Stem Cell Therapy for Cardiac Repair
2006; Lippincott Williams & Wilkins; Volume: 114; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.105.590653
ISSN1524-4539
AutoresAndrew Boyle, Steven P. Schulman, Joshua M. Hare,
Tópico(s)Electrospun Nanofibers in Biomedical Applications
ResumoHomeCirculationVol. 114, No. 4Stem Cell Therapy for Cardiac Repair Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBStem Cell Therapy for Cardiac RepairReady for the Next Step Andrew J. Boyle, MBBS, PhD, Steven P. Schulman, MD and Joshua M. Hare, MD Andrew J. BoyleAndrew J. Boyle From the Department of Medicine, Division of Cardiology, Institute for Cell Engineering, and Specialized Center for Cell-Based Therapy, The Johns Hopkins University School of Medicine, Baltimore, Md. , Steven P. SchulmanSteven P. Schulman From the Department of Medicine, Division of Cardiology, Institute for Cell Engineering, and Specialized Center for Cell-Based Therapy, The Johns Hopkins University School of Medicine, Baltimore, Md. and Joshua M. HareJoshua M. Hare From the Department of Medicine, Division of Cardiology, Institute for Cell Engineering, and Specialized Center for Cell-Based Therapy, The Johns Hopkins University School of Medicine, Baltimore, Md. Originally published25 Jul 2006https://doi.org/10.1161/CIRCULATIONAHA.105.590653Circulation. 2006;114:339–352Coronary heart disease and heart failure continue to be significant burdens to healthcare systems in the Western world. In the United States alone, there are 7.1 million survivors of myocardial infarction (MI) and 4.9 million people living with congestive heart failure (CHF).1 Despite recent advances in medical and device therapy for heart failure, the incidence, hospitalization, and mortality rates continue to rise. After receiving a diagnosis of CHF, 1 in 5 patients will be dead within 12 months.1 Therefore, any new treatment modality that benefits heart failure patients has the potential to result in a dramatic improvement in health outcomes and substantial cost savings for the community.Response by Oettgen p 352The possibility of using stem cell–based therapies for people suffering an acute MI or living with CHF has captured the imagination of both the medical and popular communities. Since early reports in animal models >10 years ago,2,3 the stem cell field has made enormous advances in moving toward clinically applicable treatment options, and we now stand at the dawn of a new therapeutic era. An abundance of preclinical data demonstrate safety, feasibility, and efficacy, justifying the current entry into clinical trials of stem cell therapy in humans.4–8 This position, however, is extremely controversial, with some arguing that trials are premature because mechanistic insights are insufficiently addressed.9,10 Here, we argue that properly conducted rigorous clinical trials are a key and appropriate next step not only to start the long process of therapeutic development but also as an essential component in the process of understanding the scientific underpinnings of cardiac regeneration and its therapeutic utilization. The field of regenerative medicine will advance through the parallel conduct of in vitro/animal model studies and clinical trials, the latter frequently guiding the former.The publication of Menasche et al11 describing the first patients to receive skeletal myoblasts spawned a profusion of small clinical studies investigating cellular therapy for cardiac repair. At present, a number of early clinical studies have been published and are summarized in Table 1. Several points are immediately apparent from this table. First, >400 patients have completed these published studies, yet most of them are small pilot studies that lack randomization or control groups. Second, despite the fact that several cell types have been studied using different delivery methods, the overwhelming message from all of these studies is that cell therapy is safe and feasible. In addition, the results of these studies provide encouraging, albeit preliminary, signs of efficacy. Finally, although these trials represent the currently published data, they have formed the basis for numerous larger, ongoing trials accruing more patient data (Table 2). TABLE 1. Clinical Studies of Stem Cell Therapy for Cardiac RepairStudyTreated, nCell TypeMode of DeliveryRandomizedPrimary End PointPCPC indicates circulating progenitor cell; GCSF, granulocyte colony stimulating factor; PBMNC, peripheral blood mononuclear cell; CFR, coronary flow reserve; and LVEF, LV ejection fraction.Strauer et al 5010BMMNCsIntracoronary−SafetyNATOPCARE-AMI51,5259BMMNCs/CPCsIntracoronary+/−Safety and feasibilityNAStamm et al103,10412BMMNCsOpen heart surgery−Safety and feasibilityNATse et al1058BMMNCsEndomyocardial−Safety and feasibilityNAPerin et al5614BMMNCsEndomyocardial−SafetyNABOOST5330BMMNCsIntracoronary+LVEF0.0026Fernandez-Aviles et al10620BMMNCsIntracoronary−Safety and feasibilityNALi et al1076BMMNCsOpen heart surgerySafety and feasibilityNAIACT study10818BMMNCsIntracoronary−Not statedNAJanssens et al5433BMMNCsIntracoronary+LVEF0.36Chen et al7234MSCsIntracoronary+LVEF0.01Katritsis et al10911MSCs+EPCsIntracoronary−Scar size0.02Galinanes et al11014Bone marrowOpen heart surgery−SafetyNAFuchs et al11110Bone marrowEndomyocardial−Safety and feasibilityNAMAGIC cell11220GCSF-mobilized PBMNCsIntracoronary+Safety and feasibilityNAOzbaran et al1136GCSF-mobilized PBMNCsOpen heart surgery−Safety and feasibilityNAErb et al7813GCSF-mobilized CPCsIntracoronary+CFR and LVEF<0.05Boyle et al1145GCSF-mobilized CD34+Intracoronary−Safety and feasibilityNAPompilio et al1154GCSF-mobilized AC133+Open heart surgery−Safety and feasibilityNADib et al11630Skeletal myoblastsOpen heart surgery−Safety and feasibilityNAPOZNAN11710Skeletal myoblastsTranscoronary-venous−Safety and feasibilityNAInce et al1186Skeletal myoblastsEndomyocardial−Safety and feasibilityNASiminiak et al4510Skeletal myoblastsOpen heart surgery−Safety and feasibilityNASmits et al1195Skeletal myoblastsEndomyocardial−Safety and feasibilityNAMenasche et al4410Skeletal myoblastsOpen heart surgery−Safety and feasibilityNAPagani et al1205Skeletal myoblastsOpen heart surgery−HistologyNAHerreros et al12112Skeletal myoblastsOpen heart surgery−Safety and feasibilityNATABLE 2. Clinical Trials of Stem Cell Therapy for Cardiac Repair Registered With ClinicalTrials.govCell Type UsedTrial Design, PhaseCondition TreatedRandomizedTotal Patients to Be Enrolled, nPrimary OutcomeSponsorRegionCABG indicates coronary artery bypass grafting; VAD, ventricular assist device.Intramyocardial autologous MSCsI/IIMyocardial ischemia−40PerfusionRigshospitaletCopenhagen, DenmarkAutologous BMMNCsICHF undergoing CABG+75LV functionUniversity of PittsburghPittsburgh, PaAutologous BMMNCsICHF undergoing VAD implantation−10LV functionUniversity of PittsburghPittsburgh, PaIntramyocardial BMMNCsIIschemic cardiomyopathy+30SafetyTexas Heart InstituteTexasIntracoronary BMMNCsIAcute MI+60SafetyMinneapolis Heart Institute FoundationMinneapolis, MinnIntravenous MSCsIAcute MI+48SafetyOsiris TherapeuticsMulticenter, United StatesAutologous Intramyocardial CD34+IChronic myocardial ischemia+24Not statedSt Elizabeth's Medical CenterBoston, MassAutologous CD34+I/IIChronic myocardial ischemia−10PerfusionTranslational Research Informatics Center, JapanKobe, JapanIntramyocardial autologous BMMNCsIIIschemic cardiomyopathy−35LV functionOdense University HospitalOdense, DenmarkIntracoronary autologous BMMNCsIIAcute MI+100Myocardial viabilityNantes University HospitalNantes, FranceIntramyocardial autologous skeletal myoblastsIIschemic cardiomyopathy−15SafetyBioheartMulticenter, United StatesIntramyocardial autologous skeletal myoblastsIIIschemic cardiomyopathy+Not statedLV functionGenzymeMulticenter, Europe/United KingdomIntramyocardial autologous skeletal myoblastsIIschemic cardiomyopathy undergoing CABG−15SafetyBioheartMulticenter, United StatesMechanism of Action of Stem CellsOne of the major obstacles in progressing to large-scale clinical trials of cardiac stem cell therapy is the ongoing debate regarding the mechanism of action by which stem cell therapy leads to cardiac repair. The classic idea that provided the primary motivation for stem cell therapy is that delivery of the appropriate stem cells would repair a damaged heart via active myocardial regeneration resulting from transdifferentiation of the administered stem cells.4,12–14 However, new data have led to the recognition of alternative mechanisms of action (Figure 1): Exogenous stem cells may also stimulate proliferation of endogenous cardiac precursors or stem cells through neovascularization6,15 or paracrine signaling actions.16 In fact, observations in preclinical and clinical scenarios that all of these events occur allow us to generate a new concept that cellular therapy contributes to the restoration of stem cell niches, facilitating the ability of the heart to heal itself.17 Still other mechanisms are proposed: Exogenous stem cells may lead to cardiac repair via fusion of donor cells with host cardiomyocytes.18 Finally, other investigators suggest that the effects of stem cells are mediated by altering mechanical properties to strengthen the MI scar, thereby preventing deterioration in cardiac function19 (see Figure 1). This ongoing debate about mechanism fuels the case for slowing the pace of clinical trials; ie, we should not pursue work in patients until we thoroughly understand, with a high degree of scientific precision, the outcome of cell therapy in in vitro systems and animal models.9,10 We would suggest that we have reached the appropriate point in the development of cellular therapeutics to enter into the clinic; in fact, entry into the clinic is the next step that will guide our understanding of the mechanistic underpinning for effective cellular therapeutics. Download figureDownload PowerPointFigure 1. Possible mechanisms for successful cardiac regenerative therapy. See text for details.Types of Cells Contemplated for Cellular Regenerative TherapyEmbryonic Stem CellEmbryonic stem (ES) cells are derived from the inner cell mass of the blastocyst-stage embryo, late in the first week after fertilization. They are considered to be pluripotent, able to give rise to many different cell lineages. For cardiac regeneration therapy, there is a growing body of knowledge from animal models regarding the steps of isolation, differentiation, and clinical application.Human ES cells differentiate into spontaneously beating cells with a cardiomyocyte phenotype. The morphology and ultrastructure of these cells are organized with sarcomeric structures, formation of intercalated disks, desmosomes, and gap junctions, characteristic of cardiomyocytes,20,21 and they demonstrate the presence of a functional syncitium with action potential propagation.21,22 When transplanted into infarcted myocardium, ES cell–derived cardiomyocytes engraft and improve cardiac function in several rodent models.23–26 In the failing heart, in addition to replenishing cardiomyocytes by ES–derived cells, a simultaneous increase in the blood supply may be necessary for optimal and prolonged engraftment. Hence, it is of interest that ES cells differentiate to all cell lines necessary for formation of new blood vessels. Both murine and human ES cells spontaneously differentiate to form endothelial and smooth muscle cells in vitro27 and in vivo.28,29 To date, no human clinical studies have been initiated because of both the ethical issues surrounding access to embryos and the possibility of teratoma formation, suggested by a study injecting ES cells in skeletal muscle.30Resident Cardiac Stem CellsIn recent years, compelling evidence has accumulated suggesting that the heart has endogenous regenerative potential. Recent studies have isolated, from both human and murine hearts, undifferentiated cells that are clonogenic, express stem and endothelial progenitor cell (EPC) antigens/markers, and appear to have the properties of adult cardiac stem cells.31,32 These cells most likely mediate endogenous mechanisms for minor repair and for replacement of ongoing cell turnover within the adult heart. More importantly, they may represent a therapeutic target that, if enhanced, could induce cardiac self-repair.These cells have been phenotyped using different antigenic approaches. In a seminal report published in 2003, Beltrami and colleages31 separated c-kit–positive cells from the rat heart and demonstrated their clonogenicity and multipotency in vitro, as well as their capacity to participate in cardiomyocyte and blood vessel regeneration after MI. Subsequently, Oh and coworkers32 separated resident murine cardiac stem cells on the basis of the presence of stem cell antigen-1. They also demonstrated in vitro and in vivo myocardial differentiation of these cells and provided evidence supporting the fusion of these cells. In 2004, Messina and coworkers33 reported on the identification of cardiospheres, clusters of self-adherent cells that grew from cultured adult cardiac tissue derived from both human and murine hearts. These cells were shown to be clonogenic and capable of transdifferentiation in vitro, and they induced both myocardial and vascular regeneration after MI. Laugwitz and colleagues34 isolated a population of cardiac precursor cells from postnatal mouse hearts using isl-1 transcription factor as a cell marker. These cells are c-kit– and stem cell antigen-1–negative but are capable of differentiation into cardiomyocytes with electrical and contractile properties. Finally, Martin et al35 identified a side population of cells (SP cells) in the developing heart and adult heart that are capable of proliferating and differentiating into cardiac and hematopoietic lineages in vitro. These cells were identified on the basis of expressing Abcg2, an ATP-binding cassette transporter, rather than by detection of surface markers.Cardiac stem cells can be harvested from patients and expanded ex vivo to generate large numbers of cells. A recent report by Urbanek and colleagues36 demonstrated that cardiac stem cells increase in number immediately after MI, but in the chronic phase, the numbers fall, and the remaining cardiac stem cells have less regenerative potential. This suggests that the left ventricular (LV) dysfunction in ischemic cardiomyopathy may be due to a defect in or deficiency of functionally competent cardiac stem cells. In addition, Mouquet et al37 have recently shown in an experimental study that bone marrow may represent a reservoir for cardiac stem cells and suggested that depletion of this reservoir could contribute to diminished reparative capacity.To date, there are no clinical trials of human cardiac stem cells. However, Smith et al38 demonstrated that cardiospheres could be grown from human endomyocardial biopsy specimens. These cardiospheres represent an easily accessible option for autologous stem cell therapy, making the possibility of clinical testing of this approach feasible. The Specialized Centers for Cell-Based Therapy initiative of the NHLBI has funded clinical trials of cardiac stem cells that should begin in the near future.Skeletal MyoblastsAutologous skeletal myoblasts are another potential source for cardiac repair because of their biological properties and lack of ethical and immunological problems. Skeletal myoblasts or satellite cells are the reservoir of regenerative cells for skeletal muscle tissue; they have the ability for self-renewal and differentiation if muscle injury occurs.39 They have many desirable features as donor cells, including the ability to be amplified in an undifferentiated state in vitro and high resistance to tissue ischemia. They also have been shown to continue proliferation in vivo to a certain extent, which gives rise to a larger graft size.3 Satellite cells are committed solely to the myogenic lineage. Therefore, regardless of environmental influences, even if implanted into a scar made up mainly of fibroblasts, myoblasts differentiate into functional muscle cells. A growing body of experimental data and initial clinical studies has shown not only engraftment of donor cells but also improvement in global cardiac pump function.8,11,40–42 However, the exact mechanism by which they improve LV function is still debated. There may be beneficial effects of contracting noncardiac myocytes, some paracrine actions and an effect on scar strengthening to prevent LV dilatation and remodeling.43 The critical importance of progressing to clinical trials is underscored by the early clinical experience with skeletal myoblasts. Myoblast transfer in early studies44,45 was associated with sustained ventricular tachycardia, a life-threatening arrhythmia. This finding guided changes in future protocols involving skeletal myoblasts, which now require prophylactic cardioverter-defibrillator implantation and/or amiodarone therapy to prevent ventricular tachycardia. This protocol change resulted in less frequent clinically evident arrhythmias and is a powerful demonstration of how clinical trials are integral in guiding and refining the way in which stem cell therapy should be administered in patients. Phase II studies of skeletal myoblast therapy are presently underway.Human Adult Bone Marrow–Derived Stem CellsThe observation that bone marrow elements contribute to cardiac repair in the infarcted heart served as the rationale for adult bone marrow cell therapy after MI. Jackson and coworkers46 transplanted wild-type mice with green fluorescent protein (GFP)–positive bone marrow and then induced MI through coronary artery ligation and reperfusion. They demonstrated that bone marrow elements contributed to cardiomyocyte and endothelial cell formation after MI by finding GFP-positive cardiomyocytes and endothelial cells. It appeared that there is an intrinsic repair mechanism for minor cardiac damage within the bone marrow but that it is not adequate to repair larger amounts of damage such as that after MI. Substantial effort has been expended to try to enhance this endogenous repair mechanism and use bone marrow as a potential source of stem cells for cardiac repair. Orlic and coworkers4 have shown that lineage-negative, c-kit–positive bone marrow–derived cells differentiate into new cardiomyocytes after MI. This regenerative therapy can be harnessed by either direct injection into the peri-infarct rim of functioning myocardium or by using chemoattractant cytokines to mobilize the cells from bone marrow. In 1 experiment, bone marrow was harvested from male mice, labeled with GFP, and injected into the peri-infarct rim of female mice. This resulted in a substantial increase in myocytes in the infarct zone, and the myocytes were of donor origin (on the basis of Y chromosome staining and GFP expression). There was a corresponding improvement in hemodynamic parameters after only 9 days.The same group showed that mobilization of lineage-negative, c-kit+ cells with granulocyte colony-stimulating factor and stem cell factor before and after MI in mice resulted in growth of new cardiomyocytes in the infarct zone and improved ventricular function and led to substantial improvement in survival of the treated group. Endothelial and smooth muscle cells also were proliferating, but new myocyte growth predominated.47 However, in contrast to these findings, Murry and colleagues48 and Balsam and coworkers49 reported that lineage-negative, c-kit+ cells did not differentiate into cardiomyocytes. In the latter study, bone marrow cells transplanted into ischemic myocardium adopted hematopoietic fates rather than transdifferentiating into myocardium yet interestingly still prevented LV dilatation and dysfunction associated with postinfarction remodeling. Despite the conflicting evidence regarding the ability of bone marrow–derived cells to transdifferentiate, their efficacy in preventing remodeling has been demonstrated in many laboratories; therefore, clinical efficacy trials have progressed in parallel with ongoing mechanistic laboratory trials to determine the precise molecular mechanism by which these cells exert their beneficial effects. Kamihata et al7 isolated mononuclear cells from swine bone marrow and injected them into the infarct zone and peri-infarct region of pigs after MI induced by left anterior descending coronary artery ligation. This was associated with an improvement in myocardial perfusion by contrast echocardiography, increased numbers of capillaries, increased coronary collateral circulation on angiography, improved ejection fraction, and reduction in infarct size compared with controls. Of note, the endothelial lining of newly formed capillaries was derived from the donor bone marrow cells, but the fibroblasts in the fibrotic area of the infarct were not. This suggests that the microenvironment of MI is proangiogenic rather than fibrosis-inducing for this population of cells.This evidence that precursors of both cardiomyocytes and endothelial cells exist within the mononuclear cell fraction of adult bone marrow forms the basis for the use of bone marrow mononuclear cells (BMMNCs) in clinical trials (Table 1). In just the past 3 years, BMMNC transplantation has become the most widely studied cell-based therapy for human applications (Table 1). Several studies using autologous bone marrow warrant special mention. The initial studies used intracoronary delivery of BMMNCs in the post-MI setting because animal studies demonstrate that tissue damage in MI resulted in bone marrow stem cell homing to the infarcted myocardium.6 In the first published human trial, Strauer et al50 aspirated BMMNCs and reinfused them into the infarct-related artery 7 days after MI in 10 patients and had a control group comprising 10 patients who refused the treatment. This method resulted in significantly improved myocardial perfusion and wall motion indexes. The Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) investigators51,52 randomized 59 patients after acute MI to receive intracoronary infusion of BMMNCs or ex vivo expanded circulating progenitor cells. They delivered the cells into the infarct-related artery 4 days after MI and showed improvement in LV ejection fraction from 51% to 58% (P<0.001), as well as significantly enhanced myocardial viability and regional wall motion in the infarct area. Interestingly, they were unable to show a difference between the 2 active cell treatment groups. In the BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, Wollert and coworkers53 randomized 60 patients after successful percutaneous coronary intervention for acute MI to receive either intracoronary BMMNCs or standard therapy. They demonstrated an improvement in LV ejection fraction of 6.7% in the treatment group and 0.7% in the control group at 6 months (P=0.0026). Taken together, these studies with control groups suggest that BMMNCs are safe and may improve cardiac function by a substantial and clinically meaningful degree following MI. However, more recently, Janssens and colleagues presented their findings that intracoronary transfer of BMMNCs failed to achieve their primary end point, improvement in global LV function.54 They demonstrated a significant reduction in scar size and an improvement in regional function, but there was no improvement in LV ejection fraction (P=0.36). Their patient population differed from the BOOST trial in that they were reperfused earlier and may therefore have gained only a small benefit from cell therapy because they derived maximal benefit from earlier reperfusion. In the 18-month follow-up to the BOOST study, the improvement in LV ejection fraction in the cell therapy group was sustained.55 However, the control group also had improved by this time, and the difference between the 2 groups was no longer significantly different. This catch-up phenomenon in the control group suggests that, rather than the effect of cell therapy being transient, cell therapy may in fact accelerate the postinfarction LV functional recovery that is achievable with standard medical therapy.In contrast to the acute MI setting, patients with chronic ischemic cardiomyopathy are unlikely to release signals from damaged myocardium to induce stem cell homing. Therefore, an alternative approach to intracoronary infusion of cells in this setting is endomyocardial injection of cells to deliver them to the exact location where their effect is required. Perin et al56 enrolled 14 subjects and 7 control subjects with ischemic cardiomyopathy. The treatment group received endomyocardial injection of ≈30 million BMMNCs. They showed a significant reduction in reversible myocardial perfusion defects and a significant improvement in overall LV function. Notably, they enrolled subjects with significant LV dysfunction at baseline; therefore, their results may be more clinically relevant to the CHF patient group than previous studies that enrolled patients with normal or mildly impaired LV function after MI. Currently, a number of phase II studies are ongoing with BMMNCs (Table 2).Mesenchymal Stem CellsMesenchymal stem cells (MSCs) are found in bone marrow, muscle, skin, and adipose tissue and are characterized by the potential to differentiate into any tissue of mesenchymal origin, including muscle, fibroblasts, bone, tendon, ligament, and adipose tissue.57 MSCs from adult bone marrow can be separated by density gradient centrifugation and adhering-cell culture in defined serum-containing medium.58 The cells isolated after adherence in culture are negative for CD34 and CD45, unlike hematopoietic progenitors from bone marrow, and characteristically express CD29, CD44, CD71, CD90, CD105, CD106, CD120a, CD124, SH2, SH3, and SH4.59–61 Some studies demonstrate that MSCs transdifferentiate into cardiomyocytes and vascularlike structures.62–66 MSCs differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart in both noninjury and MI models. These cells have been strictly characterized by immunohistochemistry and stain positively for cardiac and endothelial specific markers, as well as gap junction proteins.64,65,67,68 Myocardial function and capillary formation are significantly increased in experimental groups treated with MSCs compared with controls.69,70 These results suggest that MSCs act by regenerating functionally effective, integrated cardiomyocytes and possibly new blood vessels. MSCs also have been injected into infarcted myocardium via a catheter-based approach in pigs, resulting in regeneration of myocardium, reduced infarct size, and improved regional and global cardiac contractile function.5 Importantly, the latter study used allogeneic MSCs, which did not produce evidence of rejection.Whereas autologous cell-based therapy poses no risk of rejection, an "off the shelf" allogeneic cell product would be much more cost effective and much easier to administer and could potentially allow delivery of greater numbers of cells than autologous cell therapy. MSCs appear to avoid the problem of rejection by being hypoimmunogenic. These cells lack MHC-II and B-7 costimulatory molecule expression, thereby preventing T-cell responses, and induce a suppressive local microenvironment through the production of prostaglandins and other soluble mediators.58,71 As such, MSCs may allow allogeneic cell therapy while avoiding rejection.MSCs also have been studied clinically. Chen and colleagues72 randomized 69 patients after MI to receive intracoronary autologous MSCs or placebo. They demonstrated a significant improvement in global and regional LV function and a significant reduction in the size of the perfusion defect, suggesting that MSC therapy can regenerate infarcted myocardium or protect against LV remodeling.Currently, several studies have been published using MSCs for noncardiac disorders (see Table 3), and allogeneic MSCs are in clinical trials for myocardial regeneration in the United States under the sponsorship of Osiris Therapeutics (Table 2). In addition, the Specialized Centers for Cell-Based Therapy program also plans to conduct clinical trials of MSCs for patients with CHF. TABLE 3. Clinical Studies Using MSCsStudyTreated, nAutologous/AllogeneicIndicationRandomizedGVHD indicates graft-versus-host disease.Chen et al7234AutologousMI+Bang et al1225AutologousStroke−Garcia-Olmo et al1235AutologousCrohn's disease fistula−Horwitz et al1246AllogeneicOsteogenesis imperfecta−LeBlanc et al1251AllogeneicGVHD−Endothelial Progenitor CellsCells with phenotypic and functional characteristics similar to the fetal angioblast also are present in adult human bone marrow.6 These cells, known as EPCs, express some, but not all, cell surface markers characteristic of mature endothelium, certain surface markers of hematopoietic cells, and transcription factors that identify them as precursor cells.27,73–75 In addition to endothelial cell surface markers, EPCs also express markers of immature cells, including AC133, a novel hematopoietic stem cell marker76 not expressed on mature endothelial cells.77 After MI, intravenously injected EPCs homed to the infarct region within 48 hours.6 At 14 days, there was a marked increase in the number of capillaries in the infarct zone and the peri-infarct rim resulting from the induction of both vasculogenesis and angiogenesis, but there was no change in the noninfarcted regions of the heart. There was a significant reduction in collagen deposition and apoptosis of cardiomyocytes and an improvement in cardiac function on echocardiography.6 It appears that neovascularization induced by these cells leads to the prevention of apoptosis and LV remodeling and may lead to some degree of cardiomyocyte regeneration.15Erb and colleagues78 randomized patients with recanalized, chronically occluded coronary arteries to receive intracoronary progenitor cells or placebo. They mobilized bone m
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