The International Journal of Artificial Organs / Vol. 30 / no. 6, 2007 / pp. 541-549
Review
Mesothelial cell transplantation in myocardial infarction I. ELMADBOUH1,2, J.-B. MICHEL1, J.C. CHACHQUES2 1 2
Inserm unit 698, Cardiovascular Remodelling, CHU Xavier Bichat-Claude Bernard, Paris - France Department of Cardiovascular Surgery, European Hospital Georges Pompidou, University of Paris-5, Paris - France
ABSTRACT: Mesothelial cells (MCs) are accessible in human patients by excision and digestion of epiploon or from peritoneal fluid or lavage. MCs are easy to culture to obtain large quantities in vitro and they can be genetically modified with interesting therapeutic genes. The important potential of MCs in tissue engineering has been shown during epiplooplasty to different organs and also in creating artificial blood conduits. MC of epicardium is probably the precursor of coronary arteries during embryogenesis. MCs secrete a broad spectrum of angiogenic cytokines, growth factors and extracellular matrix, which could be useful for repairing damaged tissues. MCs are transitional mesodermal-derived cells and considered as progenitor stem cell, have similar morphological and functional properties with endothelial cells and conserve properties of transdifferentiation. MC therapy in myocardial infarction induced neoangiogenesis in infarcted scar and preserved heart function. In conclusion, a potential therapeutic strategy would be to implant or re-implant genetically modified MCs in post-infarction injury to enhance tissue repair and healing. Imparting therapeutic target genes such as angiogenic genes would also be useful for inducing neovascularization. (Int J Artif Organs 2007; 30: 541-9) KEY WORDS: Cells, Cell therapy, Gene therapy, Myocardial infarction, Angiogenesis, Myocardium regeneration
INTRODUCTION Certain organs such as the heart, brain, liver and skeletal muscles have resident stem cells that participate in tissue repair for any minor damage. Previously, the cardiomyocyte was thought to be terminally differentiated (1). These ideas are challenged by recent work suggesting that large numbers of Y chromosome-positive cells are present in hearts in which a female heart is transplanted into a male subject (2-4). The Y-cells may be derived from circulating stem cells released from bone marrow that “home” to the transplanted heart (5). Alternatively, these cells may be derived from “cardiac” stem cells resident in remnants of recipient heart (i.e, atrial stump) that have migrated into the donor heart. Although the cardiac stem cells did not express markers suggesting a hemopoietic or endothelial lineage, there is still the possibility these cells were derived from other sources such as the bone marrow (3). The cells might represent a local
resident cardiac stem cell population derived from the mesothelium of epicardium, from which it has been proposed that a subset of progenitor cells is able to migrate into the myocardium and differentiate into different cardiac cell types including new blood vessels or any cell comprising the whole organ (6). Recently, preclinical and clinical cell transplantation into myocardial infarction revealed that satellite skeletal myoblast could differentiate into muscle cells; bone marrow cells and its derivative can differentiate into endothelial and blood cells (7, 8). Transplanted endothelial cells stimulated angiogenesis and were incorporated into the new vessels (9), whereas, the transplanted stromal cells differentiated in situ and contributed about 10-22% of the endothelial cells of newly formed blood vessels plus having cardiomyogenic differentiation potential (10). Mesothelial cell (MC) transplantation can participate in new blood vessel formation (11). Most human potential donor cells are difficult to isolate, purify and expand ex vivo and do not yield adequate
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numbers of cells for transplantation (7, 12). Some donor cells even have deleterious effects and lead to complications such as arrhythmia, calcification, teratoma or tumor formation (12). Therefore, it is of interest to explore the effect of MC seeding in cardiovascular diseases.
Mesothelial cell characterization The two forms of mesothelial cells, squamous-like and cuboidal cells, show differences ultrastructurally. Mesothelial cells are bipolar or multipolar in appearance but at confluence they adopt a cobble stone appearance and also become increasingly fibroblast-like with repeated passage. These cells are predominantly elongated, flattened, squamous-like cells, approximately 25 µm in diameter, with the cytoplasm rising over a central round or oval nucleus (13, 14). Static mesothelial cells, ranging in diameter from 16 to 40 µm, have thin cytoplasm and a centrally placed, small, round nucleus. When the serosa is injured, MCs undergo remarkable morphological changes and display features of reactive mesothelial cells (RMCs). RMC have thick cuboidal cytoplasm and a large, round nucleus, and may be multinucleated or stratified. These features often make it difficult to distinguish RMC from adenocarcinoma cell in cytological preparations. There are no clear morphological boundaries between static mesothelial cells and RMCs, mesothelial cells having a minor axis of nuclei measuring 8 µm as RMC (15). In particular, cuboidal cells have abundant mitochondria and rough endoplasmic reticulium, a well developed Golgi apparatus, microtubules and a greater number of microfilaments that are located parallel to the cell surface and suited deep to the cytoplasm, compared to squamous cells, suggesting a more metabolically active state (16). MCs could be distinguished from other cells by using monoclonal antibodies directed against human pancytokeratin (i.e. types 7, 8, 18, 19 and clone MNF116) (Fig. 1A, B), (17, 18) and also human vimentin V9. Anticytokeratin and anti-vimentin immunoreactivity was positive in RMCs and negative in static mesothelial cells. Lectin DSA reactivity was significantly higher in static mesothelial cells than in RMC. The morphological differences between static mesothelial cell and RMC are likely to be due to differences in cytoskeletal composition, with accompanying changes in cell-surface lectin-binding patterns (15).
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Some MCs are positive immunostained with monoclonal antibodies specific for endothelial cells (anti-CD34) (19).
Healing process after mesothelium injury The mesothelium has shown to be damaged upon peritonitis, surgery or biopsy, chronic inflammation, and after long-term peritoneal dialysis in patients (20). Under normal conditions, serosal healing is completed within 710 days (21). The process of remesothelialisation and the origin of new mesothelial cells remain controversial. New mesothelium was derived from mature mesothelial cells, which detach from the opposing peritoneal surface (21), migrate from the border of the injury (21), or originate from a free-floating mesothelial cell/progenitor in serosal fluid (17). Serosal injury can lead to the formation of internal scars or adhesions (20). This is supposed to be the main regeneratory mechanism, particularly if the basement membrane is intact. Following such an injury, the polygonal epithelial-like cells temporarily transform into a spindle-shaped fibroblastic morphology. These cells attach or migrate to the defect, where they later become flattened to cover the surface (17). Mesothelial regeneration has also been assumed to occur from fibroblast-like multipotential subserosal cells. Particularly when the basement membrane is affected, these cells are supposed to migrate to the surface, during which process they gradually acquire epithelial characteristics (22). Some gene products may be useful markers for differentiation and activation in serosal tissue (23). In contrast, some changes in the human peritoneal mesothelial cells occur during aging (24).
Mesothelial cells participate during embryology of blood vessels Vascular systems of the heart and gut have several striking similarities. Most significantly, the major vessels to the heart and gut run on the surface of the organ and are intimately associated with their mesothelial covering. Blood vessel development in coelomic organs has been observed in many studies, such as those encased in the pericardial and peritoneal cavities. These studies have shown that the mesothelial covering of the embryonic heart (the proepicardium and its derivative the epicardium) is a major source of cells to the coronary system (25).
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Fig. 1 - Identification of transplanted mesothelial cell (MC) in vitro and in vivo. Cultured MCs were typical “cobblestone” appearance (A, X400), and stained by cytokeratin (B, X400) in vitro. In infarcted scar, some grafted MCs still expressed cytokeratin at 15 (C, X400) and 30 days (D, X600). Some MCs were proliferating within the scar (PCNAcytokeratin positive double stained) and in vessel luminal position (E, X400). Some DAPI-positive cells were localised in luminal position of blood vessels 1 month after injection of DAPI-labeled MCs (F, arrow head).
Similarily, blood vessels of gut were derived from serosal mesothelium (26). It has been shown that mesotheliumderived cells can transdifferentiate into endothelial cells in the liver with remaining transient cytokeratin expression (6, 25). Subsequently, a sub-population of these cells undergoes epithelial-mesenchymal transition, migrates within the heart or gut, and gives rise to vascular smooth muscle cells that populate all major vessels of heart or gut (25, 26). MCs are transitional mesodermal-derived cells, but share similar morphological and functional
properties with endothelial cells (27) and conserve properties of transdifferentiation (28). MCs become endothelial-like by transdifferentiation to take on the endothelial phenotype in situ. It has been shown that mesotheliumderived cells can transdifferentiate into endothelial cells in the liver and that the precursors of the coronary endothelium are probably derived from epicardial mesothelial cells, which are able to differentiate into fibroblasts, endothelial, smooth muscle and valvuloseptal mesenchymal cells (6, 25, 28).
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Adult mesothelial progenitor “stem” cells Adult MCs are capable of transdifferentiating from an epithelial to mesenchymal phenotype and this seems to depend on the presence of certain growth factors or cytokines (29, 30). However, in light of recent findings it is also possible that a population of MCs may have the ability to form cells of different mesenchymal lineages. These progenitor cells may be resident in the mesothelial layer, free-floating in the serosal fluid or alternatively, may be derived from a circulating multipotential cell population, which enters serosal cavities via vasculature. Growth factor levels, cell-cell interactions, cell density and physical and mechanical stimuli may all contribute to the end product of differentiation, for example, levels of cytokines and growth factors, proteases, oxygen, and pH, may also affect ultimate progenitor cell fate (28). Numerous studies suggest that a mesothelial cell progenitor exists (31). One of studies in which mice were denuded of their mesothelial cells and engrafted with an enriched population of c-kit+, Sca+, Lin- bone marrow cells (mesenchymal stem cells) of donor mice has indicated a possible mesothelial progenitor cell in the bone marrow (32).
Mesothelial cell transplantations used previously in other models Successful mesothelial cell transplantation has been reported after acute inflammation, chronic inflammation and after surgery in various animal models and even in patients on peritoneal dialysis. These promising results suggested that mesothelial cell transplantation might offer an excellent approach to preserve the integrity and improve the performance of the peritoneal membrane during the resolution phase of peritonitis (20, 33, 34). Transplantation of mesothelial cells has recently been performed using mesothelial cells preembedded in collagen matrix, to be incorporated onto denuded areas of the peritoneal membrane (35). Exploitation of mesothelial progenitor cells may offer a challenging therapeutic approach for both surgery and peritoneal dialysis (36). The mesothelial layer is extremely important because it possesses fibrinolytic and anticoagulant activity (37), and intraperitoneal transplantation of mesothelial cells in vivo is an effective way of reducing the formation of adhesions 544
after peritoneal abration (33, 34). Also, transplanted MC sheets, fabricated from cells isolated from the tunica vaginalis, have effectively prevented adhesion formation in a rat hernia model (14). Mesothelial cells behaved like endothelial cells derived from veins when seeded onto polytetrafluoroethylene prostheses in patients, showing high levels of prostacyclin production (19, 27). Synthetic grafts seeded with mesothelial cells have been reported to have a high patency rate similar to grafts seeded with endothelium (38). However, the mesothelial cells can be successfully seeded on Dacron arterial prostheses (39). Thus mesothelial cell seeding might be useful in promoting a healed graft surface. In dogs bilateral superficial femoral artery replacement using knitted Dacron have been performed, with luminal release of prostacyclin and 6-ketoprostaglandin F1 alpha than control (40).
Mesothelium used as graft for tissue engineering An artificial blood conduit of any required length and diameter can be manufactured from the cells of the host for autologous transplantation. These grafts (silastic tubing) are inserted into the peritoneal cavity of rat and rabbits for 2 weeks. This tube resembled the blood vessel with an inner layer of nonthrombotic mesothelial cells (endotheliumlike “intema”), with a “media” of smooth muscle–like cells (myofibroblasts), collagen and elastin, with an outer collagenous “adventitia”. These novel vascular grafts have been used as autologous coronary artery bypass grafts or as arteriovenous access fistulae for hemodialysis patients (41, 42). Whether prior seeding of vascular scaffolds with mesothelial cells isolated from the omentum or peritoneal fluid is a better method for generating tissue engineered grafts awaits further investigating. Until then, the use of mesothelial cells as endothelial cell replacements still remains a possibility and may prove important in, for example, the development of autologous coronary artery bypass grafts or arteriovenous access fistulae for hemodialysis patients. Part of the omentum’s ability to “rescue” injured tissue is likely to be due to its angiogenic (43) and neurotrophic properties (44), hence, its use as a pedicle graft tissue for clinical conditions involving revascularization of ischemic parts of the brain, kidney, spleen, heart and spinal cord (45, 46). Epiplooplasty, a common surgical approach in
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various pathologies, could be used as a source of mesothelial cells for autologous cell therapy applicable in humans in the prevention of infarct scar remodeling (45). Free omental grafts may be used to facilitate nerve graft regeneration in rats by surrounding the nerve graft with omentum. The use of nerve replacements composed of artificial tubes seeded with isolated mesothelial cells as an alternative to primary nerve suture has been introduced as a biological approach to nerve injuries (47).
Mesothelial cell-based gene therapy in myocardial infarction Cell therapy proposed for myocardial regeneration has been to perfuse the hibernating cells (angiogenesis) and replace the lost cells (myogenesis) (48-50). The choice of cell type may depend upon the injury. In the early post-MI patient where reperfusion is the primary objective, angiogenic cells such as bone marrow-derived cells, mononuclear or peripheral blood progenitor cells, angioblasts, endothelial or mesothelial cells are a logical choice (7, 8, 11). However, in patients with end-stage heart failure where restoration of contractile function is the clinical goal, myogenic cells are a logical cell choice where myogenesis is needed. Theoretically, heart cells are the most ideal contractile cells but they are not feasible for clinical use. Other potential contractile cells such as myoblasts, smooth muscle cells, cardiac stem cells, embryonic cells or other mesenchymal progenitors driven down a muscle lineage may also be of use (7). Combination of cell therapy with either protein or plasmid of angiogenic genes, have also been used in different animal models and clinical applications (51). Also, donor cells were genetically modified by transfection with therapeutic targets plasmid ex vivo, using viral or non-viral gene delivery agents, and
subsequently re-implanted back into the subject (52-54). Mesothelial cells have excellent secretory function following transfection and can devote up to 3% of their total proteins synthesis to a single secreted protein (35, 55). Thus, mesothelial cells may be suitable clinical tools for ex vivo gene therapy due to the fact that they are easy to biopsy, propagate, genetically engineer in culture and transplant, and they also express systemic therapeutic proteins at useful levels as shown in Table I. MCs were selected as a source of non-cardiac cells for transplantation into infarction scars for several reasons: i) MCs are easy to culture to obtain large quantities in vitro. They are abundant as they cover the internal surface of the three body cavities (i.e pleural space, the pericardium and peritoneum) and constitute a total surface area of 1-2 square meters in humans. The covering of the internal organs is referred to as the visceral mesothelium, whereas the lining of the body cavities is known as the parietal mesothelium (13, 18). Human MCs can be safely obtained by laparoscope-assisted needle aspiration from normal peritoneal fluid present in the cul-de-sac region of the lower peritoneal cavity, or from collection of peritoneal lavage during abdominal surgery or excision of epiploon by a celioscopic biopsy and cell cultured (27, 56). ii) MCs are similar to and behave as endothelial cells (57). iii) The mesenchymal cellular precursors of coronary arteries such as endothelial cells, vascular smooth muscle cells and advential fibroblasts orginate from an epithelial-mesenchymal transformation of the mesothelium of epicardium (25). Therefore, the mesothelial cells have a potential angiogenic effect. iv) MCs have several functions involving production of cytokines such as stromalderived factor (SDF-1 α) (11, 58), and a variety of the growth factors as reported in several studies in vitro such as vascular endothelial growth factor (VEGF) (59), basic fibroblast growth factor (bFGF) (60), Transforming growth
TABLE I - MESOTHELIAL CELL-BASED GENE TRANSFER IN DIFFERENT EXPERIMENTAL MODELS Type of cells
Species of cells
Vectors
Target gene
Mode of delivery
Experimental model
Reference
Peritoneal Peritoneal Peritoneal, cell lines
Rat Human
Retrovirus Adenovirus
LacZ reporter gene Human growth factor
Intraperitoneal Intraperitoneal
Denuded peritonium Athymic mice
18 56
Human
Naked plasmid
HSVTK/GCV
Mouse ovarian cancer
57
Peritoneal Peritoneal Peritoneal
Human Rat Rat
Retrovirus Adenovirus Non-viral cationic vector
Erythropoietin LacZ reporter gene SEAP reporter gene
Intraperitoneal cell seeding in ovary Intraperitoneal Intraperitoneal Intramyocardial
Uremic mice Acute and chronic peritonitis Infarcted scar
35 34 11
HSVTK/GCV: herpes simplex virus thymidine kinase/ganciclovir; SEAP: secreted alkaline phosphatase.
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factor (TGF-β) (61, 62), platelet derived growth factor (63), insulin-like growth factor (64), hepatocyte growth factor/scatter factor (65, 66), epidermal growth factor (67), endothelin-1 and keratinocyte growth factors (66). v) MCs produce extracellular matrix constituents (68) such as cytokeratin 7, 8, 18, 19 and vimentin, E-, N-, and Pcadherins (69), zonula occludens-1 proteins and synthesize fibronectin, laminin, α-actin, vinculin; non-specific esterase and collagen type I and III in an in vitro study (17, 28). vi) MCs also have anti-inflammatory and immunomodulatory properties which are mediated by secreting SDF-1α (70), prostaglandins (cyclooxygenase) and prostacycline (71, 72), surfactant proteins types A and D (73), plasminogen activator inhibitor-1 (71, 74) and tissue inhibitor of metalloproteinases (13, 28). Taken together, the angiogenic, anti-inflammatory and their production of many proteins can be useful to repopulate myocardial infarction, all of which could be useful for decreasing LV remodeling (70, 75).
Mesothelial cells for myocardial regeneration in animal models In cellular cardiomyoplasty the mortality of implanted stem cells is important due to the reduced irrigation of infarcted scars. In the past, omentum flaps have been used to increase the vascularization of ischemic hearts. In rat models, MCs can survive after transplantation in MI and express a potential therapeutic gene (SEAP reporter gene using cationic non-viral vector) for short period up to 10 days, and the grafted MCs identified by cytokeratin positive one month post implantation with some proliferating cells (PCNA-positive) incorporated in neovessels observed in double staining (cytokeratinPCNA). Some of MCs labeled by DAPI were observed in a luminal position of large and small vessels in some MCimplanted hearts (Fig. 1C-F). SDF-1α levels were higher in transplanted groups indicating that MCs promote neovasculogenesis with a significant improvement of cardiac function and preservation of heart function (11). Recently, we applied autologous MC transplantation (80 million cells/sheep) in infarcted scars in a large model. In 22 sheep, a LV myocardial infarction was created by surgical ligature of 2 coronary branches (for developing reasonable infarction scars after 3 weeks) (76). This study evaluated and compared the histological and hemodynamic evolution of myocardial infarcts treated with
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mesothelial angiogenic cells (isolated from the omentum) with infarcts treated with skeletal myoblasts. In both cell treated groups echocardiographic studies at 3 months showed significant limitation of ventricular dilatation and improvement of ejection fraction (EF%). In the group treated with mesothelial cells, histologic studies showed a significant angiogenesis and arteriogenesis (increased number of capillaries and arterioles) compared to control and myoblast groups. Furthermore, mesothelial cells limited postischemic LV remodeling, improved EF% and induced neovascularization of infarcted areas in a large animal model of ischemic heart disease. These cells could be proposed for the regeneration of hibernating and partially ischemic myocardium.
Future perspectives Recently, attempts to induce neovascularization have raised appropriate concerns regarding the possibility of inducing unwanted or pathological vessel growth. These safety concerns will undoubtedly influence the choice of transplantable cells, type of vectors, method of gene transfer, therapeutic target gene and method of delivery for gene therapy. Thus far, with more than 900 patients treated in various trials of angiogenic gene-and cellbased therapies, there has been no indication of increased cancer incidence, retinopathy, or acceleration of atherosclerosis. It is reasonable to assume that we would obtain the maximum synergestic angiogenic effect in the infarcted scar when MCs are transfected ex vivo by angiogenic genes such as VEGF, FGF, SDF-1α, TGF1β, etc. In the future, mesothelial cells could be seeded alone or transfected ex vivo with the SDF-1α gene, into the myocardial scar. The synergistic transient overexpression of SDF-1α from this combination of gene and cell therapy in the scar should increase the concentration gradient of SDF-1α in the heart. The chemotactic activity of the SDF-1α should then promote the mobilization of stem cells from bone marrow and cause their homing and recruitment in the peri-infarct zone. Moreover, mesothelial cells can transdifferentiate into an endothelial phenotype and participate in angiogenesis and vasculogenesis within the infarct scar. In conclusion, our data highlight the suitability of MCs for clinical applications and open up new perspectives in the search for therapeutic strategies.
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Address for correspondence: Juan Carlos Chachques, MD Department of Cardiovascular Surgery European Hospital Georges Pompidou 20 rue Leblanc 75015 Paris, France e-mail:
[email protected]
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