomography study with F-18 FP-CIT. Eur Radiol 2015; 25(5): 1487-96. Schwerk A, Altschuler J, Roch M, et al. Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning. Cytotherapy 2015; 17(2): 199-214. Suzuki S, Kawamata J, Iwahara N, et al. Intravenous mesenchymal stem cell administration exhibits therapeutic effects against 6-

Pe rs

[123]

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

344 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

[178]

[179] [180] [181]

[182] [183] [184] [185]

[186] [187]

[188] [189] [190]

[191]

nl y [197]

[198]

[199]

[200]

[201]

bu tio n

[177]

[196]

tri

[176]

[195]

O

[175]

[194]

cells to differentiate into neuron-like cells in poly(lactic-acid-coglycolic acid) multiple-channel conduit. Cells, Tissues, Organs 2012; 195: 313-22. Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003; 9: 589-95. Slevin JT, Gerhardt GA, Smith CD, et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 2005; 102: 216-22. Tatard VM, D'Ippolito G, Diabira S, et al. Neurotrophin-directed differentiation of human adult marrow stromal cells to dopaminergic-like neurons. Bone 2007; 40: 360-73. Strübing C, Ahnert-Hilger G, Shan J, et al. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech Dev 1995; 53: 275-87. Kriks S, Shim J-W, Piao J, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011; 480: 547-51. Kikuchi T, Morizane A, Doi D, et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. J Parkinsons Dis 2011; 1(4): 395-412. Grow DA, Simmons DV, Gomez JA, et al. Differentiation and Characterization of Dopaminergic Neurons From Baboon Induced Pluripotent Stem Cells. Stem Cells Transl Med 2016; 5(9): 113344. Swistowski A, Peng J, Liu Q, et al. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 2010; 28(10): 1893-904. Liste I, Garcia-Garcia E, Martinez-Serrano A. The generation of dopaminergic neurons by human neural stem cells is enhanced by Bcl-XL, both in vitro and in vivo. J Neurosci 2004; 24(48): 1078695. Martinez-Serrano A, Castillo CG, Courtois ET, Garcia-Garcia E, Liste I. Modulation of the generation of dopaminergic neurons from human neural stem cells by Bcl-X(L): mechanisms of action. Vitam Horm 2011; 87: 175-205. Roy NS, Cleren C, Singh SK, et al. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 2006; 12(11): 1259-68. Rhee YH, Ko JY, Chang MY, et al. Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. J Clin Invest 2011; 121(6): 2326-35. Liang Y, Walczak P, Bulte JW. The survival of engrafted neural stem cells within hyaluronic acid hydrogels. Biomaterials 2013; 34(22): 5521-9. Rockenstein E, Desplats P, Ubhi K, et al. Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease. Stem Cell Res 2015; 15(1): 54-67. Lindvall O. Treatment of Parkinson's disease using cell transplantation. Philos Trans R Soc Lond B Biol Sci 2015; 370(1680): 20140370. Ko TL, Fu YY, Shih YH, et al. A high-efficiency induction of dopaminergic cells from human umbilical mesenchymal stem cells for the treatment of hemiparkinsonian rats. Cell Transplant 2015; 24(11): 2251-62. Cova L, Armentero M-T, Zennaro E, et al. Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson's disease. Brain Res 2010; 1311: 12-27. Blandini F, Cova L, Armentero MT, et al. Transplantation of undifferentiated human mesenchymal stem cells protects against 6hydroxydopamine neurotoxicity in the rat. Cell Transplant 2010; 19(2): 203-17. Campeau L, Soler R, Sittadjody S, et al. Effects of allogeneic bone marrow derived mesenchymal stromal cell therapy on voiding function in a rat model of Parkinson disease. J Urol 2014; 191(3): 850-9. Thomas MG, Stone L, Evill L, et al. Bone marrow stromal cells as replacement cells for Parkinson's disease: generation of an anatomical but not functional neuronal phenotype. Transl Res 2011; 157: 56-63.

[202]

is

[174]

[193]

se

[173]

[192]

[203]

rD

[172]

U

[171]

Fo

[170]

ot

[169]

on al

[168]

N

[167]

Park HJ, Shin JY, Kim HN, Oh SH, Lee PH. Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model. Neurobiol Aging 2014; 35(8): 1920-8. Azari MF, Mathias L, Ozturk E, et al. Mesenchymal stem cells for treatment of CNS injury. Curr Neuropharmacol 2010; 8: 316-23. Ferguson IA, Koide T, Rush RA. Stimulation of corticospinal tract regeneration in the chronically injured spinal cord. Eur J Neurosci 2001; 13: 1059-64. Kim EY, Lee K-B, Yu J, et al. Neuronal cell differentiation of mesenchymal stem cells originating from canine amniotic fluid. Human cell 2014; 27: 51-8. Paldino E, Cenciarelli C, Giampaolo A, et al. Induction of dopaminergic neurons from human Wharton's jelly mesenchymal stem cell by forskolin. J Cellular Physiol 2014; 229: 232-44. Tio M, Tan KH, Lee W, Wang TT, Udolph G. Roles of db-cAMP, IBMX and RA in aspects of neural differentiation of cord blood derived mesenchymal-like stem cells. PloS One 2010; 5: e9398. Dworkin S, Heath JK, DeJong-Curtain TA, et al. CREB activity modulates neural cell proliferation, midbrain-hindbrain organization and patterning in zebrafish. Dev Biol 2007; 307: 127-41. Mantamadiotis T, Lemberger T, Bleckmann SC, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 2002; 31: 47-54. Tremblay RG, Sikorska M, Sandhu JK, et al. Differentiation of mouse Neuro 2A cells into dopamine neurons. J Neurosci Methods 2010; 186: 60-7. Jori FP, Napolitano MA, Melone MAB, et al. Molecular pathways involved in neural in vitro differentiation of marrow stromal stem cells. J Cell Biochem 2005; 94: 645-55. Wang TT, Tio M, Lee W, Beerheide W, Udolph G. Neural differentiation of mesenchymal-like stem cells from cord blood is mediated by PKA. Biochem Biophys Res Commun 2007; 357: 1021-7. Neirinckx V, Coste C, Rogister B, Wislet-gendebien S. Neural Fate of Mesenchymal Stem Cells and Neural Crest Stem Cells: Which Ways to Get Neurons for Cell Therapy Purpose? In: WisletGendebien S, Ed. Trends in Cell Signaling Pathways in Neuronal Fate Decision: InTech; 2013. p. 327-57. Lepski G, Jannes CE, Maciaczyk J, et al. Limited Ca2+ and PKApathway dependent neurogenic differentiation of human adult mesenchymal stem cells as compared to fetal neuronal stem cells. Exp Cell Res 2010; 316: 216-31. Litingtung Y, Chiang C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 2000; 3: 979-85. Litingtung Y, Chiang C. Control of Shh activity and signaling in the neural tube. Dev Dyn 2000; 219: 143-54. Trzaska KA, Kuzhikandathil EV, Rameshwar P. Specification of a dopaminergic phenotype from adult human mesenchymal stem cells. Stem cells (Dayton, Ohio) 2007; 25: 2797-808. Maden M. Retinoid signalling in the development of the central nervous system. Nature reviews. Neuroscience 2002; 3: 843-53. Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cellular Physiology 2011; 226: 322-30. Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nature reviews. Neuroscience 2003; 4: 299-309. Levy YS, Gilgun-Sherki Y, Melamed E, Offen D. Therapeutic potential of neurotrophic factors in neurodegenerative diseases. BioDrugs 2005; 19: 97-127. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annual review of biochemistry 2003; 72: 609-42. Mei J, Niu C. Effects of engineered conserved dopamine neurotrophic factor-expressing bone marrow stromal cells on dopaminergic neurons following 6-OHDA administrations. Mol Med Rep 2015; 11(2): 1207-13. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc London B Biol Sci 2006; 361: 1545-64. Lim JY, Park SI, Oh JH, et al. Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways. J Neurosci Res 2008; 86: 2168-78. Zhang Y-q, He L-m, Xing B, et al. Neurotrophin-3 gene-modified Schwann cells promote TrkC gene-modified mesenchymal stem

Pe rs

[166]

Venkatesh and Sen

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

MSC-Derived Dopamine Cells in the Treatment of PD

[223] [224]

[225]

[226]

[227]

[228]

[229]

[230] [231]

[232]

[233]

nl y

[238]

[239]

O

[240]

[241]

[242]

[243]

[244] [245]

bu tio n

[222]

[237]

tri

[221]

[236]

[246] [247]

[248]

[249] [250]

[251] [252]

[253]

[254]

[255]

345

ing of embryonic dopamine neurons in the rat. Neurobiol Dis 2006; 22(2): 334-45. Maries E, Kordower JH, Chu Y, et al. Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats. Neurobiol Dis 2006; 21(1): 165-80. Piccini P, Pavese N, Hagell P, et al. Factors affecting the clinical outcome after neural transplantation in Parkinson's disease. Brain 2005; 128(Pt 12): 2977-86. Bach FH, Albertini RJ, Joo P, Anderson JL, Bortin MM. Bonemarrow transplantation in a patient with the Wiskott-Aldrich syndrome. Lancet 1968; 2(7583): 1364-6. Almeida WAO de E, Am., Almeida-Junior CLD., Frank MK., Mariano MO., Frussa-Filho R., Tufik S., Mello MTD. The effects of long-term dopaminergic treatment on locomotor behavior in rats. Sleep Science 2014; 7(4): 203-8. Hasenfuss G, Just H. Clinical relevance of long-term therapy with levodopa and orally active dopamine analogues in patients with chronic congestive heart failure. Basic Res Cardiol 1989; 84 Suppl 1: 191-6. Björklund A, Dunnett SB, Brundin P, et al. Neural transplantation for the treatment of Parkinson's disease. Lancet Neurol 2003; 2: 437-45. Lindvall O, Brundin P, Widner H, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science (New York, N.Y.) 1990; 247: 574-7. Gonzalez R, Garitaonandia I, Abramihina T, et al. Deriving dopaminergic neurons for clinical use. A practical approach. Scientific reports 2013; 3: 1463. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 2011; 11: 268-77. Ghosh Z, Huang M, Hu S, et al. Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells. Cancer Res 2011; 71: 5030-9. Lindvall O. Dopaminergic neurons for Parkinson's therapy. Nat Biotechnol 2012; 30: 56-8. Chang W, Song B-W, Hwang K-C. Mesenchymal stem cell survival in infarcted myocardium: adhesion and anti-death signals. stem cells and cancer stem cells, Volume 10. Dordrecht: Springer Netherlands; 2013. p. 35-43. Duffy CRE, Zhang R, How S-E, et al. Long term mesenchymal stem cell culture on a defined synthetic substrate with enzyme free passaging. Biomaterials 2014; 35: 5998-6005. Blocki A, Beyer S, Dewavrin J-Y, et al. Microcapsules engineered to support mesenchymal stem cell (MSC) survival and proliferation enable long-term retention of MSCs in infarcted myocardium. Biomaterials 2015; 53: 12-24. Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (20102015). Stem Cell Res Ther 2016; 7(1): 82. Pendleton C, Li Q, Chesler DA, et al. Mesenchymal stem cells derived from adipose tissue vs bone marrow: in vitro comparison of their tropism towards gliomas. PloS One 2013; 8: e58198. Wagner W, Wein F, Seckinger A, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 2005; 33: 1402-16. Cai J, Li W, Su H, et al. Generation of human induced pluripotent stem cells from umbilical cord matrix and amniotic membrane mesenchymal cells. J Biol Chem 2010; 285: 11227-34. Tsai M-S, Lee J-L, Chang Y-J, Hwang S-M. Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod (Oxford, England) 2004; 19: 1450-6. Mamidi MK, Nathan KG, Singh G, et al. Comparative cellular and molecular analyses of pooled bone marrow multipotent mesenchymal stromal cells during continuous passaging and after successive cryopreservation. J Cellular Biochem 2012; 113: 3153-64. Otsuru S, Hofmann TJ, Olson TS, Dominici M, Horwitz EM. Improved isolation and expansion of bone marrow mesenchymal stromal cells using a novel marrow filter device. Cytotherapy 2013; 15: 146-53. Kadar K, Kiraly M, Porcsalmy B, et al. Differentiation potential of stem cells from human dental origin - promise for tissue engineering. J Physiol Pharmacol 2009; 60 Suppl 7: 167-75.

is

[220]

[235]

se

[219]

[234]

rD

[218]

U

[217]

Fo

[216]

ot

[215]

on al

[214]

N

[213]

Khoo MLM, Tao H, Meedeniya ACB, Mackay-Sim A, Ma DDF. Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents. PloS One 2011; 6: e19025. Kumar A, Dudhal S, T AS, et al. Dopaminergic-primed fetal liver mesenchymal stromal-like cells can reverse parkinsonian symptoms in 6-hydroxydopamine-lesioned mice. Cytotherapy 2016; 18(3): 307-19. Lindvall O, Brundin P, Widner H, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 1990; 247(4942): 574-7. Grealish S, Diguet E, Kirkeby A, et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. Cell stem cell 2014; 15: 653-65. Sawle GV, Bloomfield PM, Bjorklund A, et al. Transplantation of fetal dopamine neurons in Parkinson's disease: PET [18F]6-Lfluorodopa studies in two patients with putaminal implants. Ann Neurol 1992; 31(2): 166-73. Peschanski M, Defer G, N'Guyen JP, et al. Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 1994; 117 ( Pt 3): 487-99. Wenning GK, Odin P, Morrish P, et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann Neurol 1997; 42(1): 95-107. Lenka N, Ramasamy SK. Neural induction from ES cells portrays default commitment but instructive maturation. PloS One 2007; 2: e1349. Kanafi M, Majumdar D, Bhonde R, Gupta P, Datta I. Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons. Journal of cellular physiology 2014; 229: 1369-77. Katzenschlager R, Lees AJ. Treatment of Parkinson's disease: levodopa as the first choice. J Neurol 2002; 249 Suppl 2: II19-24. Bjorklund A, Dunnett SB, Brundin P, et al. Neural transplantation for the treatment of Parkinson's disease. Lancet Neurol 2003; 2(7): 437-45. Lindvall O. Neural transplantation: a hope for patients with Parkinson's disease. Neuroreport 1997; 8(14): iii-x. Freed CR, Breeze RE, Rosenberg NL, et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 1992; 327(22): 1549-55. Freed CR, Breeze RE, Rosenberg NL, et al. Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year. Arch Neurol 1990; 47: 505-12. Watts RL, Subramanian T, Freeman A, et al. Effect of stereotaxic intrastriatal cografts of autologous adrenal medulla and peripheral nerve in Parkinson's disease: two-year follow-up study. Exp Neurol 1997; 147(2): 510-7. Kopyov OV, Jacques DS, Lieberman A, Duma CM, Rogers RL. Outcome following intrastriatal fetal mesencephalic grafts for Parkinson's patients is directly related to the volume of grafted tissue. Exp Neurol 1997; 146(2): 536-45. Kordower JH, Cochran E, Penn RD, Goetz CG. Putative chromaffin cell survival and enhanced host-derived TH-fiber innervation following a functional adrenal medulla autograft for Parkinson's disease. Ann Neurol 1991; 29(4): 405-12. Kordower JH, Rosenstein JM, Collier TJ, et al. Functional fetal nigral grafts in a patient with Parkinson's disease: chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol 1996; 370(2): 203-30. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003; 54(3): 403-14. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. New Engl J Med 2001; 344: 710-9. Carlsson T, Winkler C, Lundblad M, et al. Graft placement and uneven pattern of reinnervation in the striatum is important for development of graft-induced dyskinesia. Neurobiol Dis 2006; 21(3): 657-68. Lane EL, Winkler C, Brundin P, Cenci MA. The impact of graft size on the development of dyskinesia following intrastriatal graft-

Pe rs

[212]

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

346 Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4

[267]

[268]

[269]

[270] [271]

[272]

[273] [274]

[275]

[276] [277]

[278]

nl y

[283]

O

[284]

[285]

[286]

[287]

[288]

bu tio n

[266]

[282]

tri

[265]

[281]

neural markers rather than inducing neural differentiation. Stem Cells Dev 2009; 18: 387-98. Kondo T, Johnson SA, Yoder MC, Romand R, Hashino E. Sonic hedgehog and retinoic acid synergistically promote sensory fate specification from bone marrow-derived pluripotent stem cells. Proc Natl Acad Sci USA 2005; 102: 4789-94. Liqing Y, Jia G, Jiqing C, et al. Directed differentiation of motor neuron cell-like cells from human adipose-derived stem cells in vitro. Neuroreport 2011; 22: 370-3. Schwerk A, Altschuler J, Roch M, et al. Adipose-derived human mesenchymal stem cells induce long-term neurogenic and antiinflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regen Med 2015; 10(4): 431-46. Ying C, Hu W, Cheng B, Zheng X, Li S. Neural differentiation of rat adipose-derived stem cells in vitro. Cell Mol Neurobiol 2012; 32: 1255-63. Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S. Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells (Dayton, Ohio) 2008; 26: 1787-95. Chun SY, Soker S, Jang YJ, Kwon TG, Yoo ES. Differentiation of human dental pulp stem cells into dopaminergic neuron-like cells in vitro. J Korean Med Sci 2016; 31(2): 171-7. Wang J, Wang X, Sun Z, et al. Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells. Stem Cells Dev 2010; 19: 1375-83. Fu Y-S, Cheng Y-C, Lin M-YA, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells (Dayton, Ohio) 2006; 24: 115-24. van Horne CG, Quintero JE, Gurwell JA, et al. Implantation of autologous peripheral nerve grafts into the substantia nigra of subjects with idiopathic Parkinson's disease treated with bilateral STN DBS: a report of safety and feasibility. J Neurosurg 2016: 1-8. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001; 344(10): 710-9. Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med 2010; 2(38): 38ra46. Hagell P, Piccini P, Bjorklund A, et al. Dyskinesias following neural transplantation in Parkinson's disease. Nat Neurosci 2002; 5(7): 627-8. Olanow CW, Gracies JM, Goetz CG, et al. Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson's disease: a double blind video-based analysis. Mov Disord 2009; 24(3): 336-43. Mendez I, Sanchez-Pernaute R, Cooper O, et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain 2005; 128(Pt 7): 1498-510. Diamond SG, Markham CH, Rand RW, Becker DP, Treciokas LJ. Four-year follow-up of adrenal-to-brain transplants in Parkinson's disease. Arch Neurol 1994; 51(6): 559-63. Goetz CG, Stebbins GT, 3rd, Klawans HL, et al. United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up. Neurology 1991; 41(11): 1719-22. Goetz CG, Stebbins GT, 3rd, Klawans HL, et al. United Parkinson Foundation Neurotransplantation Registry: multicenter US and Canadian data base, presurgical and 12 month follow-up. Prog Brain Res 1990; 82: 611-7. Watts R.L. FA, Graham S, Bakay, R.A.E. Early Experience with Autologous Intrastriatal Adrenal Medulla/Nerve Cografting in Parkinson's Disease. J Neural Transplant Plast 1992; 3(4): 272–3. Freeman TB, Olanow CW, Hauser RA, et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann Neurol 1995; 38(3): 379-88. Spencer DD, Robbins RJ, Naftolin F, et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N Engl J Med 1992; 327(22): 1541-8. Widner H, Tetrud J, Rehncrona S, et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-

[289]

is

[264]

[280]

se

[263]

[279]

[290]

rD

[262]

U

[261]

Fo

[260]

ot

[259]

on al

[258]

N

[257]

Seifrtová M, Havelek R, Cmielová J, et al. The response of human ectomesenchymal dental pulp stem cells to cisplatin treatment. Int Endod J 2012; 45: 401-12. Schüring AN, Schulte N, Kelsch R, et al. Characterization of endometrial mesenchymal stem-like cells obtained by endometrial biopsy during routine diagnostics. Fertil Steril 2011; 95: 423-6. Jiao F, Wang J, Dong Z-L, et al. Human mesenchymal stem cells derived from limb bud can differentiate into all three embryonic germ layers lineages. Cell Reprogram 2012; 14: 324-33. Ab Kadir R, Zainal Ariffin SH, Megat Abdul Wahab R, Kermani S, Senafi S. Characterization of mononucleated human peripheral blood cells. ScientificWorldJournal 2012; 2012: 843843. Raynaud CM, Maleki M, Lis R, et al. Comprehensive characterization of mesenchymal stem cells from human placenta and fetal membrane and their response to osteoactivin stimulation. Stem Cells Int 2012; 2012: 658356. Rotter N, Oder J, Schlenke P, et al. Isolation and characterization of adult stem cells from human salivary glands. Stem Cells Dev 2008; 17: 509-18. Bartsch G, Yoo JJ, De Coppi P, et al. Propagation, expansion, and multilineage differentiation of human somatic stem cells from dermal progenitors. Stem cells and development 2005; 14: 337-48. Riekstina U, Muceniece R, Cakstina I, Muiznieks I, Ancans J. Characterization of human skin-derived mesenchymal stem cell proliferation rate in different growth conditions. Cytotechnology 2008; 58: 153-62. Morito T, Muneta T, Hara K, et al. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford, England) 2008; 47: 1137-43. Hou T, Xu J, Wu X, et al. Umbilical cord Wharton's Jelly: a new potential cell source of mesenchymal stromal cells for bone tissue engineering. Tissue Eng Part A 2009; 15: 2325-34. Sato H, Kuwashima N, Sakaida T, et al. Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors. Cancer Gene Ther 2005; 12: 757-68. Bai L, Lennon DP, Caplan AI, et al. Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models. Nat Neurosci 2012; 15: 862-70. Liu XS, Li JF, Wang SS, et al. Human umbilical cord mesenchymal stem cells infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson's disease model. Biomed Res Int 2014; 2014: 909657. Ji JF, He BP, Dheen ST, Tay SSW. Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells (Dayton, Ohio) 2004; 22: 415-27. Kyurkchiev D, Bochev I, Ivanova-Todorova E, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells 2014; 6: 552-70. Semon JA, Nagy LH, Llamas CB, et al. Integrin expression and integrin-mediated adhesion in vitro of human multipotent stromal cells (MSCs) to endothelial cells from various blood vessels. Cell Tissue Res 2010; 341: 147-58. Siegel G, Kluba T, Hermanutz-Klein U, et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med 2013; 11: 146. Delarosa O, Dalemans W, Lombardo E. Toll-like receptors as modulators of mesenchymal stem cells. Front Immunol 2012; 3: 182. Lin X, Zhang Y, Dong J, et al. GM-CSF enhances neural differentiation of bone marrow stromal cells. Neuroreport 2007; 18: 11137. Nandy SB, Mohanty S, Singh M, Behari M, Airan B. Fibroblast Growth Factor-2 alone as an efficient inducer for differentiation of human bone marrow mesenchymal stem cells into dopaminergic neurons. J Biomed Sci 2014; 21: 83. Suon S, Yang M, Iacovitti L. Adult human bone marrow stromal spheres express neuronal traits in vitro and in a rat model of Parkinson's disease. Brain Res 2006; 1106: 46-51. Zhang L, Seitz LC, Abramczyk AM, Liu L, Chan C. cAMP initiates early phase neuron-like morphology changes and late phase neural differentiation in mesenchymal stem cells. Cell Mol Life Sci 2011; 68: 863-76. Rooney GE, Howard L, O'Brien T, Windebank AJ, Barry FP. Elevation of cAMP in mesenchymal stem cells transiently upregulates

Pe rs

[256]

Venkatesh and Sen

[291]

[292]

[293]

[294]

[295]

[296] [297]

[298]

[299]

MSC-Derived Dopamine Cells in the Treatment of PD [302]

is

tri

bu tio n

O se rD Fo

ot

347

Venkataramana NK, Pal R, Rao SA, et al. Bilateral transplantation of allogenic adult human bone marrow-derived mesenchymal stem cells into the subventricular zone of Parkinson's disease: a pilot clinical study. Stem Cells Int 2012; 2012: 931902. Yilong Ma CT, Thomas Chaly, Paul Greene, Robert Breeze, Stanley Fahn, Curt Freed, Vijay Dhawan, David Eidelber. Dopamine Cell Implantation in Parkinson’s Disease: Long-Term Clinical and 18F-FDOPA PET Outcomes. J Nucl Med 2010; 51(1): 7-15.

nl y

[303]

U on al N

[301]

methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992; 327(22): 1556-63. Lindvall O, Sawle G, Widner H, et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann Neurol 1994; 35(2): 172-80. Bhattacharya N, Chhetri MK, Mukherjee KL, et al. Can human fetal cortical brain tissue transplant (up to 20 weeks) sustain its metabolic and oxygen requirements in a heterotopic site outside the brain? A study of 12 volunteers with Parkinson's disease. Clin Exp Obstet Gynecol 2002; 29(4): 259-66.

Pe rs

[300]

Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 4