Curr Pathobiol Rep (2015) 3:9–16 DOI 10.1007/s40139-015-0070-6 TISSUE ENGINEERING AND REGENERATION, (BRYAN BROWN AND CHRISTOPHER DEARTH, SECTION EDITORS)
Placenta as a Source of Stem Cells for Regenerative Medicine Jason A. Meierhenry • Volodymyr Ryzhuk • Maricel G. Miguelino • Lee Lankford • Jerry S. Powell • Diana Farmer • Aijun Wang
Published online: 3 February 2015 Springer Science+Business Media New York 2015
Abstract The development of effective cell transplantation therapies is currently the focus of biomedical research worldwide, and numerous cell types and sources have been explored for applications in regenerative medicine. The placenta is a unique organ of fetomaternal origin that plays an important role in fetal development, and multiple types of placenta-derived stem cells show great promise for application in regenerative medicine. This review concisely summarizes the recent proceedings on the characterization, biological properties, and applications of mesenchymal stem cells that have been isolated from various anatomic regions of the placenta and at different gestational ages. In addition, this review summarizes recent studies that have isolated amniotic epithelial cells, hematopoietic stem cells, and trophoblast stem cells from placental tissue. Keywords Placenta derived stem cells Mesenchymal stem cells Hematopoietic stem cells Cell-based therapy Regenerative medicine
This article is part of the Topical Collection on Tissue Engineering and Regeneration. J. A. Meierhenry V. Ryzhuk L. Lankford D. Farmer A. Wang (&) Department of Surgery, Surgical Bioengineering Laboratory, University of California, Davis Medical Center, Sacramento, CA 95817, USA e-mail:
[email protected] M. G. Miguelino J. S. Powell Division of Hematology/Oncology, Department of Internal Medicine, University of California, Davis Medical Center, Sacramento, CA 95817, USA
Introduction Over the past few decades, cellular transplantation therapy has emerged as a potential tool for tissue repair and regenerative medicine. Pre-clinical studies have shown promising results for the treatment of a wide range of degenerative diseases, and currently, investigators continue to push forward the application of cell therapy into clinical trials. However, in spite of these advancements, questions still remain in regard to which cell types and tissue sources are most beneficial for specific therapeutic applications (i.e., replacement of damaged tissue, modulation of endogenous body responses, etc.). Bone marrow has typically been the primary source of mesenchymal stem cells (MSCs) for both experimental and clinical studies; however, the low number of MSCs and the invasive procedure associated with obtaining bone marrow-derived MSCs (BM-MSCs) can make their use problematic [1]. More recently, gestational tissues, such as the placenta, placental membranes, umbilical cord, and amniotic fluid, have been recognized as potential cell sources for regenerative medicine [1]. Placental tissues in particular have been shown to be a rich source of stem cells with strong immunosuppressive properties, and these tissues demonstrate strong potential for cell therapy. The placenta is a unique organ of fetomaternal origin that facilitates nutrient and gas exchange between fetal and maternal blood. It is considered ‘‘extra-embryonic,’’ in that it develops outside of the developing fetus during gestation and will eventually become inoperative when the fetus is born and begins breathing on its own. As a fetomaternal organ, the placenta develops from the trophectoderm layer of the fetal blastocyst. The trophectoderm layer is crucial for the implantation of the embryo into maternal uterine tissue and is needed for decidualization of the endometrial
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layer of the uterus. During gestation, the placenta develops into discrete anatomic regions beginning from the decidua basalis (located most proximal to the uterus) and terminating at the umbilical cord. Each of these regions contains a variety of cell types that can potentially be used for cell therapy. MSCs can be readily isolated from essentially all of the anatomic regions of the placenta, with the amniotic membrane serving as a source for obtaining epithelial cells and the chorionic villi serving as a source for hematopoietic stem cells (HSCs) and trophoblasts. The placenta is partially comprised of fetal tissue, which allows for the development of therapies autologous to the fetus for in utero treatment of congenital anomalies. Due to their developmental significance, fetal cells may possess unique properties that other adult primary cell types lack. The means of obtaining placenta-derived cells may also be minimally invasive compared to other candidate tissue sources, such as bone marrow or adipose tissue. For example, chorionic villi from early gestation placenta can be readily obtained using chorionic villus sampling (CVS), which is a technique generally utilized to sample fetal DNA for prenatal diagnosis. In addition, term placenta is commonly discarded after birth and can be collected as a non-invasive tissue source for cells. For these reasons, utilizing the placenta as a source of cells for cellular therapy shows promise for targeted therapies for numerous pathological conditions. This review will cover the characterization, biological properties, specific tissue sources, and applications of placenta-derived mesenchymal stem cells (PMSCs), as well as recent studies on amniotic epithelial cells (AEC), HSCs, and trophoblast stem cells (TSCs) that have been isolated from placental tissue.
utilized stem cells in translational studies and are expected to be in high demand by clinical therapies in the near future. According to www.clinicaltrials.gov, a publicly available database with information on publicly and privately supported clinical studies, there are currently over 450 registered clinical trials that employ MSC-based therapies. MSCs can be successfully isolated from a number of tissues, including bone marrow, adipose tissue, muscle, lungs, tooth buds, umbilical cord blood, Wharton’s jelly, amniotic fluid, and different regions of the placenta [5, 6]. Depending on the tissue of origin, MSCs exhibit varied degrees of plasticity, rate of division, and secretion. A number of recent publications suggest that placenta- and amnion-derived mesenchymal stem cells have a wide range of cell-based therapeutic applications, including pancreatic and liver regeneration, neurological diseases, and myocardial and lung rescue cell therapies [5, 7–9]. Phenotype of PMSCs
PMSCs
Both BM-MSCs and PMSCs have been demonstrated to adhere to plastic and possess morphology similar to fibroblasts [10]. Overall, the size and shape of PMSCs are more heterogeneous than stem cells derived from bone marrow. The human PMSC surface marker phenotype is consistent with adult MSCs, indicated by the presence of CD44, CD73, CD90, and CD105 and by the absence of CD11, CD45, and CD79. Gene expression profiles are not significantly altered within differently sourced MSCs [9]; however, the expression levels of specific factors vary depending on the source of cells. For instance, the level of hepatocyte growth factor expression, a cytokine primarily responsible for angiogenesis and many other biological functions, was shown to be much higher in PMSCs when compared to adult MSCs [11].
Introduction to MSCs
Differentiation of PMSCs
In order to be classified as MSCs, cells must meet the following criteria [2]:
Both PMSCs and BM-MSCs show tri-lineage differentiation potential (the ability to differentiate into chondrocytes, adipocytes, and osteocytes), but the efficiency of differentiation varies depending on the source of stem cells [10]. Studies have found that PMSCs are less efficient than BMMSCs at differentiating into adipocytes and osteocytes [12]. On the other hand, PMSCs are ontogenically related to embryonic stem cells, sharing their immunoprivileged characteristics and surpassing adult MSCs in broader plasticity and augmented proliferation rate [13]. For example, amnion-derived mesenchymal stem cells (AMSCs) express the pluripotent genetic marker OCT-4, do not form tumors in vivo, and can be successfully induced to differentiate into six lineages (myogenic, adipogenic, osteogenic, endothelial, hepatic and neuronal) [14].
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Being capable of adhering to plastic in standard culture conditions. Expressing characteristic cell surface markers such as CD73, CD90, and CD105 and lacking the expression of CD11b/CD14, CD34, CD45, CD79a/CD19, and HLADR markers. Being capable of differentiating into chondroblasts, osteoblasts, and adipocytes.
MSCs were first derived from bone marrow stroma, and BM-MSCs have been considered the gold standard for MSCs due to the relative ease of isolation, extended plasticity, and proven clinical applications [3, 4]. MSCs are one of the most
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Proliferation of PMSCs Barlow et al. demonstrated higher growth rate of PMSCs than BM-MSCs. PMSCs were able to withstand higher number of passages and lower seeding density than BMMSCs in culture [10]. AMSCs are highly proliferative and clonogenic and have the potential to expand for 15 passages [15]. MSCs obtained from preterm placenta maintain long telomeres and express markers associated with pluripotency, such as OCT-4 and SSEA-3 [14]. Secretion of PMSCs Currently, studies are exploring the potential of MSCs to replace cells of damaged tissue, and investigators are interested in the ability of MSCs to modulate the local environment by releasing chemokines, cytokines, and prostaglandins that may promote vascularization and inhibit inflammation [16]. Recent studies suggest that the therapeutic effects exerted by PMSCs are likely due to the secretion of bioactive substances [6]. Lee et al. demonstrated that the exosomes secreted by MSCs have cytoprotective properties [17]. PMSCs express wide range of cytokines involved in wound healing, including IL-6 and IL-8, VEGF, angiogenin, PDGF, TGF-beta 2, and TIM-1 [18, 19]. When compared to BM-MSCs, AMSCs exhibited a different paracrine factor profile [20]. The pathway for cytokine secretion activation was also different in fetal PMSCs compared to maternal PMSCs when exposed to immunostimulatory factors [11]. Essentially, the secretion of PMSCs is a key factor of their therapeutic utility and should be taken into consideration for therapeutic applications. Immunomodulation of PMSCs Organ and cell transplantation approaches are often limited due to the graft-versus-host disease (GVHD). One of the most attractive properties of MSCs is their immunomodulatory effect that may overcome GVHD [21]. Their immunosuppression qualities are linked to inhibition of T cell and other immune cells response [22], and administration of BM-MSCs was correlated with a decrease or even absence of GVHD after transplantation of bone marrow and liver [23, 24]. The unique ability of the placenta to maintain fetomaternal tolerance indicates the immunomodulatory potential of PMSCs, and recently, PMSCs were shown to have regenerative immunomodulatory capabilities similar to BM-MSC, including T cell proliferation and cytokine secretion inhibition [25]. Moreover, PMSCs are more efficient when used for expansion of CD34? HSCs from umbilical cord blood, which are regularly used in cell replacement therapies in blood and immune system diseases. As a result, PMSCs
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can serve as an alternative to bone marrow stromal cells for use in the expansion of blood progenitor cells in vitro and as support for hematopoiesis in vivo. In another study, PMSCs were shown to diminish chronic lung allograft rejection in a murine model [26], and tissues treated with PMSC as well as PMSC-conditioned medium demonstrated increase epithelial progenitor cells and reduction of neutrophils and activated T cells. These results suggest a possible role for PMSCs in the reduction of chronic rejection followed by organ transplantation, and interestingly, chorionic plate-derived mesenchymal stem cells were also shown to slow the formation of fibrosis and CCl4-induced cirrhosis in mice [27]. Thus, there is significant evidence for PMSCs as potent anti-inflammatory and immunomodulatory agents.
PMSCs from Different Placenta Regions The placenta consists of four anatomic regions: amniotic epithelial, amniotic mesenchymal, chorionic mesenchymal, and chorionic trophoblastic [28], and the decidua is the section of uterine lining that forms the maternal part of the placenta during pregnancy. Due to the high level of complexity of the human placenta and the limited scope of this review, only the amnion, chorion, and decidua will be discussed as sources of stem cells in this review paper. AEC, amniotic mesenchymal stromal cells (AMSCs), chorionic mesenchymal stromal cells (CMSCs), and chorionic trophoblastic cells (CTCs) can be isolated from these regions [28]. Other placental sources such as umbilical cord, Wharton’s Jelly, cord blood, and amniotic fluid will not be included in this review. The human fetal membranes—the amnion and chorion—envelop the fetus and its surrounding amniotic fluid, forming a highly specialized interface between mother and fetus that carries out important functions during pregnancy [29]. The amnion is a thin, avascular membrane composed of a single layer of epithelial cells and a layer of mesenchymal stromal cells, and these two cell layers are the sources of human amniotic multipotent epithelial cells (hAECs) and amniotic MSCs (AMSCs) [28]. The chorion consists of a chorionic mesenchymal stromal layer covering a chorionic trophoblast cell layer, which are the sources of chorionic MSCs (CMSCs) and hCTCs, respectively [28]. The chorionic plate is a multilayered structure that consists of the amniotic membrane and the chorion, and the chorionic plate extends from the chorionic disc to enclose the fetus in the amniotic cavity. Chorionic villi originate from the chorionic plate and anchor the placenta through the trophoblast of the basal plate and maternal endometrium [28]. As the fetus grows, the fetal membranes enlarge, such that the chorion pushes into—and
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subsequently adheres to—the overlying decidua parietalis, which is of maternal origin [29]. The chorion with attached decidua parietalis is called the choriodecidua. From the maternal side, protrusions of the basal plate within the chorionic villi produce the placental septa, which divide the parenchyma into irregular cotyledons. Table 1 presents a brief overview of recent studies that have used term PMSCs from amnion, chorion, and decidua for experiments in regenerative medicine. Preterm PMSCs, hAECs, and CTCs will be addressed later in this review paper. Effect of Gestational Age on PMSC Properties Preterm PMSCs present a potential source of autologous MSCs for cell therapy and regenerative medicine. In their review chapter ‘‘Fetal Mesenchymal Stem Cells are More Primitive than Adult Mesenchymal Stem Cells’’ [42], Go¨therstro¨m et al. present a brief overview of prior experiments involving first- and second-trimester fetal tissues. Human MSCs have been isolated from several fetal tissues, including first trimester blood, bone marrow, liver, and placenta [43–45] and from second trimester blood, bone marrow, liver, lung, spleen, pancreas, kidney, brain, and amniotic fluid [46–51]. Collection of fetal somatic tissues during the first trimester is technically challenging, but the placenta is a larger and easier tissue to separate than other fetal tissues and is a more realistic candidate for cell banking. However, acquiring fetal tissue or preterm placenta can require termination of the pregnancy, which makes them ethically contentious as a cell source for autologous applications [52••]. This ethical concern contrasts sharply to term placenta, which is commonly discarded after term delivery and therefore lacks many of the ethical concerns of preterm placenta. As a result, the ability to research preterm PMSCs is limited compared to term PMSCs. However, preterm PMSCs can also be isolated in ongoing pregnancies from surplus tissues obtained during routine prenatal diagnostic procedures, such as chorionic villous sampling [45, 53, 54] and amniocentesis [55–57]. Table 2 presents a brief overview of recent studies that shows the potential of PMSCs for regenerative medicine. The results demonstrate that PMSCs have varied phenotypic characteristics depending on the developmental stage of the placenta, and these findings suggest that early gestational placentas are closer to the embryonic stage than the late full term placentas are [52••]. Current results suggest that preterm PMSCs may exhibit greater growth capacity [58], proliferation potential [58, 59], differentiation potential [60], and stability for long-term cultivation [61•, 62] than term PMSCs. These results suggest significant potential for the use of preterm PMSCs for tissue engineering and regenerative therapy [9, 52••]; however,
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further studies and examination of ethical issues are needed.
Amniotic Epithelial Cells AEC from the placenta have been investigated due to their phenotypic similarity to embryonic stem cells and their ability to differentiate into all types of cells from three germ layers [14, 64]. Marongiu et al. demonstrated the transdifferentiation potential of human AECs into hepatocytes, and after transplantation of human AECs into SCID/ Beige mice, Marongiu et al. also examined the capacity of AECs to repopulate the liver and differentiate into functional hepatocytes [65]. In vitro hepatocyte differentiation of hAECs showed expression of hepatocyte markers similar to fetal hepatocytes, and after a 3-week differentiation protocol using extracellular matrix (ECM) as a substrate for differentiation, there was an up-regulation of liver genes, such as Albumin, A1AT, CYP3A4, 3A7, 1A2, 2B6, and the Asialoglycoprotein receptor 1 (ASGPR1). In vivo, naive human AECs transplanted into SCID/Beige mice pretreated with retrorsine (RS) expressed mature liver genes 6 months after transplantation. This study suggests that a suitable microenvironment for hepatocyte differentiation is needed for high-level long-term engraftment of transdifferentiated hAECs. To improve survivability of AECs and prevent the effects of immunogenicity, Vaghjiani et al. encapsulated AECs in barium alginate microcapsules [66]. Examination of phenotype and function of AECs after a four-week differentiation of AECs demonstrated functional hepatocytes exhibiting the ability to synthesize urea and metabolize drugs via cytochrome P450. After encapsulation, cells remained viable, and liver functions were improved. The use of alginate capsules may be a viable approach for avoidance of immune rejection. However, cell-to-cell contact and exchange of nutrients into the encapsulated cells are limitations to this approach.
Hematopoietic Stem Cells (HSCs) HSCs are capable of generating cells that populate the blood and immune system, and HSCs are among the most extensively studied type of stem cell for therapy. In adults, HSCs reside in the bone marrow, and they are effectively the driving component behind efficacy of bone marrow transplantation. In the fetal environment, however, hematopoiesis (the process of forming blood cells and components) occurs in several regions prior to the bone marrow. Recently, researchers have discovered that the placenta is a hematopoietic organ capable of
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Table 1 Recent studies using term PMSCs in regenerative medicine Source
Year
Author
Investigation
Experimental findings
Amnion
2010
Chang et al. [30]
Identified MSCs from the amniotic membrane mesoderm
AMSCs demonstrated MSC tri-lineage potential and neuronal differentiation in vitro
Amnion
2011
Sus¸ man et al. [31]
Evaluated the effect of co-culture technique on exocrine pancreatic cells and placental stem cells
AMSCs changed in phenotype from mesenchymal to epithelial-like cells and expressed pancreatic amylase
Amnion
2012
Warrier et al. [32]
Investigated the potential of AMSCs for wound healing and blood vessel formation
AMSCs have pro-angiogenic, anti-fibrotic, and low immunogenicity properties
Amnion
2013
Avanzi et al. [33]
Investigated the susceptibility of AMSCs to human herpes virus infection
AMSCs were fully permissive to infection from several herpes viruses
Amnion
2014
Carbone et al. [34]
Investigated the regenerative and reparative potential of AMSCs for treatment of lung diseases
AMSC reduced pulmonary fibrosis and inflammation in an in vivo bleomycininduced lung injury model
Amnion, chorionic villi, chorionic plate
2012
Lee et al. [35]
Compared the hepatogenic differentiation potential of PMSCs with AMSCs, BMMSCs, and UCB-MSCs
PMSCs showed higher hepatogenic differentiation efficiency than AMSCs, BM-MSCs, and UCB-MSCs
Amnion, chorion
2014
Kinzer et al. [36]
Evaluated the effects of PMSCs on neovascularization in a mouse model
PMSC/EC co-culture promoted neovascularization in the mouse model
Chorionic villi
2010
Fazekasova et al. [37]
Compared immunomodulatory properties of PD-MSCs to BM-MSCs
BM-MSCs were more immunomodulatory than PD-MSCs
Chorion
2011
Tran et al. [38]
Isolated CD349? and CD349- fractions from PMSCS and examined effect on fractured bone and blood flow in ischemic regions of mouse models
CD349? and CD349- fractions facilitated new bone calcification in fractured femurs
Chorionic plate
2012
Lee et al. [21]
Compared immunomodulatory function of CP-MSCs with that of BM-MSCs and ADMSCs
CP-MSCs secrete cytokines differently than BM-MSCs and AMSCS, and CP-MSCs may have advantages in regenerative capacity and immunomodulation
Decidua basalis
2012
Fan et al. [39]
Explored TEBs constructed by PMSCs and their effect for the repair of osteoperiosteal defects
TEBs constructed by both PMSCs and BMSCs repaired the osteoperiosteal defects in a ‘multipoint’ manner
Decidua Parietalis
2012
Castrechini et al. [29]
To determine if decidua parietalis is an MSC niche
Decidua parietalis can serve as a niche for vascular stem cells
Decidua parietalis
2013
Fukusumi et al. [40]
Examined PCM from DP-MSCs for longterm stable maintenance of IPSCs
PCM from DM-MSCs can be used for the feeder-cell-free generation and long-term stable maintenance of IPSCs
Decidua parietalis
2011
Kanematsu et al. [41]
Compared the cellular properties of DPMSCs and adult BM-MSCs
DP-MSCs showed high proliferation capacity, differentiated well into chondrocytes, and moderately well into adipocytes. DP-MSCs hardly differentiated into osteoblasts
Mixed
2014
Zhao et al. [26]
Investigated effect of PMSCs in reducing development of bronchiolitis obliterans in a murine heterotopic tracheal transplant model
PMSCs are protective against the development of bronchiolitis obliterans in a heterotopic tracheal transplant model
AMSC amnion-derived mesenchymal stem cells, BM-MSCs bone marrow-derived mesenchymal stem cells, CP-MSCs chorionic plate-derived mesenchymal stem cells, DP-MSCs decidua parietalis-derived mesenchymal stem cells, EC endothelial cells, IPSCs induced pluripotent stem cells, PCM pericellular matrix, PMSCs placenta-derived mesenchymal stem cells, TEB tissue-engineered bone, UCB-MSCs umbilical cord blood-derived mesenchymal stem cells
supporting hematopoiesis and certain key points in development [67, 68•]. While the placenta has not generally been known as a source for HSCs to be used in therapy, the new identification of these cells within the placenta may drive future research into the isolation and
potential expansion of HSCs from the placenta. One study identified CD34? CD45? cells that had clonogenic potential and were capable of generating myeloid and erythroid progenitors, as well as natural killer cells and B cells in vitro [68•]. The researchers noted, however, that
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Table 2 Recent publications using preterm PMSCs in regenerative medicine Year
Author
Tissue
Investigation
Experimental findings
2010
Sung et al. [58]
First-trimester (8–12 weeks) and third-trimester (38–40 weeks) chorionic plate amnion
Evaluated the proliferation capacity, phenotypic expression, mesoderm differentiation, and expression of pluripotency stem cell markers between preterm and term MSCs
Preterm PMSCs had better growth capacity and proliferation potential with the expression of pluripotency markers
2011
Poloni et al. [61•]
2012
Jones et al. [52••]
First-trimester (11–13 weeks) chorionic villi Preterm (8–12 weeks) and term chorionic villous
Evaluated susceptibility of PMSCs to malignant transformation after longterm culture Investigated whether preterm or term placental chorionic stem cells are superior for cell therapy and tissue engineering
Fetal MSCs can be expanded long term with no increase in telomerase activity and no evidence of genetic changes Preterm PMSCs have smaller size, faster kinetics, and more favorable genetic markers for use in regenerative medicine
2013
Park et al. [63]
First-trimester and thirdtrimester placenta
Compared the pluripotency of firsttrimester and third-trimester placenta
Preterm PMSCs have 2–11-fold higher expression of pluripotency-coupled genes than term PMSCs, implying greater differentiation potential
2013
Roselli et al. [62]
First-trimester (11–12 weeks) chorionic villi
Determined the genetic stability of chorionic villi in long-term culture
CV-MSCs are genetically stable in longterm cultures at least up to passage 10
2014
Di bernardo et al. [9]
Preterm (34–39 weeks) chorion
Investigated the effects of preterm PMSCs as a potential therapy for neonatal respiratory failure secondary to pulmonary hypoplasia
Preterm PMSCs enhanced perinatal lung growth
2014
Youssef et al. [59]
Preterm (10–13 weeks) and term (37–42 weeks) PMSCs
Investigated the impact of varying concentrations of oxygen tension and IGF-I on preterm and term PMSC multipotency
Preterm PMSCs had greater proliferation response to IGF-I, were enhanced by low-oxygen tension, and were more multipotent than term PMSCs
AMSC amnion-derived mesenchymal stem cells, BM-MSCs bone marrow-derived mesenchymal stem cells, CP-MSCs chorionic plate-derived mesenchymal stem cells, CV-MSC chorionic villi-derived mesenchymal stem cells, DP-MSCs decidua parietalis-derived mesenchymal stem cells), IPSCs induced pluripotent stem cells, PCM pericellular matrix, PMSCs placenta-derived mesenchymal stem cells, UCB-MSCs umbilical cord blood-derived mesenchymal stem cells
the presence of these cells peaked within 5–8 weeks gestation, making them a difficult source to obtain for cell therapy. Still, more research is needed to determine if HSCs can be obtained from the placenta later in gestation or even at term in order for the placenta to remain a viable option as a source of HSCs for future therapy.
derived neural stem cells were able to regenerate the dopaminergic nigrostriatal pathway in both acute and chronic Parkinson’s disease rat models. While this study indicates the great potential for these cells to be utilized for regenerative medicine, much work still needs to be done in order to understand the potential benefits of using trophoblasts as compared to other more commonly used cell types such as MSCs.
Trophoblast Stem Cells Trophoblasts are a cell population entirely unique to the placenta, and they arise from the trophectoderm layer of the blastocyst early in development and facilitate embryo implantation and formation of the placenta. They have been widely studied for their importance in the developmental process, but it may be possible to utilize isolated trophoblasts and TSCs for cell therapy. Lee et al. demonstrated the capability of TSCs obtained from ectopic pregnancies to differentiate into neural stem cells [69], and the study found that after transplantation, these trophoblast-
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Conclusion The placenta is a unique organ of fetomaternal origin that can serve as a source of multiple types of stem cells for autologous and allogeneic cell transplantation. PMSCs, AECs, HSCs, and TSCs can be isolated from different anatomic regions of the placenta, and these stem cells have great potential, due to their expansion rate, differentiation capability, secretion, and immunomodulation functions. However, more in vivo disease model research is needed to
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verify the safety and efficacy of placenta-derived stem cells for application in regenerative medicine. Compliance with Ethics Guidelines Conflict of Interest Jason A. Meierhenry, Volodymyr Ryzhuk, Maricel G. Miguelino, Lee Lankford, Jerry S. Powell, Diana Farmer and Aijun Wang declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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