Heart stem cells: fact or fantasy?
https://doi.org/10.15829/1560-4071-2019-11-84-90
Abstract
In the spring of 2018, Harvard Medical School and the Brigham and Women’s Hospital reported the retraction of 31 articles of Dr. Piero Anversa lab, who have been studying heart stem cells for more than 15 years, due to the fact that these articles “included falsified and/or fabricated data”. This extremely unpleasant incident cast suspicion on other research groups studying regenerative effects ofcells harvested from the myocardium. It contributed to skeptical opinion about thepossibilities of regenerative technologies in cardiology in general and the complete denial of any regenerative potential of heart. This review presents an analysis of Dr. Piero Anversa lab studies and other works devoted to the study of regenerative processes in the heart, a modern view on the mechanisms of the heart regenerative potential and the regenerative effects of progenitor cells harvested from the myocardium, and the prospects for the development of cellular technologies in cardiology.
Supporting agencies: This study was supported by a grant from the Russian Science Foundation № 19-15-00384
About the Author
E. V. Parfenova
National Medical Research Center of Cardiology; Moscow State University
Russian Federation
Russian Federation
Moscow.
References
1. Sylva M, van den Hoff MJ, Moorman AF. Development of the human heart. Am J Med Genet A. 2014 Jun;164A(6):1347-71. doi: 10.1002/ajmg.a.35896.
2. Beltrami AP, Barlucchi L, Torella D et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003 Sep 19;114(6):763-76. DOI: 10.1016/s0092-8674(03)00687-1
3. Urbanek K, Torella D, Sheikh F et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure.Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8692-7. DOI: 10.1073/pnas.0500169102
4. Barile L, Messina E, Giacomello A et al. Endogenous cardiac stem cells. Prog Cardiovasc Dis. 2007 Jul-Aug;50(1):31-48. DOI: 10.1016/j.pcad.2007.03.005
5. Bearzi C, Rota M, Hosoda T et al. Human cardiac stem cells. Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14068-73. DOI: 10.1073/pnas.0706760104.
6. Nadal-Ginard B, Anversa P, Kajstura J et al. Cardiac stem cells and myocardial regeneration. Novartis Found Symp. 2005;265:142-54.
7. Urbanek K, Rota M, Cascapera S et al. Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival.Circ Res. 2005 Sep 30;97(7):663-73. DOI: 10.1161/01.RES.0000183733.53101.11
8. Linke A, Müller P, Nurzynska D et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71. DOI: 10.1073/pnas.0502678102
9. Ellison GM, Torella D, Dellegrottaglie S et al. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol. 2011 Aug 23;58(9):977-86. doi: 10.1016/j.jacc.2011.05.013.
10. Rota M, Padin-Iruegas ME, Misao Y et al. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res. 2008 Jul 3;103(1):107-16. doi: 10.1161/CIRCRESAHA.108.
11. Cai CL, Molkentin JD. The elusive progenitor cell in cardiac regeneration: slip slidin’ away.Circ Res. 2017; 120:400–406. doi: 10.1161/CIRCRESAHA.116.309710.
12. Maliken BD, Molkentin JD. Undeniable Evidence That the Adult Mammalian Heart Lacks an Endogenous Regenerative StemCell. Circulation. 2018 Aug 21;138(8):806-808. doi: 10.1161/CIRCULATIONAHA.118.035186
13. Dergilev K, Tsokolaeva Z, Makarevich P et al. C-Kit Cardiac Progenitor Cell Based Cell Sheet Improves Vascularization and Attenuates Cardiac Remodeling following Myocardial Infarction in Rats. Biomed Res Int. 2018 Jun 25;2018:3536854. doi: 10.1155/2018/3536854.
14. Zwetsloot PP, Végh AM, Jansen of Lorkeers SJ et al. Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies.Circ Res. 2016 Apr 15;118(8):1223-32. doi: 10.1161/CIRCRESAHA.115.307676.
15. Kajstura J, Gurusamy N, Ogórek B et al. Myocyte turnover in the aging human heart. Circ Res. 2010 Nov 26;107(11):1374-86. Retracted. doi: 10.1161/CIRCRESAHA.110.231498.
16. Kajstura J, Rota M, Cappetta D et al. Cardiomyogenesis in the aging and failing human heart. Circulation. 2012 Oct 9;126(15):1869-81. Retracted. doi: 10.1161/CIRCULATIONAHA.112.118380.
17. Bergmann O, Bhardwaj RD, Bernard S et al. Evidence for cardiomyocyte renewal in humans. Science. 2009 Apr 3;324(5923):98-102. doi: 10.1126/science.1164680.
18. Lázár E, Sadek HA, Bergmann O. Cardiomyocyte renewal in the human heart: insights from the fall-out. Eur Heart J. 2017 Aug 7;38(30):2333-2342. doi: 10.1093/eurheartj/ehx343.
19. Aquila I, Marino F, Cianflone E et al. The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin. Pharmacol Res. 2018 Jan;127:116-128. doi: 10.1016/j.phrs.2017.06.012.
20. Anversa P, Rota M, Urbanek K et al Myocardial aging--a stem cell problem. Basic Res Cardiol. 2005 Nov;100(6):482-93. DOI: 10.1007/s00395-005-0554-3
21. Leri A, Rota M, Pasqualini FS et al. Origin of cardiomyocytes in the adult heart. Circ Res. 2015 Jan 2;116(1):150-66. doi: 10.1161/CIRCRESAHA.116.303595.
22. Senyo SE, Steinhauser ML, Pizzimenti CL et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493:433–436. doi: 10.1038/nature11682.
23. Ali SR, Hippenmeyer S, Saadat LV et al. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A. 2014;111:8850–8855. doi: 10.1073/pnas.1408233111.
24. van Berlo JH, Kanisicak O, Maillet M et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014;509:337–341. doi: 10.1038/nature13309.
25. Sultana N, Zhang L, Yan J et al. Resident c-kit(+) cells in the heart are not cardiac stem cells. Nat Commun. 2015;6:8701. doi: 10.1038/ncomms9701.
26. Wang WE, Li L, Xia X et al. Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury. Circulation. 2017 Aug 29;136(9):834-848. doi: 10.1161/CIRCULATIONAHA.116.024307.
27. Barile L, Milano G, Vassalli G. Beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia. Stem Cell Investig. 2017; 4:93. doi: 10.21037/sci.2017.11.06.
28. Xiao J, Pan Y, Li XH et al. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis. 2016 Jun 23;7(6):e2277. doi: 10.1038/cddis.2016.181.
29. Ibrahim AG, Cheng K, Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports. 2014 May 8;2(5):606-19. doi: 10.1016/j.stemcr.2014.04.006.
30. Wang X., Ha T., Liu L et al. Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 2013;97:432–442. 30. doi: 10.1093/cvr/cvs356.
31. Mol EA, Goumans MJ, Sluijter JPG. Cardiac Progenitor-Cell Derived Exosomes as Cell-Free Therapeutic for Cardiac Repair. Adv Exp Med Biol. 2017;998:207-219. doi: 10.1007/978-981-10-4397-0_14.
32. Sahoo S, Losordo DW. Exosomes and cardiac repair after myocardial infarction. Circ Res. 2014 Jan 17;114(2):333-44. doi: 10.1161/CIRCRESAHA.114.300639
33. Keith MC, Bolli R. "String theory" of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results. Circ Res. 2015 Mar 27;116(7):1216-30. doi: 10.1161/CIRCRESAHA.116.305557.
34. Gambini E, Pompilio G, Biondi A et al. C-kit+ cardiac progenitors exhibit mesenchymal markers and preferential cardiovascular commitment. Cardiovascular research. 2011;89:362–373. doi: 10.1093/cvr/cvq292.
35. Blazquez-Martinez A, Chiesa M, Arnalich F et al. C-kit identifies a subpopulation of mesenchymal stem cells in adipose tissue with higher telomerase expression and differentiation potential. Differentiation; research in biological diversity. 2014;87:147–160. doi: 10.1016/j.diff.2014.02.007.
36. Limana F, Capogrossi MC, Germani A. The epicardium in cardiac repair: From the stem cell view. Pharmacology & therapeutics. 2011;129:82–96. doi: 10.1016/j.pharmthera.2010.09.002.
37. Limana F, Bertolami C, Mangoni A et al. Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: Role of the pericardial fluid. Journal of molecular and cellular cardiology. 2010;48:609–618. doi: 10.1016/j.yjmcc.2009.11.008.
38. Smits AM, Dronkers E, Goumans MJ. The epicardium as a source of multipotent adult cardiac progenitor cells: Their origin, role and fate. Pharmacol Res. 2018 Jan;127:129-140. doi: 10.1016/j.phrs.2017.07.020.
39. Zhou B, Honor LB, He H et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest. 2011;121:1894–1904. doi: 10.1172/JCI45529.
40. Bolli R, Chugh AR, D'Amario D et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378:1847–1857. Retracted. doi: 10.1016/S0140-6736(11)61590-0.
41. Makkar RR, Smith RR, Cheng K et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379:895–904.
42. Chakravarty T, Makkar RR, Ascheim DD et al. ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design. Cell Transplant. 2017 Feb 16;26(2):205-214. doi: 10.3727/096368916X692933.
43. Sanz-Ruiz R, Casado Plasencia A, Borlado LR et al. Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction). Circ Res. 2017 Jun 23;121(1):71-80. doi: 10.1161/CIRCRESAHA.117.310651.
44. Chugh AR, Beache GM, Loughran JH et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy:the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viabilityby magnetic resonance. Circulation. 2012 Sep 11;126(11 Suppl 1):S54-64. DOI: 10.1161/CIRCULATIONAHA.112.092627
45. Eschenhagen T, Bolli R, Braun T et al. Cardiomyocyte Regeneration: A Consensus Statement. Circulation. 2017 Aug 15;136(7):680-686. doi: 10.1161/CIRCULATIONAHA.117.029343.
46. Oskouei BN, Lamirault G, Joseph C et al. Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl Med. 2012 Feb;1(2):116-24. doi: 10.5966/sctm.2011-0015.
47. Li TS, Cheng K, Malliaras K et al. Direct comparison of different stem cell types and subpopulations reveals superiorparacrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012 Mar 6;59(10):942-53. doi: 10.1016/j.jacc.2011.11.029.
48. Bao L, Meng Q, Li Y et al. C-Kit Positive Cardiac Stem Cells and Bone Marrow-Derived Mesenchymal Stem Cells Synergistically Enhance Angiogenesis and Improve Cardiac Function After Myocardial Infarction in a Paracrine Manne. J Card Fail. 2017 May;23(5):403-415. doi: 10.1016/j.cardfail.2017.03.002.
49. Williams AR, Hatzistergos KE, Addicott B et al. 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. 2013 Jan 15;127(2):213-23. doi: 10.1161/CIRCULATIONAHA.112.131110.
50. Afzal MR, Samanta A, Shah ZI, et al. Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and InsightsFrom Randomized Controlled Trials. Circ Res. 2015 Aug 28;117(6):558-75. doi: 10.1161/CIRCRESAHA.114.304792.
51. Aguado BA, Mulyasasmita W, Su J et al. Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. Tissue Eng A. 2012;18:806–15. doi: 10.1089/ten.TEA.2011.0391.
52. Zhang Y, Fan W, Wang K et al. Novel preparation of Au nanoparticles loaded Laponite nanoparticles/ECM injectablehydrogel on cardiac differentiation of resident cardiac stem cells to cardiomyocytes. J Photochem Photobiol B. 2019 Mar;192:49-54. doi: 10.1016/j.jphotobiol.2018.12.022.
53. Fan Z, Xu Z, Niu H et al. An Injectable Oxygen Release System to Augment Cell Survival and Promote CardiacRepair Following Myocardial Infarction. Sci Rep. 2018 Jan 22;8(1):1371. doi: 10.1038/s41598-018-19906-w
54. Madonna R, Van Laake LW, Botker HE et al. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019 Mar 1;115(3):488-500. doi: 10.1093/cvr/cvz010
55. Mohsin S, Khan M, Nguyen Jet al. Rejuvenation of human cardiac progenitor cells with Pim-1 kinase. Circ Res. 2013 Oct 25;113(10):1169-79. doi: 10.1161/CIRCRESAHA.113.302302
56. Zhang LX, DeNicola M, Qin X et al. Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs. Am J Physiol Cell Physiol. 2014 Aug 15;307(4):C358-72. doi: 10.1152/ajpcell.00187.2013.
57. Madonna R, Van Laake LW, Botker HE,et al. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019 1;115(3):488-500. doi: 10.1093/cvr/cvz010.
58. Eulalio A, Mano M, Dal Ferro M et al. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 2012 Dec 20;492(7429):376-81. doi: 10.1038/nature11739.
59. Giacca M, Zacchigna S. Harnessing the microRNA pathway for cardiac regeneration. J Mol Cell Cardiol. 2015 Dec;89(Pt A):68-74. doi: 10.1016/j.yjmcc.2015.09.017.
60. Lesizza P, Prosdocimo G, Martinelli V.et al. Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction. Circ Res. 2017 14;120(8):1298-1304. doi:10.1161/CIRCRESAHA.116.309589.
61. Rojas SV, Kensah G, Rotaermel A, et al. Transplantation of purified iPSC-derived cardiomyocytes in myocardial infarction. PLoS One. 2017 May 11;12(5):e0173222. doi: 10.1371/journal.pone.0173222.
62. Duran AG, Reidell O, Stachelscheid H, et al. Regenerative Medicine/Cardiac Cell Therapy: Pluripotent Stem Cells. Thorac Cardiovasc Surg. 2018;66(1):53-62. doi: 10.1055/s-0037-1608761.
63. Kurotsu S, Suzuki T, Ieda M. Direct Reprogramming, Epigenetics, and Cardiac Regeneration. J Card Fail. 2017;23(7):552-557. doi: 10.1016/j.cardfail.2017.05.009.
64. Werner JH, Rosenberg JH, Um JY, et al. Molecular discoveries and treatment strategies by direct reprogramming in cardiac regeneration. Transl Res. 2019 Jan;203:73-87. doi: 10.1016/j.trsl.2018.07.012.
Review
For citations:
Parfenova E.V. Heart stem cells: fact or fantasy? Russian Journal of Cardiology. 2019;(11):84-90. (In Russ.) https://doi.org/10.15829/1560-4071-2019-11-84-90
Views:
1519
Email this article 