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Cell therapy trials for heart regeneration — lessons learned and future directions

Nature Reviews Cardiology volume 15, pages 659–671 (2018)Cite this article

Subjects

Abstract

The effects of cell therapy on heart regeneration in patients with chronic cardiomyopathy have been assessed in several clinical trials. These trials can be categorized as those using noncardiac stem cells, including mesenchymal stem cells, and those using cardiac-committed cells, including KIT+ cardiac stem cells, cardiosphere-derived cells, and cardiovascular progenitor cells derived from embryonic stem cells. Although the safety of cell therapies has been consistently reported, their efficacy remains more elusive. Nevertheless, several lessons have been learned that provide useful clues for future studies. This Review summarizes the main outcomes of these studies and draws some perspectives for future cell-based regenerative trials, which are largely based on the primary therapeutic target: remuscularization of chronic myocardial scars by exogenous cells or predominant use of these cells to activate host-associated repair pathways though paracrine signalling. In the first case, the study design should entail delivery of large numbers of cardiac-committed cells, supply of supportive noncardiac cells, and promotion of cell survival and appropriate coupling with endogenous cardiomyocytes. If the primary objective is to harness endogenous repair pathways, then the flexibility of cell type is greater. As the premise is that the transplanted cells need to engraft only transiently, the priority is to optimize their early retention and possibly to switch towards the sole administration of their secretome.

Key points

  • Clinical trials of cell therapy for cardiac repair and regeneration in chronic heart failure conducted so far have yielded neutral or at most marginally positive outcomes.

  • Among adult tissue sources, mesenchymal stem cells (mostly from the bone marrow or adipose tissue) seem to hold great promise owing to the high secretory profile of these cells.

  • Although robust comparative studies are lacking, cardiac-committed cells, particularly those derived from pluripotent stem cells, could provide superior benefits compared with cells of a noncardiac lineage.

  • The main driver of future clinical trial design should be the primary therapeutic target (remuscularization or enhancement of intrinsic repair); statistical models might need to be re-evaluated to streamline the implementation of these studies.

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Fig. 1: Remuscularization of the injured myocardium with exogenous cells.
Fig. 2: Activation of endogenous repair pathways.

References

  1. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Psaltis, J. P., Schwarz, N., Toledo-Flores, D. & Nicholls, J. S. Cellular therapy for heart failure. Curr. Cardiol. Rev. 12, 195–215 (2016).

    PubMed  PubMed Central  Google Scholar 

  3. Mocini, D. et al. Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting. Am. Heart J. 151, 192–197 (2006).

    PubMed  Google Scholar 

  4. Menasché, P. et al. Myoblast transplantation for heart failure. Lancet 357, 279–280 (2001).

    PubMed  Google Scholar 

  5. Menasché, P. et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117, 1189–1200 (2008).

    PubMed  Google Scholar 

  6. Miyagawa, S. et al. Phase I clinical trial of autologous stem cell–sheet transplantation therapy for treating cardiomyopathy. J. Am. Heart Assoc. 6, e003918 (2017).

    PubMed  PubMed Central  Google Scholar 

  7. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    CAS  PubMed  Google Scholar 

  8. Hendrikx, M. et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 114, I101–107 (2006).

    PubMed  Google Scholar 

  9. Ang, K.-L. et al. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone. Nat. Clin. Pract. Cardiovasc. Med. 5, 663–670 (2008).

    PubMed  Google Scholar 

  10. Pätilä, T. et al. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J. Heart Lung Transplant. 33, 567–574 (2014).

    PubMed  Google Scholar 

  11. Perin, E. C. et al. 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 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Heldman, A. W. et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 311, 62–73 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Taylor, D. A. et al. Identification of bone marrow cell subpopulations associated with improved functional outcomes in patients with chronic left ventricular dysfunction: an embedded cohort evaluation of the FOCUS-CCTRN trial. Cell Transplant. 25, 1675–1687 (2016).

    PubMed  Google Scholar 

  14. Heeschen, C. et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 109, 1615–1622 (2004).

    PubMed  Google Scholar 

  15. Contreras, A. et al. Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials. Bas. Res. Cardiol. 112, 3 (2017).

    Google Scholar 

  16. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02438306 (2018).

  17. Povsic, T. J. et al. The RENEW trial: efficacy and safety of intramyocardial autologous CD34( + ) cell administration in patients with refractory angina. JACC Cardiovasc. Interv. 9, 1576–1585 (2016).

    PubMed  Google Scholar 

  18. Stamm, C. et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J. Thorac. Cardiovasc. Surg. 133, 717–725 (2007).

    PubMed  Google Scholar 

  19. Nasseri, B. A. et al. Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur. Heart J. 35, 1263–1274 (2014).

    CAS  PubMed  Google Scholar 

  20. Noiseux, N. et al. The IMPACT-CABG trial: a multicenter, randomized clinical trial of CD133+ stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy. J. Thorac. Cardiovasc. Surg. 152, 1582–1588.e2 (2016).

    CAS  PubMed  Google Scholar 

  21. Spees, J. L., Lee, R. H. & Gregory, C. A. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res. Ther. 7, 125 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. Baron, F. & Storb, R. Mesenchymal stromal cells: a new tool against graft-versus-host disease? Biol. Blood Marrow Transplant. 18, 822–840 (2012).

    PubMed  Google Scholar 

  23. Mathiasen, A. B. et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). Eur. Heart J. 36, 1744–1753 (2015).

    CAS  PubMed  Google Scholar 

  24. Bartunek, J. et al. Cardiopoietic stem cell therapy in heart failure. J. Am. Coll. Cardiol. 61, 2329–2338 (2013).

    PubMed  Google Scholar 

  25. Bartunek, J. et al. Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 38, 648–660 (2017).

    PubMed  Google Scholar 

  26. Butler, J. et al. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II-A randomized trial. Circ. Res. 120, 332–340 (2017).

    CAS  PubMed  Google Scholar 

  27. Patel, A. N. et al. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet 387, 2412–2421 (2016).

    CAS  PubMed  Google Scholar 

  28. Povsic, T. J. & Zeiher, A. M. IxCELL-DCM: rejuvenation for cardiac regenerative therapy? Lancet 387, 2362–2363 (2016).

    PubMed  Google Scholar 

  29. Perin, E. C. et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ. Res. 117, 576–584 (2015).

    CAS  PubMed  Google Scholar 

  30. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02032004 (2016).

  31. Ascheim, D. D. et al. Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation 129, 2287–2296 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fisher, S. A., Doree, C., Mathur, A., Taggart, D. P. & Martin-Rendon, E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 12, CD007888 (2016).

    PubMed  Google Scholar 

  33. Fisher, S., Doree, C., Taggart, D., Mathur, A. & Martin-Rendon, E. Cell therapy for heart disease: trial sequential analyses of two Cochrane reviews. Clin. Pharmacol. Ther. 100, 88–101 (2016).

    CAS  PubMed  Google Scholar 

  34. Bianconi, V. et al. Endothelial and cardiac progenitor cells for cardiovascular repair: a controversial paradigm in cell therapy. Pharmacol. Ther. 181, 156–168 (2018).

    CAS  PubMed  Google Scholar 

  35. Mishra, R. et al. Characterization and functionality of cardiac progenitor cells in congenital heart patients. Circulation 123, 364–373 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bolli, R. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378, 1847–1857 (2011).

    PubMed  PubMed Central  Google Scholar 

  37. Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007).

    PubMed  Google Scholar 

  38. Malliaras, K. et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J. Am. Coll. Cardiol. 63, 110–122 (2014).

    PubMed  Google Scholar 

  39. van Berlo, J. H. et al. c-Kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. Koninckx, R. et al. Mesenchymal stem cells or cardiac progenitors for cardiac repair? A comparative study. Cell. Mol. Life Sci. CMLS 68, 2141–2156 (2011).

    CAS  PubMed  Google Scholar 

  41. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02501811 (2018).

  42. Karantalis, V. et al. Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy. J. Am. Coll. Cardiol. 66, 1990–1999 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02503280 (2017).

  44. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01458405 (2017).

  45. Capricor Therapeutics. Capricor Therapeutics provides update on ALLSTAR trial. PR Newswire https://www.prnewswire.com/news-releases/capricor-therapeutics-provides-update-on-allstar-trial-300456715.html (2017).

  46. Lundy, S. D., Gantz, J. A., Pagan, C. M., Filice, D. & Laflamme, M. A. Pluripotent stem cell derived cardiomyocytes for cardiac repair. Curr. Treat. Options Cardiovasc. Med. 16, 319 (2014).

    PubMed  PubMed Central  Google Scholar 

  47. Bellamy, V. et al. Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold. J. Heart Lung Transplant. 34, 1198–1207 (2015).

    PubMed  Google Scholar 

  48. Menasché, P. et al. Transplantation of human embryonic stem cell–derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 71, 429–438 (2018).

    PubMed  Google Scholar 

  49. Wang, L. et al. Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function. Stem Cell Res. Ther. 8, 230 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Strauer, B. E. et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction [German]. Dtsch. Med. Wochenschr. 126, 932–938 (2001).

    CAS  PubMed  Google Scholar 

  51. Reinecke, H., Poppa, V. & Murry, C. E. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J. Mol. Cell. Cardiol. 34, 241–249 (2002).

    CAS  PubMed  Google Scholar 

  52. Murry, C. E. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004).

    CAS  PubMed  Google Scholar 

  53. Lang, C. I. et al. Cardiac cell therapies for the treatment of acute myocardial infarction: a meta-analysis from mouse studies. Cell. Physiol. Biochem. 42, 254–268 (2017).

    CAS  PubMed  Google Scholar 

  54. Emmert, M. Y. et al. Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction — from cardioprotection to functional repair in a translational pig infarction model. Biomaterials 122, 48–62 (2017).

    CAS  PubMed  Google Scholar 

  55. Chimenti, I. et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106, 971–980 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chong, J. J. H. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ye, J. et al. Treatment with hESC-derived myocardial precursors improves cardiac function after a myocardial infarction. PLoS ONE 10, e0131123 (2015).

    PubMed  PubMed Central  Google Scholar 

  58. Funakoshi, S. et al. Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. Sci. Rep. 6, 19111 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Aonuma, T. et al. Apoptosis-resistant cardiac progenitor cells modified with apurinic/apyrimidinic endonuclease/redox factor 1 gene overexpression regulate cardiac repair after myocardial infarction: CPCs modified by APE1 regulate cardiac repair. Stem Cells Transl Med. 5, 1067–1078 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhu, P. et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J. Cell. Mol. Med. 19, 2232–2243 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, H. W., Haider, H. K., Jiang, S. & Ashraf, M. Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. J. Biol. Chem. 284, 33161–33168 (2009).

    PubMed  Google Scholar 

  62. Schwartz, S. D. et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385, 509–516 (2015).

    PubMed  Google Scholar 

  63. Iseoka, H. et al. Pivotal role of non-cardiomyocytes in electromechanical and therapeutic potential of induced pluripotent stem cell-derived engineered cardiac tissue. Tissue Eng. Part A 24, 287–300 (2017).

    PubMed  Google Scholar 

  64. Chen, H.-S. V., Kim, C. & Mercola, M. Electrophysiological challenges of cell-based myocardial repair. Circulation 120, 2496–2508 (2009).

    PubMed  PubMed Central  Google Scholar 

  65. Garbern, J. C. & Lee, R. T. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 12, 689–698 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Li, T.-S. 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. 59, 942–953 (2012).

    PubMed  PubMed Central  Google Scholar 

  67. Weil, B. R., Suzuki, G., Leiker, M. M., Fallavollita, J. A. & Canty, J. M. Comparative efficacy of intracoronary allogeneic mesenchymal stem cells and cardiosphere-derived cells in swine with hibernating myocardium. Circ. Res. 117, 634–644 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Tano, N. et al. Allogeneic mesenchymal stromal cells transplanted onto the heart surface achieve therapeutic myocardial repair despite immunologic responses in rats. J. Am. Heart Assoc. 5, e002815 (2016).

    PubMed  PubMed Central  Google Scholar 

  69. Malliaras, K. et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 125, 100–112 (2012).

    CAS  PubMed  Google Scholar 

  70. Hare, J. M. et al. Comparison of allogeneic versus autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308, 2369–2379 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Vrtovec, B. et al. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 128, S42–49 (2013).

    CAS  PubMed  Google Scholar 

  72. Hou, D. et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112, I150–156 (2005).

    PubMed  Google Scholar 

  73. van den Akker, F. et al. Intramyocardial stem cell injection: go(ne) with the flow. Eur. Heart J. 38, 184–186 (2017).

    PubMed  Google Scholar 

  74. Behfar, A. et al. Optimized delivery system achieves enhanced endomyocardial stem cell retention. Circ. Cardiovasc. Interv. 6, 710–718 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Mitsutake, Y. et al. Improvement of local cell delivery using helix transendocardial delivery catheter in a porcine heart. Int. Heart. J. 58, 435–440 (2017).

    PubMed  Google Scholar 

  76. Amer, M. H., Rose, F. R. A. J., White, L. J. & Shakesheff, K. M. A. Detailed assessment of varying ejection rate on delivery efficiency of mesenchymal stem cells using narrow-bore needles. Stem Cells Transl Med. 5, 366–378 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. O’Neill, H. S. et al. Biomaterial-enhanced cell and drug delivery: lessons learned in the cardiac field and future perspectives. Adv. Mater. Deerfield Beach Fla. 28, 5648–5661 (2016).

    Google Scholar 

  78. Levit, R. D. et al. Cellular encapsulation enhances cardiac repair. J. Am. Heart Assoc. 2, e000367 (2013).

    PubMed  PubMed Central  Google Scholar 

  79. Parekkadan, B. & Milwid, J. M. Mesenchymal stem cells as therapeutics. Annu. Rev. Biomed. Eng. 12, 87–117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Guo, Y. et al. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Bas. Res. Cardiol. 112, 18 (2017).

    Google Scholar 

  81. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02408432 (2017).

  82. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02962661 (2018).

  83. Lee, R. H. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5, 54–63 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Tang, J. et al. Targeted repair of heart injury by stem cells fused with platelet nanovesicles. Nat. Biomed. Eng. 2, 17–26 (2018).

    PubMed  PubMed Central  Google Scholar 

  85. Penicka, M. et al. One-day kinetics of myocardial engraftment after intracoronary injection of bone marrow mononuclear cells in patients with acute and chronic myocardial infarction. Heart Br. Card. Soc. 93, 837–841 (2007).

    CAS  Google Scholar 

  86. Koczera, P. et al. PBCA-based polymeric microbubbles for molecular imaging and drug delivery. J. Control. Release 259, 128–135 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kervadec, A. et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J. Heart Lung Transplant. 35, 795–807 (2016).

    PubMed  Google Scholar 

  88. Mohamed, T. M. A. et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135, 978–995 (2017).

    CAS  PubMed  Google Scholar 

  89. Mann, D. L. et al. One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure. Eur. J. Heart Fail. 18, 314–325 (2016).

    CAS  PubMed  Google Scholar 

  90. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02305602 (2017).

  91. Fischer-Rasokat, U. et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ. Heart Fail. 2, 417–423 (2009).

    CAS  PubMed  Google Scholar 

  92. Bittner, V. et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 270, 1702–1707 (1993).

    CAS  PubMed  Google Scholar 

  93. Onisko, A., Druzdzel, M. J. & Austin, R. M. How to interpret the results of medical time series data analysis: classical statistical approaches versus dynamic Bayesian network modeling. J. Pathol. Inform. 7, 50 (2016).

    PubMed  PubMed Central  Google Scholar 

  94. Fernández-Avilés, F. et al. Global position paper on cardiovascular regenerative medicine. Eur. Heart J. 38, 2532–2546 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Wang, H. et al. A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells. Sci. Rep. 6 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Elman, J. S. et al. Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells. PLoS ONE 9, e89882 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Brooks, A. et al. Concise Review: Quantitative detection and modeling the in vivo kinetics of therapeutic mesenchymal stem/stromal cells: detection and modeling kinetics of stem cells. Stem Cells Transl Med. 7, 78–86 (2018).

    PubMed  Google Scholar 

  98. Oransky, I. Harvard-Brigham heart researcher under investigation earns Lancet Expression of Concern. Retraction Watch https://retractionwatch.com/2014/04/11/harvard-brigham-heart-researcher-under-investigation-earns-lancet-expression-of-concern/ (2014).

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Nature Reviews Cardiology thanks F. Fernández-Avilés, A. Behfar, and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Cardiovascular Surgery, Université Paris Descartes, Sorbonne Paris Cité, INSERM U-970, Hôpital Européen Georges Pompidou, Paris, France

    Philippe Menasché

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Glossary

Stemness

The unique capacity of stem cells to self-renew and to differentiate into multiple lineages.

Autologous

Derived from the same individual.

Apheresis

Technology in which the blood is passed through a device that separates one particular blood constituent and returns the remainder to the bloodstream.

Cardiosphere-derived cells

Cells outgrowing from in vitro cultured tissue retrieved from the right ventricle by a transvenous endoventricular biopsy.

Embryonic stem cells

(ESCs). Cells taken from 4–6 day embryos, a stage at which the cells are still pluripotent and thus able to give rise to all cell types in response to the appropriate cues.

Induced pluripotent stem cells

(iPSCs). Adult cells that have been reprogrammed to an embryonic-like pluripotent state.

Allogeneic

Derived from genetically different individuals of the same species.

Syngeneic

Derived from genetically identical individuals and thus equivalent to autologous.

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Menasché, P. Cell therapy trials for heart regeneration — lessons learned and future directions. Nat Rev Cardiol 15, 659–671 (2018). https://doi.org/10.1038/s41569-018-0013-0

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