Perspectives on the Evolution of Stem Cell Therapy for Heart Failure (2015)

The advent of stem cell and cell-based therapy has opened the door to a non-pharmacological treatment of heart failure (HF). This exciting opportunity is at an early stage and many issues regarding optimization of this approach remain. A variety of stem cells (SCs), doses, and delivery methods are being tested in clinical trials, supporting the conclusion that there is still “no consensus on … which cell type to transplant, to improve efficacy and safety” (Silvestre and Menasché, 2015Silvestre J.S. Menasché P. The Evolution of the Stem Cell Theory for Heart Failure.EBioMedicine. 2015; 2: 1871-1879Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar). To provide a guide going forward, Silvestre and Menasché take us through the evolution of the therapeutic use of SCs for heart failure (Silvestre and Menasché, 2015Silvestre J.S. Menasché P. The Evolution of the Stem Cell Theory for Heart Failure.EBioMedicine. 2015; 2: 1871-1879Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Their main proposal is that “cardiac-committed cells” in general and “pluripotent stem cell-derived cardiac progenitors” in particular are “particularly attractive” candidates for cell therapy. Many clinical trials have suggested SC efficacy. While early trials have focused on attempting to show improvements in morphologic measures such as left ventricular ejection fraction (LVEF), end diastolic volume (LVEDV), end systolic volume (LVESV), ventricular mass and scar size, others have attempted to examine surrogate clinical endpoints such as 6-min walk distance and Minnesota Living with Heart Failure scores. To adequately address which cell type is superior, direct cell-to-cell comparisons in pre-clinical studies on large animals and in clinical trials are needed. To date, numerous clinical and pre-clinical studies illustrate the therapeutic benefits of mesenchymal stem cells (MSCs), regardless of their tissue source. For example, in the TAC-HFT trial, MSCs improved cardiac function in chronic ischemic cardiomyopathy equal to or better than BM-mononuclear cells (Heldman et al., 2014Heldman A.W. DiFede D. Fishman J.E. Zambrano J.P. Trachtenberg B.H. Karantalis V. Mushtaq M. Williams A.R. Suncion V.Y. McNiece I.K. et al.Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT Randomized Trial.JAMA. 2014; 311: 62-73Crossref PubMed Scopus (403) Google Scholar). The POSEIDON clinical trial compared intra-myocardial injection of autologous and allogeneic bone marrow-derived (BM-) MSCs, and demonstrated a significant reduction in LVEDV in the allogeneic group (Hare et al., 2009Hare J.M. Traverse J.H. Henry T.D. Dib N. Strumpf R.K. Schulman S.P. Gerstenblith G. DeMaria A.N. Denktas A.E. Gammon R.S. et al.A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.J. Am. Coll. Cardiol. 2009; 54: 2277-2286Crossref PubMed Scopus (1112) Google Scholar). Unexpectedly, there appears to be an inverse relationship between cell number (20 million vs. 200 million) and therapeutic efficacy. Furthermore, analysis of patients from the POSEIDON-DCM and TRIDENT trials showed that intracardiac administration of allogeneic, but not autologous MSCs improved endothelial function 3 months after treatment (Premer et al., 2015Premer C. Blum A. Bellio M. Schulman I.H. Hurwitz B.E. Parker M. Dermarkarian C.R. DiFede D.L. Balkan W. Khan A. et al.Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells.EBioMedicine. 2015; 2: 467-475https://doi.org/10.1016/j.ebiom.2015.03.020Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar). The patient population and their different types of HF complicate the ongoing search for the best stem cell to improve cardiac function. Most studies have focused on ischemic cardiomyopathy; however, acute and chronic diseases do not necessarily respond similarly to a given cell type. Therefore it is not ideal to target one cell line and call it “the best”. Instead it may be more advantageous for us to ask the question: are the parameters we focus on, such as EF, the best predictor of future morbidity and mortality? Many factors play a role in global EF; therefore segmental changes in EF may provide a better correlation with clinical outcomes. Clinical trials that have failed to produce the best results with respect to EF nevertheless improved quality of life as indicated by improvements in the Minnesota Living with Heart Failure score and the 6-min walk test (Sanina and Hare, 2015Sanina C. Hare J.M. Mesenchymal stem cells as a biological drug for heart disease. Where are we with cardiac cell-based therapy?.Circ. Res. 2015; 117: 229-233Crossref PubMed Scopus (52) Google Scholar). Silvestre and Menasché propose that cardiac-committed cells are superior therapeutically. However, in direct comparisons between MSCs and either induced pluripotent cell-derived cardiomyocytes (Weil et al., 2015Weil B.R. Suzuki G. Leiker M.M. Fallavollita J.A. Canty Jr., J.M. Comparative efficacy of intracoronary allogeneic mesenchymal stem cells and cardiosphere-derived cells in swine with hibernating myocardium.Circ. Res. 2015; 117: 634-644Crossref PubMed Scopus (58) Google Scholar) (iPSC-CM) or cardiosphere-derived cells (CDCs) (Li et al., 2012Li T.S. Cheng K. Malliaras K. Smith R.R. Zhang Y. Sun B. Matsushita N. Blusztajn A. Terrovitis J. Kusuoka H. et al.Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells.J. Am. Coll. Cardiol. 2012; 59: 942-953Crossref PubMed Scopus (366) Google Scholar), MSCs provided equal cardiac functional improvements compared with both of these “cardiogenic” cell types except that MSCs were less effective at scar size reduction. Future therapies may be best served by combining cells. Recent studies show that the combination of c-kit + cardiac stem cells (CSCs) with either MSCs (Karantalis et al., 2015Karantalis V. Suncion-Loescher V.Y. Bagno L. Golpanian S. Wolf A. Sanina C. Premer C. Kanelidis A.J. McCall F. Wang B. et al.Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy.J. Am. Coll. Cardiol. 2015; 66: 1990-1999Crossref PubMed Scopus (120) Google Scholar, Williams et al., 2013Williams A.R. Hatzistergos K.E. Addicott B. McCall F. Carvalho D. Suncion V.Y. Morales A.R. Da Silva J. Sussman M.A. Heldman A.W. et al.Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and restore cardiac function after myocardial infarction.Circulation. 2013; 127: 213-223Crossref PubMed Scopus (340) Google Scholar) or CDCs (Li et al., 2012Li T.S. Cheng K. Malliaras K. Smith R.R. Zhang Y. Sun B. Matsushita N. Blusztajn A. Terrovitis J. Kusuoka H. et al.Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells.J. Am. Coll. Cardiol. 2012; 59: 942-953Crossref PubMed Scopus (366) Google Scholar) is more effective at restoring cardiac function than CSCs (Williams et al., 2013Williams A.R. Hatzistergos K.E. Addicott B. McCall F. Carvalho D. Suncion V.Y. Morales A.R. Da Silva J. Sussman M.A. Heldman A.W. et al.Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and restore cardiac function after myocardial infarction.Circulation. 2013; 127: 213-223Crossref PubMed Scopus (340) Google Scholar) or MSCs (Karantalis et al., 2015Karantalis V. Suncion-Loescher V.Y. Bagno L. Golpanian S. Wolf A. Sanina C. Premer C. Kanelidis A.J. McCall F. Wang B. et al.Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy.J. Am. Coll. Cardiol. 2015; 66: 1990-1999Crossref PubMed Scopus (120) Google Scholar, Williams et al., 2013Williams A.R. Hatzistergos K.E. Addicott B. McCall F. Carvalho D. Suncion V.Y. Morales A.R. Da Silva J. Sussman M.A. Heldman A.W. et al.Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and restore cardiac function after myocardial infarction.Circulation. 2013; 127: 213-223Crossref PubMed Scopus (340) Google Scholar) alone in pig models of HF. In a recent murine study, Quijada et al. showed that a fusion of CSCs with MSCs was superior to the individual cells in improving left ventricular function and structure (Quijada et al., 2015Quijada P. Salunga H.T. Hariharan N. Cubillo J.D. El-Sayed F.G. Moshref M. Bala K.M. Emathinger J.M. De La Torre A. Ormachea L. et al.Cardiac stem cell hybrids enhance myocardial repair.Circ. Res. 2015; 117: 695-706Crossref PubMed Scopus (66) Google Scholar). Perhaps cardiogenic cells are superior, and this property is manifested when they are combined with another cell type. Another approach is to pre-incubate or co-inject cytokines (or other factors) with cells. Regardless of the cell type or injection route, SCs exhibit limited engraftment in the heart, suggesting that much of their effect is due to their paracrine release of growth factors, mitochondria, and/or exosomes. Silvestre and Menasché suggest that allogeneic cells are superior “biofactories” compared with autologous cells and produce higher levels of (or better) paracrine factors. Therefore, the milieu from which the cell is isolated may promote favorable interactions and prime cells to increase their production of growth factor(s), a property that may be more important than the type of cell used. The use of stem cells therapeutically is still at an investigational stage and many of these questions will remain unanswered until rigorous head to head clinical trials are performed with clinical outcomes. This work was supported by the National Institutes of Health grant R01HL084275 awarded to Dr. Hare. Dr. Hare is also supported by the National Institutes of Health grants R01HL107110, UM1HL113460, and R01HL110737; and grants from the Starr Foundation and the Soffer Family Foundation. Dr. Hare has a patent for cardiac cell-based therapy; he holds equity in Vestion Inc.; and maintains a professional relationship with Vestion as a consultant and member of the Board of Directors and Scientific Advisory Board. Vestion did not play any role in the design or conduct of the study. The Evolution of the Stem Cell Theory for Heart FailureVarious stem cell-based approaches for cardiac repair have achieved encouraging results in animal experiments, often leading to their rapid proceeding to clinical testing. However, freewheeling evolutionary developments of the stem cell theory might lead to dystopian scenarios where heterogeneous sources of therapeutic cells could promote mixed clinical outcomes in un-stratified patient populations. This review focuses on the lessons that should be learnt from the first generation of stem cell-based strategies and emphasizes the absolute requirement to better understand the basic mechanisms of stem cell biology and cardiogenesis. Full-Text PDF Open Access