Abstract
Despite the much advancement that have been made in the field of cardiovascular research, heart failure is still associated with a poor prognosis and high mortality worldwide. The discovery that adult cardiomyocytes have an extremely low turnover rate has prompted researchers to investigate stem cells as a therapeutic option for cardiac regeneration. With stem cell therapy now approaching its third decade, numerous clinical trials have been completed and questions surrounding stem cell therapy are starting to be answered. It is now fairly well established that stem cell therapy has a positive safety profile, but only has produced neutral to moderately positive clinical outcomes. It is also clear that current stem cell therapies lack a significant ability to engraft and remuscularize the myocardium, suggesting cardiac repair occurs primarily through paracrine signaling mechanisms. Innovative strategies involving cardiac bioengineering, cell-free biomolecules, and combination therapies likely hold the key to advancing the field to the next stage. Looking ahead, we remain cautiously optimistic that stem cell therapeutics will have a significant place in the future of cardiovascular treatments, but there are still many questions that need to be answered before routine clinical application is possible.
MRH and IW collected the data and wrote this chapter. RA devised the project, developed the main conceptual ideas and edited the manuscript. All authors revised and approved the final version
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Abbreviations
- AAV:
-
Adeno-associated virus
- ACC/AHA:
-
American College of Cardiology and the American Heart Association
- ANP:
-
Atrial natriuretic peptide
- BMDSC:
-
Bone marrow-derived stem cell
- BMMNC:
-
Bone marrow mononuclear cell
- BNP:
-
Brain natriuretic peptide
- CABG:
-
Coronary artery bypass grafting
- CDC:
-
Cardiosphere-derived cell
- CDCP:
-
Center for Disease Control and Prevention
- CM:
-
Cardiomyocyte
- CPC:
-
Cardiac progenitor cell
- CSC:
-
Cardiac stem cell
- ECM:
-
Extracellular matrix
- EDV:
-
End diastolic volume
- EF:
-
Ejection fraction
- ESC:
-
Embryonic stem cell
- ESV:
-
End systolic volume
- FGF:
-
Fibroblast growth factor
- hESC-CP:
-
Human embryonic stem cell cardiac progenitor
- HF:
-
Heart failure
- HFpEF:
-
HF with preserved ejection fraction
- HFrEF:
-
HF with reduced ejection fraction
- IC:
-
Intracoronary
- IGF-1:
-
Insulin-like growth factor-1
- IM:
-
Intramuscular
- iPSC:
-
Induced-pluripotent stem cell
- IV:
-
Intravenous
- LV:
-
Left ventricular
- LVEDV:
-
Left ventricular end diastolic volume
- LVEF:
-
Left ventricular ejection volume
- LVESV:
-
Left ventricular end systolic volume
- MI:
-
Myocardial infarction
- MLHFQ:
-
Minnesota Living with HF Questionnaire
- MPC:
-
Mesenchymal precursor cell
- MSC:
-
Mesenchymal stem cell
- NYHA:
-
New York Heart Association
- PCI:
-
Percutaneous coronary intervention
- PDGF-B:
-
Platelet-derived growth factor B
- PSC:
-
Pluripotent stem cell
- SDF-1:
-
Stromal cell-derived factor-1
- SM:
-
Skeletal myoblast
- VEGF:
-
Vascular endothelial growth factor
References
Abbafati C, Machado DB, Cislaghi B, Salman OM, Karanikolos M, McKee M, Abbas KM et al (2020) Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396:1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9
Abraham MR, Henrikson CA, Tung L, Chang MG, Aon M, Xue T, Li RA et al (2005) Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res 97:159–167. https://doi.org/10.1161/01.RES.0000174794.22491.a0
Ahmed RPH, Haider KH, Buccini S, Shujia J, Ashraf M (2011a) Reprogramming of skeletal myoblasts for induction of pluripotency for tumor free cardiomyogenesis in the infarcted hear. Circ Res 109:60–70
Ahmed RPH, Ashraf M, Buccini S, Shujia J, Haider KH (2011b) Cardiac tumorigenic potential of induced pluripotent stem cells in immunocompetent host: a note of caution. Regen Med 6:171–178
Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, Eckey T et al (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107:2134–2139. https://doi.org/10.1161/01.CIR.0000062649.63838.C9
Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S et al (2014) The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 63:1123–1133. https://doi.org/10.1016/j.jacc.2013.11.053
Assmus B, Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Tonn T, Seifried E et al (2007) Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ Res 100:1234–1241. https://doi.org/10.1161/01.RES.0000264508.47717.6b
Assmus B, Walter DH, Seeger FH, Leistner DM, Steiner J, Ziegler I, Lutz A et al (2013) Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 309:1622–1631. https://doi.org/10.1001/jama.2013.3527
Barile L, Chimenti I, Gaetani R, Forte E, Miraldi F, Frati G, Messina E et al (2007) Cardiac stem cells: isolation, expansion and experimental use for myocardial regeneration. Nat Clin Pract Cardiovasc Med 1:S9–S14. https://doi.org/10.1038/ncpcardio0738
Bartolucci J, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset C, Rojo P et al (2017) Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy]). Circ Res 121:1192–1204. https://doi.org/10.1161/CIRCRESAHA.117.310712
Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, El Nakadi B et al (2013) Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol 61:2329–2338. https://doi.org/10.1016/j.jacc.2013.02.071
Bartunek J, Terzic A, Davison BA, Filippatos GS, Radovanovic S, Beleslin B, Merkely B, … CHART Program (2017) Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur Heart J 38:648–660. https://doi.org/10.1093/eurheartj/ehw543
Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J et al (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102. https://doi.org/10.1126/science.1164680
Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL et al (2015) Dynamics of cell generation and turnover in the human heart. Cell 161:1566–1575. https://doi.org/10.1016/j.cell.2015.05.026
Blocklet D, Toungouz M, Berkenboom G, Lambermont M, Unger P, Preumont N, Stoupel E et al (2006) Myocardial homing of nonmobilized peripheral-blood CD34+ cells after intracoronary injection. Stem Cells 24:333–336. https://doi.org/10.1634/stemcells.2005-0201
Bolli R, Hare JM, March KL, Pepine CJ, Willerson JT, Perin EC, Yang PC, … Cardiovascular Cell Therapy Research Network (CCTRN) (2018) Rationale and design of the CONCERT-HF trial (combination of mesenchymal and c-kit+ cardiac stem cells as regenerative therapy for heart failure). Circ Res 122:1703–1715. https://doi.org/10.1161/CIRCRESAHA.118.312978
Borow KM, Yaroshinsky A, Greenberg B, Perin EC (2019) Phase 3 DREAM-HF trial of mesenchymal precursor cells in chronic heart failure. Circ Res 125:265–281. https://doi.org/10.1161/CIRCRESAHA.119.314951
Brickwedel J, Gulbins H, Reichenspurner H (2014) Long-term follow-up after autologous skeletal myoblast transplantation in ischaemic heart disease. Interact Cardiovasc Thorac Surg 18:61–66. https://doi.org/10.1093/icvts/ivt434
Bruyneel AA, Sehgal A, Malandraki-Miller S, Carr C (2016) Stem cell therapy for the heart: blind alley or magic bullet? J Cardiovasc Transl Res 9:405–418. https://doi.org/10.1007/s12265-016-9708-y
Campbell NG, Suzuki K (2012) Cell delivery routes for stem cell therapy to the heart: current and future approaches. J Cardiovasc Transl Res 5:713–726. https://doi.org/10.1007/s12265-012-9378-3
Cannatà A, Ali H, Sinagra G, Giacca M (2020) Gene therapy for the heart lessons learned and future perspectives. Circ Res 126:1394–1414. https://doi.org/10.1161/CIRCRESAHA.120.315855
Chen K, Huang Y, Singh R, Wang ZZ (2020) Arrhythmogenic risks of stem cell replacement therapy for cardiovascular diseases. J Cell Physiol 235:6257–6267. https://doi.org/10.1002/jcp.29554
Cheung MM, Jahan N (2020) Can stem cells improve left ventricular ejection fraction in heart failure? A literature review of skeletal myoblasts and bone marrow-derived cells. Cureus 12:e11598. https://doi.org/10.7759/cureus.11598
Chien KR, Frisén J, Fritsche-Danielson R, Melton DA, Murry CE, Weissman IL (2019) Regenerating the field of cardiovascular cell therapy. Nat Biotechnol 37:232–237. https://doi.org/10.1038/s41587-019-0042-1
Chiu RC, Zibaitis A, Kao RL (1995) Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann Thorac Surg 60:12–18
Chiu LL, Iyer RK, Reis LA, Nunes SS, Radisic M (2012) Cardiac tissue engineering: current state and perspectives. Front Biosci (Landmark Ed) 17:1533–1550. https://doi.org/10.2741/4002
Chung ES, Miller L, Patel AN, Anderson RD, Mendelsohn FO, Traverse J, Silver KH et al (2015) Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur Heart J 36:2228–2238. https://doi.org/10.1093/eurheartj/ehv254
Cingolani E (2019) MY APPROACH to stem cell therapy for heart failure patients: not all cells are created equally. Trends Cardiovasc Med 29:374. https://doi.org/10.1016/j.tcm.2019.02.005
Connolly R, O’Brien T, Flaherty G (2014) Stem cell tourism – a web-based analysis of clinical services available to international travellers. Travel Med Infect Dis 12:695–701. https://doi.org/10.1016/j.tmaid.2014.09.008
Correia C, Koshkin A, Duarte P, Hu D, Carido M, Sebastião MJ, Gomes-Alves P et al (2018) 3D aggregate culture improves metabolic maturation of human pluripotent stem cell derived cardiomyocytes. Biotechnol Bioeng 115:630–644. https://doi.org/10.1002/bit.26504
Cyranoski D (2018) ‘Reprogrammed’ stem cells approved to mend human hearts for the first time. Nature 557:619–620. https://doi.org/10.1038/d41586-018-05278-8
Domenech M, Polo-Corrales L, Ramirez-Vick JE, Freytes DO (2016) Tissue engineering strategies for myocardial regeneration: acellular versus cellular scaffolds? Tissue Eng Part B Rev 22:438–458. https://doi.org/10.1089/ten.TEB.2015.0523
Duckers HJ, Houtgraaf J, Hehrlein C, Schofer J, Waltenberger J, Gershlick A, Bartunek J et al (2011) Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. EuroIntervention 6:805–812. https://doi.org/10.4244/EIJV6I7A139
Elmadbouh I, Haider KH, Ashraf M, Chachques J-C (2011) Preconditioning of human skeletal myoblast with stromal cell-derived factor-1α promotes cytoprotective effects against oxidative and anoxic stress. Int J Stem Cells 4:50–60
Eschenhagen T, Bolli R, Braun T, Field LJ, Fleischmann BK, Frisén J, Giacca M et al (2017) Cardiomyocyte regeneration: a consensus statement. Circulation 136:680–686. https://doi.org/10.1161/CIRCULATIONAHA.117.029343
Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E (2016a) Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 12. https://doi.org/10.1002/14651858.CD007888.pub3
Fisher SA, Doree C, Taggart DP, Mathur A, Martin-Rendon E (2016b) Cell therapy for heart disease: trial sequential analyses of two Cochrane reviews. Clin Pharmacol Ther 100:88–101. https://doi.org/10.1002/cpt.344
Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, Palasis M et al (2006) A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 27:1114–1122. https://doi.org/10.1093/eurheartj/ehi818
Gaglianello NA, Mahr C, Benjamin I (2016) Heart failure and cardiomyopathy. In: Benjamin IJ, Griggs RC, Wing EJ, Fitz JG (eds) Andreoli and Carpenter’s Cecil essentials of medicine, 9th edn. Elsevier/Saunders, Philadelphia, pp 55–66
Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R, Tseliou E et al (2017) Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J 38:201–211. https://doi.org/10.1093/eurheartj/ehw240
Gao L, Gregorich ZR, Zhu W, Mattapally S, Oduk Y, Lou X, Kannappan R et al (2018) Large cardiac muscle patches engineered from human induced-pluripotent stem cell-derived cardiac cells improve recovery from myocardial infarction in swine. Circulation 137:1712–1730. https://doi.org/10.1161/CIRCULATIONAHA.117.030785
Gerbin KA, Murry CE (2015) The winding road to regenerating the human heart. Cardiovasc Pathol 24:133–140. https://doi.org/10.1016/j.carpath.2015.02.004
Goussetis E, Manginas A, Koutelou M, Peristeri I, Theodosaki M, Kollaros N, Leontiadis E et al (2006) Intracoronary infusion of CD133+ and CD133−CD34+ selected autologous bone marrow progenitor cells in patients with chronic ischemic cardiomyopathy: cell isolation, adherence to the infarcted area, and body distribution. Stem Cells 24:2279–2283. https://doi.org/10.1634/stemcells.2005-0589
Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS, Barnard D et al (2016) Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 387:1178–1186. https://doi.org/10.1016/S0140-6736(16)00082-9
Haider KH, Tan T, Aziz S, Chachques JC, Sim EKW (2004a) Myoblast transplantation for cardiac repair: a clinical perspective. Mol Ther 9:14–23
Haider KH, Jiang SJ, Aziz S, Lei Y, Law PK, Sim EKW (2004b) Effectiveness of transient immunosupression using cyclosporine for xenomyoblast transplantation for cardiac repair. Transplant Proc 36:232–235
Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M et al (2012) Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308:2369–2379. https://doi.org/10.1001/jama.2012.25321
Hare JM, DiFede DL, Rieger AC, Florea V, Landin AM, El-Khorazaty J, Khan A et al (2017) Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J Am Coll Cardiol 69:526–537. https://doi.org/10.1016/j.jacc.2016.11.009
Haubner BJ, Adamowicz-Brice M, Khadayate S, Tiefenthaler V, Metzler B, Aitman T, Penninger JM (2012) Complete cardiac regeneration in a mouse model of myocardial infarction. Aging 4:966–977. https://doi.org/10.18632/aging.100526
He X, Wang Q, Zhao Y, Zhang H, Wang B, Pan J, Li J et al (2020) Effect of intramyocardial grafting collagen scaffold with mesenchymal stromal cells in patients with chronic ischemic heart disease: a randomized clinical trial. JAMA Netw Open 3:e2016236. https://doi.org/10.1001/jamanetworkopen.2020.16236
Heallen T, Morikawa Y, Leach J, Tao G, Willerson JT, Johnson RL, Martin JF (2013) Hippo signaling impedes adult heart regeneration. Development 140:4683–4690. https://doi.org/10.1242/dev.102798
Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, Mushtaq M et al (2014) Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 311:62–73. https://doi.org/10.1001/jama.2013.282909
Hoeeg C, Frljak S, Qayyum AA, Vrtovec B, Kastrup J, Ekblond A, Follin B (2020) Efficacy and mode of action of mesenchymal stem cells in non-ischemic dilated cardiomyopathy: a systematic review. Biomedicines 8:570. https://doi.org/10.3390/biomedicines8120570
Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC et al (2005) Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112:I150–I156. https://doi.org/10.1161/CIRCULATIONAHA.104.526749
Hu S, Liu S, Zheng Z, Yuan X, Li L, Lu M, Shen R et al (2011) Isolated coronary artery bypass graft combined with bone marrow mononuclear cells delivered through a graft vessel for patients with previous myocardial infarction and chronic heart failure: a single-center, randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 57:2409–2415. https://doi.org/10.1016/j.jacc.2011.01.037
Hulot JS, Ishikawa K, Hajjar RJ (2016) Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J 37:1651–1658. https://doi.org/10.1093/eurheartj/ehw019
Inamdar AA, Inamdar AC (2016) Heart failure: diagnosis, management and utilization. J Clin Med 5:62. https://doi.org/10.3390/jcm5070062
Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, … Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators (2009) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID trial), a first-in-human phase 1/2 clinical trial. J Card Fail 15:171–181. https://doi.org/10.1016/j.cardfail.2009.01.013
Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, … Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators (2011) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 124:304–313. https://doi.org/10.1161/CIRCULATIONAHA.111.022889
Kadota S, Shiba Y (2019) Pluripotent stem cell-derived cardiomyocyte transplantation for heart disease treatment. Curr Cardiol Rep 21:73. https://doi.org/10.1007/s11886-019-1171-3
Kadota S, Minami I, Morone N, Heuser JE, Agladze K, Nakatsuji N (2013) Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets. Eur Heart J 34:1147–1156. https://doi.org/10.1093/eurheartj/ehs418
Kadota S, Tanaka Y, Shiba Y (2020) Heart regeneration using pluripotent stem cells. J Cardiol 76:459–463. https://doi.org/10.1016/j.jjcc.2020.03.013
Karantalis V, Suncion-Loescher VY, Bagno L, Golpanian S, Wolf A, Sanina C, Premer C et al (2015) Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. J Am Coll Cardiol 66:1990–1999. https://doi.org/10.1016/j.jacc.2015.08.879
Kishore R, Khan M (2016) More than tiny sacks: stem cell exosomes as cell-free modality for cardiac repair. Circ Res 118:330–343. https://doi.org/10.1161/CIRCRESAHA.115.307654
Kupatt C, Hinkel R, Pfosser A, El-Aouni C, Wuchrer A, Fritz A, Globisch F et al (2010) Cotransfection of vascular endothelial growth factor-A and platelet-derived growth factor-B via recombinant adeno-associated virus resolves chronic ischemic malperfusion role of vessel maturation. J Am Coll Cardiol 56:414–422. https://doi.org/10.1016/j.jacc.2010.03.050
Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, Devereaux PJ et al (2018) Safety and efficacy of adult stem cell therapy for acute myocardial infarction and ischemic heart failure (SafeCell heart): a systematic review and meta-analysis. Stem Cells Transl Med 7:857–866. https://doi.org/10.1002/sctm.18-0120
Law PK, Sim EKW, Haider KH, Fang G, Chua FK, Kakuchaya T, Repin VS, Bockeria LA (2003) Chapter 17. Myoblast genome therapy and the regenerative heart. In: Kipshidze N, Serruys P (eds) Handbook of cardiovascular cell transplantation. Martin Dunitz, London, pp 241–257
Lei Y, Haider KH, Toh WC, Beng W, Tan R, Law PK, Su L et al (2007) Transplantation of nanoparticle based skeletal myoblasts over-expression vascular endothelial growth factor-165 for cardiac repair. Circulation 116:I-113–I-120
Lei Y, Zhang W, Su L-P, Haider KH, Poh K-K, Galupo MJ, Songco G et al (2011) Nanoparticle based delivery of hypoxia-regulated VEGF transgene system combined with myoblast engraftment for myocardial repair. Biomaterials 32:2424–2431
Liew LC, Ho BX, Soh BS (2020) Mending a broken heart: current strategies and limitations of cell-based therapy. Stem Cell Res Ther 11:138. https://doi.org/10.1186/s13287-020-01648-0
Lin Z, von Gise A, Zhou P, Gu F, Ma Q, Jiang J, Yau AL et al (2014) Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model. Circ Res 115:354–363. https://doi.org/10.1161/CIRCRESAHA.115.303632
Liu YW, Chen B, Yang X, Fugate JA, Kalucki FA, Futakuchi-Tsuchida A, Couture L et al (2018) Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol 36:597–605. https://doi.org/10.1038/nbt.4162
Liu Z, Mikrani R, Zubair HM, Taleb A, Naveed M, Baig MMFA, Zhang Q et al (2020) Systemic and local delivery of mesenchymal stem cells for heart renovation: challenges and innovations. Eur J Pharmacol 876:173049. https://doi.org/10.1016/j.ejphar.2020.173049
Lo B, Parham L (2009) Ethical issues in stem cell research. Endocr Rev 30:204–213. https://doi.org/10.1210/er.2008-0031
Lopez JJ, Laham RJ, Stamler A, Pearlman JD, Bunting S, Kaplan A, Carrozza JP et al (1998) VEGF administration in chronic myocardial ischemia in pigs. Cardiovasc Res 40:272–281. https://doi.org/10.1016/s0008-6363(98)00136-9
Madonna R, Ferdinandy P, De Caterina R, Willerson JT, Marian AJ (2014) Recent developments in cardiovascular stem cells. Circ Res 115:e71–e78. https://doi.org/10.1161/CIRCRESAHA.114.305567
Maghin E, Garbati P, Quarto R, Piccoli M, Bollini S (2020) Young at heart: combining strategies to rejuvenate endogenous mechanisms of cardiac repair. Front Bioeng Biotechnol 8:447. https://doi.org/10.3389/fbioe.2020.00447
Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379:895–904. https://doi.org/10.1016/S0140-6736(12)60195-0
Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Kofoed KF, Haack-Sørensen M, Ekblond A et al (2020) Bone marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: final 4-year follow-up of the MSC-HF trial. Eur J Heart Fail 22:884–892. https://doi.org/10.1002/ejhf.1700
Mazzola M, Di Pasquale E (2020) Toward cardiac regeneration: combination of pluripotent stem cell-based therapies and bioengineering strategies. Front Bioeng Biotechnol 8:455. https://doi.org/10.3389/fbioe.2020.00455
Menasché P (2018) Cell therapy trials for heart regeneration – lessons learned and future directions. Nat Rev Cardiol 15:659–671. https://doi.org/10.1038/s41569-018-0013-0
Menasché P, Hagège AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K et al (2001) Myoblast transplantation for heart failure. Lancet 357(9252):279–280. https://doi.org/10.1016/S0140-6736(00)03617-5
Menasché P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, Vilquin JT et al (2008) The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117:1189–1200. https://doi.org/10.1161/CIRCULATIONAHA.107.734103
Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Parouchev A, Cacciapuoti I et al (2018) Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J Am Coll Cardiol 71:429–438. https://doi.org/10.1016/j.jacc.2017.11.047
Micheu MM (2019) Moving forward on the pathway of cell-based therapies in ischemic heart disease and heart failure – time for new recommendations? World J Stem Cells 11:445–451. https://doi.org/10.4252/wjsc.v11.i8.445
Mohite PN, Sabashnikov A, Simon AR, Weymann A, Patil NP, Unsoeld B, Bireta C et al (2015) Does CircuLite Synergy assist device as partial ventricular support have a place in modern management of advanced heart failure? Expert Rev Med Devices 12:49–60. https://doi.org/10.1586/17434440.2015.985208
Mouton AJ, Rivera OJ, Lindsey ML (2018) Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding. Am J Physiol Heart Circ Physiol 315:H71–H79. https://doi.org/10.1152/ajpheart.00131.2018
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB (2016) American Heart Association Statistics Committee; Stroke Statistics Subcommittee Heart disease and stroke statistics-2016 update: A report from the american heart association. Circulation 26:e38–360. https://doi.org/10.1161/CIR.0000000000000350
Murry CE, Reinecke H, Pabon LM (2006) Regeneration gaps: observations on stem cells and cardiac repair. J Am Coll Cardiol 47:1777–1785. https://doi.org/10.1016/j.jacc.2006.02.002
Nair N, Gongora E (2020) Stem cell therapy in heart failure: where do we stand today? Biochim Biophys Acta Mol Basis Dis 1866:165489. https://doi.org/10.1016/j.bbadis.2019.06.003
Nakamura K, Murry CE (2019) Function follows form – a review of cardiac cell therapy. Circ J 83:2399–2412. https://doi.org/10.1253/circj.CJ-19-0567
Narita T, Shintani Y, Ikebe C, Kaneko M, Campbell NG, Coppen SR, Uppal R et al (2013) The use of scaffold-free cell sheet technique to refine mesenchymal stromal cell-based therapy for heart failure. Mol Ther 21:860–867
Nasseri BA, Ebell W, Dandel M, Kukucka M, Gebker R, Doltra A, Knosalla C et al (2014) Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 35:1263–1274. https://doi.org/10.1093/eurheartj/ehu007
Natsumeda M, Florea V, Rieger AC, Tompkins BA, Banerjee MN, Golpanian S, Fritsch J et al (2017) A combination of allogeneic stem cells promotes cardiac regeneration. J Am Coll Cardiol 70:2504–2515. https://doi.org/10.1016/j.jacc.2017.09.036
Niagara MI, Haider KH, Jiang S, Ashraf M (2007) Pharmacological preconditioning renders skeletal myoblasts resistant to oxidative stress and enhances their cardiac repair ability via expression of paracrine factors after transplantation. Circ Res 100:545–555
Nigro P, Bassetti B, Cavallotti L, Catto V, Carbucicchio C, Pompilio G (2018) Cell therapy for heart disease after 15 years: unmet expectations. Pharmacol Res 127:77–91. https://doi.org/10.1016/j.phrs.2017.02.015
Oikonomopoulos A, Kitani T, Wu JC (2018) Pluripotent stem cell-derived cardiomyocytes as a platform for cell therapy applications: progress and hurdles for clinical translation. Mol Ther 26:1624–1634. https://doi.org/10.1016/j.ymthe.2018.02.026
Ozkan J (2019) Piero Anversa and cardiomyocyte regeneration. Eur Heart J 40:1036–1037. https://doi.org/10.1093/eurheartj/ehz096
Park SR, Kim JW, Jun HS, Roh JY, Lee HY, Hong IS (2018) Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol Ther 26:606–617. https://doi.org/10.1016/j.ymthe.2017.09.023
Park SJ, Kim RY, Park BW, Lee S, Choi SW, Park JH, Choi JJ et al (2019) Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction. Nat Commun 10:3123. https://doi.org/10.1038/s41467-019-11091-2
Penn MS, Mendelsohn FO, Schaer GL, Sherman W, Farr M, Pastore J, Rouy D et al (2013) An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ Res 112:816–825. https://doi.org/10.1161/CIRCRESAHA.111.300440
Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI et al (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107:2294–2302. https://doi.org/10.1161/01.CIR.0000070596.30552.8B
Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV et al (2012) Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 307:1717–1726. https://doi.org/10.1001/jama.2012.418
Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080. https://doi.org/10.1126/science.1200708
Poulin MF, Deka A, Mohamedali B, Schaer GL (2016) Clinical benefits of stem cells for chronic symptomatic systolic heart failure: a systematic review of the existing data and ongoing trials. Cell Transplant 25:1911–1923. https://doi.org/10.3727/096368916X692087
Povsic TJ, O’Connor CM, Henry T, Taussig A, Kereiakes DJ, Fortuin FD, Niederman A et al (2011) A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction. Am Heart J 162:654–662. https://doi.org/10.1016/j.ahj.2011.07.020
Prockop DJ, Olson SD (2007) Clinical trials with adult stem/progenitor cells for tissue repair: let’s not overlook some essential precautions. Blood 109:3147–3151. https://doi.org/10.1182/blood-2006-03-013433
Regenberg AC, Hutchinson LA, Schanker B, Mathews DJ (2009) Medicine on the fringe: stem cell-based interventions in advance of evidence. Stem Cells 27:2312–2319. https://doi.org/10.1002/stem.132
Reinecke H, Poppa V, Murry CE (2002) Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 34:241–924. https://doi.org/10.1006/jmcc.2001.1507
Robey TE, Saiget MK, Reinecke H, Murry CE (2008) Systems approaches to preventing transplanted cell death in cardiac repair. J Mol Cell Cardiol 45:567–581. https://doi.org/10.1016/j.yjmcc.2008.03.009
Rojas SV, Haverich A (2019) Heart failure: ventricular assist devices and cardiac transplantation: a review of current surgical innovations. Der Chirurg; Zeitschrift fur alle Gebiete der Operativen Medizen 90:110–116. https://doi.org/10.1007/s00104-018-0774-3
Romagnuolo R, Masoudpour H, Porta-Sánchez A, Qiang B, Barry J, Laskary A, Qi X et al (2019) Human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias. Stem Cell Rep 12:967–981. https://doi.org/10.1016/j.stemcr.2019.04.005
Ronaldson-Bouchard K, Ma SP, Yeager K, Chen T, Song L, Sirabella D, Morikawa K et al (2018) Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556:239–243. https://doi.org/10.1038/s41586-018-0016-3
Ryan KA, Sanders AN, Wang DD, Levine AD (2010) Tracking the rise of stem cell tourism. Regen Med 5:27–33. https://doi.org/10.2217/rme.09.70
Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, Ogasawara T et al (2016) Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538:388–391. https://doi.org/10.1038/nature19815
Sim EKW, Lei Y, Jiang SJ, Lim YL, Ooi OC, Haider KH (2003) Skeletal myoblast transplant in heart failure. J Card Surg 18:319–327
Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzeźniczak J, Rozwadowska N, Kurpisz M (2004) Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 148(3):531–537. https://doi.org/10.1016/j.ahj.2004.03.043
Simons M, Raposo G (2009) Exosomes – vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581. https://doi.org/10.1016/j.ceb.2009.03.007
Singh VK, Saini A, Kalsan M, Kumar N, Chandra R (2016) Describing the stem cell potency: the various methods of functional assessment and in silico diagnostics. Front Cell Dev Biol 4:134. https://doi.org/10.3389/fcell.2016.00134
Skinner JS, Cooper A (2011) Secondary prevention of ischaemic cardiac events. BMJ Clin Evid 2011:0206
Sobhani A, Khanlarkhani N, Baazm M, Mohammadzadeh F, Najafi A, Mehdinejadiani S, Sargolzaei AF (2017) Multipotent stem cell and current application. Acta Med Iran 55:6–23
Spannbauer A, Mester-Tonczar J, Traxler D, Kastner N, Zlabinger K, Hašimbegović E, Riesenhuber M et al (2020) Large animal models of cell-free cardiac regeneration. Biomolecules 10:1392. https://doi.org/10.3390/biom10101392
Strauer BE, Yousef M, Schannwell CM (2010) The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 12:721–729. https://doi.org/10.1093/eurjhf/hfq095
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. https://doi.org/10.1016/j.cell.2006.07.024
Tanai E, Frantz S (2015) Pathophysiology of heart failure. Compr Physiol 6:187–214. https://doi.org/10.1002/cphy.c140055
Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD et al (1998) Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 4:929–933. https://doi.org/10.1038/nm0898-929
Teerlink JR, Metra M, Filippatos GS, Davison BA, Bartunek J, Terzic A, Gersh BJ, … CHART Investigators (2017) Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail 19:1520–1529. https://doi.org/10.1002/ejhf.898
Tehzeeb J, Manzoor A, Ahmed MM (2019) Is stem cell therapy an answer to heart failure: a literature search. Cureus 11:e5959. https://doi.org/10.7759/cureus.5959
Terrovitis J, Lautamäki R, Bonios M, Fox J, Engles JM, Yu J, Leppo MK et al (2009) Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol 54:1619–1626. https://doi.org/10.1016/j.jacc.2009.04.097
Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE, Doevendans PA, Piek JJ et al (2007) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1:129–137. https://doi.org/10.1016/j.scr.2008.02.002
Turner D, Rieger AC, Balkan W, Hare JM (2020) Clinical-based cell therapies for heart disease – current and future state. Rambam Maimonides Med J 11. https://doi.org/10.5041/RMMJ.10401
van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyöngyösi M, Sluijter JP, Cramer MJ et al (2011) Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res 91:649–658. https://doi.org/10.1093/cvr/cvr113
Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, … American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee (2021) Heart disease and stroke Statistics – 2021 update: a report from the American Heart Association. Circulation 143:e254–e743. https://doi.org/10.1161/CIR.0000000000000950
Wang J, Liu S, Heallen T, Martin JF (2018) The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration. Nat Rev Cardiol 15:672–684. https://doi.org/10.1038/s41569-018-0063-3
Weinberger F, Eschenhagen T (2021) Cardiac regeneration: new hope for an old dream. Annu Rev Physiol 83:59–81. https://doi.org/10.1146/annurev-physiol-031120-103629
Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR et al (2013) Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 127:213–223. https://doi.org/10.1161/CIRCULATIONAHA.112.131110
Xin M, Kim Y, Sutherland LB, Qi X, McAnally J, Schwartz RJ, Richardson JA et al (2011) Regulation of insulin-like growth factor signaling by Yap governs cardiomyocyte proliferation and embryonic heart size. Sci Signal 4:ra70. https://doi.org/10.1126/scisignal.2002278
Xin M, Kim Y, Sutherland LB, Murakami M, Qi X, McAnally J, Porrello ER et al (2013) Hippo pathway effector Yap promotes cardiac regeneration. Proc Natl Acad Sci U S A 110:13839–13844. https://doi.org/10.1073/pnas.1313192110
Ye L, Haider KH, Jiang S, Ling LH, Ge R, Law PK, Sim EKW (2007) Reversal of myocardial injury using genetically modulated human skeletal myoblasts in a rodent cryoinjured heart model. Eur J Heart Fail 7(6):945–952
Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z (2019) Stem cells: past, present, and future. Stem Cell Res Ther 10:68. https://doi.org/10.1186/s13287-019-1165-5
Zhang J (2015) Engineered tissue patch for cardiac cell therapy. Curr Treat Options Cardiovasc Med 17:399. https://doi.org/10.1007/s11936-015-0399-5
Zhao XF, Xu Y, Zhu ZY, Gao CY, Shi YN (2015) Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet Mol Res 14:3010–3017. https://doi.org/10.4238/2015.April.10.11
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Rheault-Henry, M., White, I., Atoui, R. (2022). Unraveling the Mystery of Regenerative Medicine in the Treatment of Heart Failure. In: Haider, K.H. (eds) Handbook of Stem Cell Therapy. Springer, Singapore. https://doi.org/10.1007/978-981-16-6016-0_16-1
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