Cardiac stem cell therapy: Checkered past, promising future?
2014; Elsevier BV; Volume: 148; Issue: 6 Linguagem: Inglês
10.1016/j.jtcvs.2014.10.077
ISSN1097-685X
AutoresJohn J. Squiers, Kelley A. Hutcheson, Jeffrey E. Thatcher, J. Michael DiMaio,
Tópico(s)Electrospun Nanofibers in Biomedical Applications
ResumoSee related article on pages 3180-8. See related article on pages 3180-8. In this issue of the Journal of Thoracic and Cardiovascular Surgery (JTCVS), Luo and colleagues1Luo J. Weaver M.S. Dennis J.E. Whalen E. Laflamme M.A. Allen M.D. Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes.J Thorac Cardiovasc Surg. 2014; 148: 3180-3188Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar have demonstrated a novel approach to transplantation of human embryonic stem cell grafts within infarcted myocardium in an animal model. We commend their emphasis on transplanting stem cell grafts as directionally oriented, infarct-spanning bands. Often missing from basic science laboratories is the understanding of the importance of these macroscopic helical Torrent-Guasp myocardial bands2Torrent-Guasp F. Ballester M. Buckberg G.D. Carreras F. Flotats A. Carrio I. et al.Spatial orientation of the ventricular muscle band: physiologic contribution and surgical implications.J Thorac Cardiovasc Surg. 2001; 122: 389-392Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar that allow for torsional deformation of the left ventricle during systole and, thus, appropriate ventricular function. By submitting their work to JTCVS, Luo and colleagues recognize that cardiac surgeons, who handle the human heart on a near daily basis, can best appreciate the importance of the heart's macro-architecture for effective cardiac function. Their demonstrated effects of CoPP preconditioning represent an important step forward in our understanding of the basic mechanisms and principles underlying regenerative stem cell therapy. This bench-top research is crucial to assist clinicians in achieving better clinical outcomes with cardiac stem cell therapy. In light of this success, however, it is essential to recognize the often-frustrating discordance between results of promising basic science research and more humbling clinical trials over the last 15 years of investigation into stem cell therapy for cardiac disease. Extensive research efforts have investigated the potential for stem cell–mediated cardiac tissue regeneration in the treatment of cardiovascular disease.3Malliaras K. Marban E. Cardiac cell therapy: where we’ve been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar Early basic science reports suggested enormous therapeutic potential,4Tomita S. Li R. Weisel R.D. Mickle D.A.G. Kim E. Sakai T. et al.Autologous transplantation of bone marrow cells improves damaged heart function.Circulation. 1999; 100: II-247-II-256Crossref Google Scholar but results from clinical trials have been disappointing to date. Basic investigators have employed various kinds of stem cells: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult progenitor cells (including skeletal myoblasts, bone marrow mononuclear cells [BMMNCs], and cardiac stem cells [CSCs]). So far, however, completed clinical trials have only reported transplantation of the various adult progenitor cells. In fact, a casual review of the clinical trials database (clinicaltrials.gov/ct2/home) shows that the overwhelming majority of trials has employed or will employ adult progenitor stem cells rather than truly pluripotent ESCs or iPSCs. An early clinical trial of skeletal myoblasts (Myoblast Autologous Grafting in Ischemic Cardiomyopathy [MAGIC]5Menasche P. Alfieri O. Janssens S. McKenna W. Reichenspurner H. Trinquart L. et al.The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: the first randomized placebo-controlled study of myoblast transplantation.Circulation. 2008; 117: 1189-1200Crossref PubMed Scopus (762) Google Scholar) was discontinued prematurely after both a lack of efficacy and an increased risk for arrhythmias in patients receiving stem cell therapy were demonstrated. A more recent skeletal myoblast trial (ie, SEISMIC6Duckers H.J. Houtgraaf J. Hehrlein C. Schofer J. Waltenberger J. Gershlick A. et al.Final results of a phase IIa, randomized, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.EuroIntervention. 2011; 6: 805-812Crossref PubMed Scopus (89) Google Scholar) did not reveal any effect of stem cell therapy on the left-ventricular ejection fraction (LVEF). Although BMMNCs have been the most commonly employed cell type for stem cell therapy trials (eg, REPAIR-AMI,7Assmus B. Rolf A. Erbs S. Elsässer A. Haberbosch W. Hambrecht R. et al.REPAIR-AMI InvestigatorsClinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction.Circ Heart Fail. 2010; 3: 89-96Crossref PubMed Scopus (241) Google Scholar TIME,8Traverse J.H. Henry T.D. Pepine C.J. Willerson J.T. Zhao D.X. Ellis S.G. et al.Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.J Am Med Assoc. 2012; 308: 2380-2389Crossref PubMed Scopus (311) Google Scholar POSEIDON9Hare J.M. Fishman J.E. Gerstenblith G. Velazquez D.L.D. Zambrano J.P. Suncion V.Y. et al.Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.J Am Med Assoc. 2012; 308: 2369-2379Crossref PubMed Scopus (882) Google Scholar), these investigations have also yielded underwhelming results. Meta-analyses of BMMNC trials for various cardiac disease indications have demonstrated only minimal increases in LVEF across the board (Table 110Fisher S.A. Dorée C. Brunskill S.J. Mathur A. Martin-Rendon E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systemic review and meta-analysis.PLoS One. 2013; 8: e64669Crossref PubMed Scopus (78) Google Scholar, 11Kandala J. Upadhyay G.A. Pokushalov E. Wu S. Drachman D.E. Singh J.P. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy.Am J Cardiol. 2013; 112: 217-225Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 12Delewi R. Hirsch A. Tijssen J.G. Schächinger V. Wojakowski W. Roncalli J. et al.Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis.Eur Heart J. 2014; 35: 989-998Crossref PubMed Scopus (111) Google Scholar). Two trials implementing CSCs (SCIPIO13Bolli R. Chugh A.R. D'Amario D. Loughran J.H. Stoddard M.F. Ikram S. et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomized phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text Full Text PDF PubMed Scopus (1105) Google Scholar and CADUCEUS14Makkar R.R. Smith R.R. Cheng K.E. Malliaras K. Thomson L.E. Berman D. et al.Intra-coronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1120) Google Scholar) were ineffective in improving meaningful clinical outcomes. Additional trials with adult progenitor cells are currently ongoing, including the ATHENA trial,15Cytori Therapeutics. Safety and feasibility trial of adipose-derived regenerative cells in the treatment of chronic myocardial ischemia. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01556022?term=cytori&rank=3. Accessed October 7, 2014.Google Scholar which is utilizing adipose-derived regenerative cells for transplantation.16Zuk P.A. Zhu M. Ashjian P. De Ugarte D.A. Huang J.I. Mizuno H. et al.Human adipose tissue is a source of multipotent stem cells.Mol Biol Cell. 2002; 13: 4279-4295Crossref PubMed Scopus (5458) Google ScholarTable 1Meta-analyses of bone marrow cell therapy for cardiac disease, encompassing 3 major indications10Fisher S.A. Dorée C. Brunskill S.J. Mathur A. Martin-Rendon E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systemic review and meta-analysis.PLoS One. 2013; 8: e64669Crossref PubMed Scopus (78) Google Scholar, 11Kandala J. Upadhyay G.A. Pokushalov E. Wu S. Drachman D.E. Singh J.P. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy.Am J Cardiol. 2013; 112: 217-225Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 12Delewi R. Hirsch A. Tijssen J.G. Schächinger V. Wojakowski W. Roncalli J. et al.Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis.Eur Heart J. 2014; 35: 989-998Crossref PubMed Scopus (111) Google ScholarStudyIndicationNo. of trialsNo. of patientsΔ LVEF (%)NotesFisher et al (2013)10Fisher S.A. Dorée C. Brunskill S.J. Mathur A. Martin-Rendon E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systemic review and meta-analysis.PLoS One. 2013; 8: e64669Crossref PubMed Scopus (78) Google ScholarRefractory angina or HF9659+3.47 ± 1.59Reduced mortality with cell therapy (RR = 0.33, 0.17-0.65)Kandala et al (2013)11Kandala J. Upadhyay G.A. Pokushalov E. Wu S. Drachman D.E. Singh J.P. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy.Am J Cardiol. 2013; 112: 217-225Abstract Full Text Full Text PDF PubMed Scopus (73) Google ScholarChronic heart failure10519+4.48 ± 2.05Intramyocardial injection may be superior to intracoronary infusion in patients with LV systolic dysfunctionDelewi et al (2014)12Delewi R. Hirsch A. Tijssen J.G. Schächinger V. Wojakowski W. Roncalli J. et al.Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis.Eur Heart J. 2014; 35: 989-998Crossref PubMed Scopus (111) Google ScholarAcute STEMI161641+2.55 ± 0.72Improvement better in young patients (<55 y) and patients with low LVEF (<40% baseline)LVEF, Left ventricular ejection fraction; HF, heart failure; RR, relative risk; LV, left ventricle; STEMI, ST-segment elevation myocardial infarction. Open table in a new tab LVEF, Left ventricular ejection fraction; HF, heart failure; RR, relative risk; LV, left ventricle; STEMI, ST-segment elevation myocardial infarction. After this surge of clinical trials employing adult progenitor stem cells yielded largely disappointing results, research efforts have been wisely redirected from the clinic back to the laboratory. In this effort to better understand the underlying principles of cardiac stem cell therapy, basic scientists and clinicians have learned from the mistakes of prior trials and sought solutions to challenging questions in the field, but many questions remain about basic mechanisms of stem cell therapy in cardiac regeneration.17Malliaras K. Kreke M. Marban E. The stuttering progress of cell therapy for heart disease.Clin Pharmacol Ther. 2011; 90: 532-541Crossref PubMed Scopus (72) Google Scholar Garbern and Lee18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar have recently outlined several of these questions expertly, 4 of which we highlight below:1.What is the precise mechanism of action by which stem cell transplantation may demonstrate clinical efficacy? Perhaps the most intuitive explanation for the therapeutic effects of stem cell transplantation is what we call the Cardiomyocyte Replacement Theory. According to this theory, transplanted stem cells differentiate into functional cardiomyocytes that integrate into the existing myocardial architecture to increase cardiac function through additional mechanical force. Nevertheless, data have consistently indicated that the vast majority of transplanted adult progenitor stem cells do not persist in their new ischemic environment for a prolonged period of time. Long-term engraftment rates have been shown to be <1%. These rates are so low because 90% of delivered cells are washed out of the heart within 24 hours, and approximately 90% of any remaining cells die within the first week of transplant.3Malliaras K. Marban E. Cardiac cell therapy: where we’ve been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar, 17Malliaras K. Kreke M. Marban E. The stuttering progress of cell therapy for heart disease.Clin Pharmacol Ther. 2011; 90: 532-541Crossref PubMed Scopus (72) Google Scholar In fact, the beneficial effects of stem cell transplantation often paradoxically outlast the survival of transplanted stem cells in the ischemic heart tissue. Therefore, a second theory, which emphasizes unspecified paracrine effects of transplanted stem cells, has recently gained traction.19Williams A.R. Hare J.M. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.Circ Res. 2011; 109: 923-940Crossref PubMed Scopus (685) Google Scholar This theory, which we call the Cardiomyocyte Repair Theory, suggests that trophic factors released by stem cells stimulate existing cardiomyocytes, leading to an increase in cardiac function. It remains to be determined which specific factors are actually released by stem cells or how they promote beneficial cardiac effects. Proposed mechanisms of the Cardiomyocyte Repair Theory include stimulation of endogenous cardiac progenitor cell populations, enhanced tissue repair, improved angiogenesis, and matrix remodeling to reduce fibrosis.20Prowse A.B.J. Timmins N.E. Yau T.M. Li R. Weisel R.D. Keller G. et al.Transforming the promise of pluripotent stem cell derived cardiomyocytes to a therapy: challenges and solutions for clinical trials.Can J Cardiol. 2014; 30: 1335-1349Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Of note, a consensus18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar has recently emerged that the mammalian heart is capable of creating a limited number of cardiac cells after birth and that some vertebrates, including neonatal mice, can regenerate the myocardium after experimentally induced ischemia.21Porello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. et al.Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1664) Google Scholar Various mechanisms have been proposed to explain how cardiomyocytes may innately regenerate following injury, as summarized in Figure 1. These include a signaling cascade that activates dormant progenitor cells, the proliferation of existing cardiomyocytes, activation of the epicardium, or the de-differentiation of cardiomyocytes into progenitor cells that then proliferate.18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar The proposed paracrine effects of stem cell therapy likely promote some or all of these innate pathways to increase function in the face of cardiac disease. The authors of this editorial favor the Cardiomyocyte Repair Theory as compared to the Cardiomyocyte Replacement Theory to explain the effects demonstrated after transplantation of adult progenitor stem cells. In fact, with various other colleagues, 2 of the authors have previously demonstrated important findings, involving identification of both potential trophic factors and mechanisms of repair, that lend credence to the paracrine cardiac repair paradigm. With Bock-Marquette and colleagues,22Bock-Marquette I. Saxena A. White M.D. DiMaio J.M. Srivastava D. Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair.Nature. 2004; 432: 466-472Crossref PubMed Scopus (570) Google Scholar, 23Bock-Marquette I. Shrivastava S. Pipes G.C. Thatcher J.E. Blystone A. Shelton J.M. et al.Thymosin β4 mediated PKC activation is essential to initiate the embryonic coronary developmental program and epicardial progenitor cell activation in adult mice in vivo.J Mol Cell Cardiol. 2009; 46: 728-738Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar DiMaio and Thatcher identified a trophic factor, thymosin β4, that promotes cardiomyocyte migration, survival, and repair. In addition, thymosin β4 is capable of organwide activation of the embryonic coronary developmental program in the adult mammalian heart after systemic administration. With Huang, Olson, and colleagues,24Huang G.N. Thatcher J.E. McAnally J. Kong Y. Qi X. Tan W. et al.C/EBP transcription factors mediate epicardial activation during heart development and injury.Science. 2012; 338: 1599-1603Crossref PubMed Scopus (154) Google Scholar DiMaio and Thatcher have also outlined how activation of the epicardium by specific transcription factors plays a role in myocardial repair following ischemic injury. Therefore, we believe it is reasonable to suggest that increases in cardiac function in animal models following stem cell transplantation may be due to paracrine effects on the endogenous cardiomyocyte population rather than cardiomyocyte replacement via stem cell differentiation processes.2.Which cell type is best suited for transplantation therapy in cardiac disease? Although the cardiomyocyte repair theory is gaining wide acceptance as the proper explanation of the results in successful basic science investigations employing adult progenitor stem cells, the next generation of stem cell trials will likely involve transplantation of ESCs and iPSCs.20Prowse A.B.J. Timmins N.E. Yau T.M. Li R. Weisel R.D. Keller G. et al.Transforming the promise of pluripotent stem cell derived cardiomyocytes to a therapy: challenges and solutions for clinical trials.Can J Cardiol. 2014; 30: 1335-1349Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In theory, ESCs and iPSCs could be better suited for stem cell therapy because of their ability to fully differentiate into functional cardiomyocytes as compared to the more limited, less versatile cell lines used in the clinical trials previously discussed. Thus, in addition to paracrine effects, future stem cells employed in regenerative therapy may have greater potential to persist as directionally oriented, infarct-spanning bands that will improve the mechanical performance of the left ventricle in systole.20Prowse A.B.J. Timmins N.E. Yau T.M. Li R. Weisel R.D. Keller G. et al.Transforming the promise of pluripotent stem cell derived cardiomyocytes to a therapy: challenges and solutions for clinical trials.Can J Cardiol. 2014; 30: 1335-1349Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In other words, these truly pluripotent cells could promote therapeutic effects via mechanisms uniting the Cardiomyocyte Regeneration and Cardiomyocyte Repair Theories. Many questions remain about how truly pluripotent cells can be optimized in stem cell therapy. The ethical concerns involving ESCs may ultimately preclude their utility in the clinical setting. iPSCs circumvent this ethical controversy, but the development of a cost-effective protocol to create sufficient quantities of iPSCs for clinical therapy is currently a challenge.18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Even given a sufficient quantity of pluripotent stem cells, further investigations must determine in what state these cells should be transplanted.20Prowse A.B.J. Timmins N.E. Yau T.M. Li R. Weisel R.D. Keller G. et al.Transforming the promise of pluripotent stem cell derived cardiomyocytes to a therapy: challenges and solutions for clinical trials.Can J Cardiol. 2014; 30: 1335-1349Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Theoretically, pluripotent cells could be delivered as cardiomyocyte progenitors, fetal-like cardiomyocytes, or adult-like cardiomyocytes. Furthermore, these cells could differentiate to become ventricular, atrial, or nodal cells, or even some combination of all 3. Much work still remains before it can be determined which option(s) may produce the greatest clinical efficacy.3.What is the optimal delivery method for transplantation of stem cells? Several delivery mechanisms have been previously employed including intramyocardial (epicardial or transendocardial), intracoronary, retrograde coronary sinus, and systemic intravenous. Each method has significant advantages and disadvantages as described by Dib et al.25Dib N. Khawaja H. Varner S. McCarthy M. Campbell A. Cell therapy for cardiovascular disease: a comparison of methods of delivery.J Cardiovasc Transl Res. 2011; 4: 177-181Crossref PubMed Scopus (73) Google Scholar In exchange for increased accuracy of delivery, the most invasive delivery routes carry a risk of perforation, arrhythmia, or embolus of cells and/or the viscous delivery suspension. On the other hand, poor cell homing and retention limit the effectiveness of less invasive procedures and require the delivery of an increased number of cells to achieve a comparable therapeutic benefit. A summary of the various delivery methods is presented in Table 2. No consensus has been reached upon how best to deliver stem cells to damaged cardiac tissue,18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar and it is likely that different methods may ultimately prove to be superior depending on the particular indication for stem cell therapy. For example, intracoronary delivery is the preferred route of transplant in patients suffering acute myocardial infarct.17Malliaras K. Kreke M. Marban E. The stuttering progress of cell therapy for heart disease.Clin Pharmacol Ther. 2011; 90: 532-541Crossref PubMed Scopus (72) Google Scholar, 25Dib N. Khawaja H. Varner S. McCarthy M. Campbell A. Cell therapy for cardiovascular disease: a comparison of methods of delivery.J Cardiovasc Transl Res. 2011; 4: 177-181Crossref PubMed Scopus (73) Google Scholar Again, we commend Luo and colleagues1Luo J. Weaver M.S. Dennis J.E. Whalen E. Laflamme M.A. Allen M.D. Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes.J Thorac Cardiovasc Surg. 2014; 148: 3180-3188Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar for addressing lingering questions about cell delivery by employing an injectable delivery method designed to regenerate Torrent-Gausp myocardial bands. In particular, their attempt to replicate the physiologic architecture of the human heart via stem cell transplantation represents a novel solution for optimal delivery.4.What adjuvants to cell delivery will maximize the benefits of stem cell therapy?Table 2Advantages and disadvantages of the various stem cell delivery methods24Huang G.N. Thatcher J.E. McAnally J. Kong Y. Qi X. Tan W. et al.C/EBP transcription factors mediate epicardial activation during heart development and injury.Science. 2012; 338: 1599-1603Crossref PubMed Scopus (154) Google ScholarMethodLeast invasiveCell retentionLow risk∗Common risks include perforation of the ventricular wall, cardiac arrhythmia secondary to local tissue inflammation, or embolus of the stem cells and/or viscous delivery suspension.Clinical experienceNotesEpicardial○●◔◑Delivery via mini-thoracotomy or with open heart procedureTransendocardial◑◕◔◑Requires delivery of percutaneous catheter to left ventricleIntracoronary◕◑◑●Preferred method during acute MIRetrograde coronary sinus◔◑◑◔Optimal in cases of severe coronary stenosisIntravenous●○●◔Very low retention due to cell trapping in lungsMI, Myocardial infarction.∗ Common risks include perforation of the ventricular wall, cardiac arrhythmia secondary to local tissue inflammation, or embolus of the stem cells and/or viscous delivery suspension. Open table in a new tab MI, Myocardial infarction. Recent investigations have demonstrated many methods to quantitatively assess cell engraftment and survival following delivery in the laboratory.26Terrovitis J.V. Smith R.R. Marbán E. Assessment and optimization of cell engraftment after transplantation into the heart.Circ Res. 2010; 106: 479-494Crossref PubMed Scopus (251) Google Scholar Experiments have consistently revealed that both engraftment and survival rates are extremely low regardless of the cell type or delivery mechanism implemented. Both cardiac blood flow, which washes away stem cells after intracoronary delivery, and myocardial contraction, which accentuates leakage of cells from an injection site, limit cell retention.26Terrovitis J.V. Smith R.R. Marbán E. Assessment and optimization of cell engraftment after transplantation into the heart.Circ Res. 2010; 106: 479-494Crossref PubMed Scopus (251) Google Scholar In addition, ischemic conditions severely inhibit the survival of any cells that successfully engraft by 24 hours posttransplant, as at least 90% of engrafted cells die within the first week. These factors limit total cell survival following transplant to <1% overall.3Malliaras K. Marban E. Cardiac cell therapy: where we’ve been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar, 17Malliaras K. Kreke M. Marban E. The stuttering progress of cell therapy for heart disease.Clin Pharmacol Ther. 2011; 90: 532-541Crossref PubMed Scopus (72) Google Scholar Reasonable estimates suggest that approximately 1 billion cardiomyocytes are required to completely replace all of the cells from the working myocardium that is lost during a myocardial infarction.27Mummery C.L. Zhang J. Ng E.S. Elliott D.A. Elefanty A.G. Kam T.J. Differentiation of human ES and iPS cells to cardiomyocytes: a methods overview.Circ Res. 2012; 111: 344-358Crossref PubMed Scopus (509) Google Scholar At current cell survival rates, stem cell therapy would require the transfer of up to 1 trillion cells (roughly equivalent to 3% of the total number of cells in the human body) to each patient in order to completely replete the devastated cell population. Therefore, various methods of tissue engineering have been investigated as adjuvant support to improve the persistence of stem cells following transplant. By increasing the viability of stem cells, these methods would allow for fewer stem cells to be transplanted while concurrently bettering clinical outcomes. Examples include cell co-culturing, biomaterial formulation, and genetic engineering of cells.17Malliaras K. Kreke M. Marban E. The stuttering progress of cell therapy for heart disease.Clin Pharmacol Ther. 2011; 90: 532-541Crossref PubMed Scopus (72) Google Scholar Cell co-culturing involves pretreating stem cells with various cofactors that induce favorable cell-signaling pathways to increase cell survival and/or homing accuracy following transplantation. Biomaterials, in which cells are engrafted, may be applied as epicardial patches that increase cell retention and survival via mechanical scaffolding to limit cell washout or controlled released of biologic agents to support cells in ischemic environments.28Menasché P. How close are we to using stem cells in routine cardiac therapy?.Can J Cardiol. 2014; 30: 1265-1269Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Many attempts at genetic engineering of cells prior to delivery have been reported, but several concerns about this manner of adjunctive therapy have been raised.26Terrovitis J.V. Smith R.R. Marbán E. Assessment and optimization of cell engraftment after transplantation into the heart.Circ Res. 2010; 106: 479-494Crossref PubMed Scopus (251) Google Scholar Specifically, how can we ensure genetic manipulation increases cell survival without interfering with proper myocardial function or without introducing a significant risk of oncogenesis? Further research is needed to elucidate which adjuvant therapies can be optimally combined with stem cell transplantation to increase cardiac function. In addition to tissue engineering of stem cells, other techniques to promote cardiac repair have been proposed. These include the direct delivery of paracrine factors isolated from stem cell colonies and the reprogramming of noncardiomyocytes into cardiomyocytes using growth factors or microRNA assays as described elsewhere.18Garbern J.C. Lee R.T. Cardiac stem cell therapy and the promise of heart regeneration.Cell Stem Cell. 2013; 12: 689-698Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar Figure 2 provides a summary of these approaches to cardiac regeneration therapy. Ultimately, all of these methods likely promote some combination of the innate cardiac repair pathways summarized above. To these questions, which are currently under investigation in the laboratory, we add our own, which cannot be resolved with basic science research alone: How can clinical trials best assess stem cell therapy in a clinically significant manner? Most completed trials have published outcomes by employing metrics such as changes in LVEF, left ventricular end-diastolic volume, and/or left ventricular end-systolic volume. Many of these trials have shown statistically significant, but clinically disappointing, improvements in these metrics. We wonder, moreover, how meaningful these metrics are to clinicians and their patients, especially given the operator-depended variability inherent in acquiring such measurements in addition to the physiologic variability of measurements of the same patient under different loading conditions. We believe that more clinically relevant outcomes, such as Vo2max and cardiac perfusion, must receive greater attention in future clinical trials. Other useful parameters include heart failure and angina classifications, quality of life metrics, and physical exercise performance.10Fisher S.A. Dorée C. Brunskill S.J. Mathur A. Martin-Rendon E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systemic review and meta-analysis.PLoS One. 2013; 8: e64669Crossref PubMed Scopus (78) Google Scholar Of course, we cannot lose sight of the most clinically significant outcomes, morbidity and mortality, as stem cell therapy becomes more widespread. Ultimately, the initial promise of stem cell transplantation research has not yielded as much success as initially hoped during the first round of clinical trials. More basic science investigation is required to elucidate the specific mechanism(s) by which transplanted stem cells promote cardiac regeneration and/or repair, which stem cell type is most effective, and how cells can be optimally delivered and engineered. As our understanding of stem cell therapy increases, it becomes more likely that clinical trials can produce truly meaningful results with implications for clinical practice. Another wave of stem cell clinical trials is fast approaching, as the NIH Heart, Lung, and Blood Institute teams with the Cardiothoracic Surgical Trials Network (CTSN) to fund and perform this research in multicentered trials.29Ascheim D.D. Gelijns A.C. Goldstein D. Moye L.A. Smedira N. Lee S. et al.Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary LVADs.Circulation. 2014; 129: 2287-2296Crossref PubMed Scopus (123) Google Scholar We remain cautiously optimistic that further investigations will yield more promising results than the first round of clinical trials, but we emphasize the tremendous challenges yet to be overcome before stem cell therapy can be a realistic therapeutic option for clinicians and their patients. Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell–derived cardiomyocytesThe Journal of Thoracic and Cardiovascular SurgeryVol. 148Issue 6PreviewGenerating myocyte grafts that bridge across infarcts could maximize their functional impact and best utilize small numbers of stem cells. To date, however, graft survival within acute infarcts has not been feasible. To enhance intrainfarct graft viability, human embryonic stem cell–derived cardiomyocytes (hESC-CMs) were pretreated before implantation with cobalt protoporphyrin (CoPP), a pharmacologic inducer of cytoprotective heme oxygenase-1. Full-Text PDF Open Archive
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