Cardiac Progenitor Cell Transplantation and Functional Recovery in Ischaemic Models

Authors

  • Kaczmarek A Department of Regenerative Medicine, Jagiellonian University, Krakow, Poland Author
  • Toft R Department of Developmental Biology, University of Copenhagen, Copenhagen, Denmark Author
  • Perkovic M Department of Biomedical Engineering, University of Zagreb, Zagreb, Croatia Author

DOI:

https://doi.org/10.5281/zenodo.22274693

Keywords:

Cardiac progenitor cells; Myocardial infarction; Lineage tracing; Cardiomyocyte regeneration; Engraftment arrhythmia

Abstract

Graphical abstract

Background: Cardiac regenerative medicine was built on the claim that resident c-kit-positive progenitors generate new
cardiomyocytes and restore contractile function in ischaemic myocardium. That claim has since been tested genetically.
Objective: To reconstruct the evidence on progenitor transplantation, distinguish retracted from superseded work, and
assess whether pluripotent-stem-cell-derived cardiomyocytes offer a route to genuine remuscularisation.
Methods: Narrative review of lineage-tracing experiments, preclinical models, randomised trials and retraction records.
Findings: Lineage tracing set the cardiomyogenic contribution of c-kit-positive cells at 0.002-0.04% of cardiomyocytes.
Individual-patient meta-analysis of 12 randomised trials (n = 1252) gave an ejection fraction difference of 0.96% (95% CI -0.2
to 2.1), and 0.0 in discrepancy-free trials. Three cited papers have been retracted.
Conclusions: The evidence supports paracrine and immune mechanisms rather than new muscle from adult progenitors.
Pluripotent-derived cardiomyocytes remuscularise but carry engraftment arrhythmia.

References

Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., et al. (2001) Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829): 701-705. Figure 2: Weighted mean effect on left ventricular ejection fraction with 95% confidence intervals in the 31 autologous bone marrow trials with sufficient data for meta-analysis, drawn from 49 randomised trials and 133 reports in human patients: 0.0 (-4.67 to 4.65) where reports contain no internal discrepancies, against 10.4 (8.44 to 12.36) where they contain more than 30 [24].

Beltrami, A.P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell, 114(6): 763-776.

Quaini, F., Urbanek, K., Beltrami, A.P., Finato, N., Beltrami, C.A., Nadal-Ginard, B., et al. (2002) Chimerism of the transplanted heart. New England Journal of Medicine, 346(1): 5-15.

Murry, C.E., Soonpaa, M.H., Reinecke, H., Nakajima, H., Nakajima, H.O., Rubart, M., et al. (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983): 664-668.

Balsam, L.B., Wagers, A.J., Christensen, J.L., Kofidis, T., Weissman, I.L., Robbins, R.C. (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428(6983): 668-673.

Ellison, G.M., Vicinanza, C., Smith, A.J., Aquila, I., Leone, A., Waring, C.D., et al. (2013) Adult c-kitpos cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell, 154(4): 827-842.

Bolli, R., Chugh, A.R., D'Amario, D., Loughran, J.H., Stoddard, M.F., Ikram, S., et al. (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. The Lancet, 378(9806): 1847-1857.

Hosoda, T., Zheng, H., Cabral-da-Silva, M., Sanada, F., Ide-Iwata, N., Ogórek, B., et al. (2011) Human cardiac stem cell differentiation is regulated by a mircrine mechanism. Circulation, 123(12): 1287-1296.

Ferreira-Martins, J., Ogórek, B., Cappetta, D., Matsuda, A., Signore, S., D'Amario, D., et al. (2012) Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells. Circulation Research, 110(5): 701-715.

Liu, Y.-W., Chen, B., Yang, X., Fugate, J.A., Kalucki, F.A., Futakuchi-Tsuchida, A., et al. (2018) Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nature Biotechnology, 36(7): 597-605.

van Berlo, J.H., Kanisicak, O., Maillet, M., Vagnozzi, R.J., Karch, J., Lin, S.-C.J., et al. (2014) c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature, 509(7500): 337-341.

Sultana, N., Zhang, L., Yan, J., Chen, J., Cai, W., Razzaque, S., et al. (2015) Resident c-kit+ cells in the heart are not cardiac stem cells. Nature Communications, 6(1): 8701.

Vagnozzi, R.J., Sargent, M.A., Lin, S.-C.J., Palpant, N.J., Murry, C.E., Molkentin, J.D. (2018) Genetic lineage tracing of Sca-1+ cells reveals endothelial but not myogenic contribution to the murine heart. Circulation, 138(25): 2931-2939.

Senyo, S.E., Steinhauser, M.L., Pizzimenti, C.L., Yang, V.K., Cai, L., Wang, M., et al. (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature, 493(7432): 433-436.

Ali, S.R., Hippenmeyer, S., Saadat, L.V., Luo, L., Weissman, I.L., Ardehali, R. (2014) Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proceedings of the National Academy of Sciences, 111(24): 8850-8855.

Bergmann, O., Bhardwaj, R.D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., et al. (2009) Evidence for cardiomyocyte renewal in humans. Science, 324(5923): 98-102.

Bergmann, O., Zdunek, S., Felker, A., Salehpour, M., Alkass, K., Bernard, S., et al. (2015) Dynamics of cell generation and turnover in the human heart. Cell, 161(7): 1566-1575.

Eschenhagen, T., Bolli, R., Braun, T., Field, L.J., Fleischmann, B.K., Frisén, J., et al. (2017) Cardiomyocyte regeneration: a consensus statement. Circulation, 136(7): 680-686.

Vagnozzi, R.J., Maillet, M., Sargent, M.A., Khalil, H., Johansen, A.K.Z., Schwanekamp, J.A., et al. (2020) An acute immune response underlies the benefit of cardiac stem cell therapy. Nature, 577(7790): 405-409.

Hong, K.U., Guo, Y., Li, Q.-H., Cao, P., Al-Maqtari, T., Vajravelu, B.N., et al. (2014) c-kit+ cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS ONE, 9(5): e96725.

Marbán, E. (2018) A mechanistic roadmap for the clinical application of cardiac cell therapies. Nature Biomedical Engineering, 2(6): 353-361.

Zwetsloot, P.P., Végh, A.M.D., Jansen of Lorkeers, S.J., van Hout, G.P.J., Currie, G.L., Sena, E.S., et al. (2016) Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circulation Research, 118(8): 1223-1232.

Gyöngyösi, M., Wojakowski, W., Lemarchand, P., Lunde, K., Tendera, M., Bartunek, J., et al. (2015) Meta-analysis of cell-based cardiac studies (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circulation Research, 116(8): 1346-1360.

Nowbar, A.N., Mielewczik, M., Karavassilis, M., Dehbi, H.-M., Shun-Shin, M.J., Jones, S., et al. (2014) Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ, 348(apr28 1): g2688.

Makkar, R.R., Smith, R.R., Cheng, K., Malliaras, K., Thomson, L.E.J., Berman, D., et al. (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. The Lancet, 379(9819): 895-904.

Makkar, R.R., Kereiakes, D.J., Aguirre, F., Kowalchuk, G., Chakravarty, T., Malliaras, K., et al. (2020) Intracoronary ALLogeneic heart STem cells to Achieve myocardial Cardiovascular Research, 3(2): 145-165. Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial. European Heart Journal, 41(36): 3451-3458.

Bolli, R., Mitrani, R.D., Hare, J.M., Pepine, C.J., Perin, E.C., Willerson, J.T., et al. (2021) A phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. European Journal of Heart Failure, 23(4): 661-674.

Chong, J.J.H., Yang, X., Don, C.W., Minami, E., Liu, Y.-W., Weyers, J.J., et al. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature, 510(7504): 273-277.

Shiba, Y., Gomibuchi, T., Seto, T., Wada, Y., Ichimura, H., Tanaka, Y., et al. (2016) Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature, 538(7625): 388-391.

Gao, L., Gregorich, Z.R., Zhu, W., Mattapally, S., Oduk, Y., Lou, X., 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(16): 1712-1730.

Menasché, P., Vanneaux, V., Hagège, A., Bel, A., Cholley, B., Parouchev, A., et al. (2018) Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. Journal of the American College of Cardiology, 71(4): 429-438.

Romagnuolo, R., Masoudpour, H., Porta-Sánchez, A., Qiang, B., Barry, J., Laskary, A., et al. (2019) Human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias. Stem Cell Reports, 12(5): 967-981.

Selvakumar, D., Clayton, Z.E., Prowse, A., Dingwall, S., Kim, S.K., Reyes, L., et al. (2024) Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias. Nature

Graphical abstract

Published

2025-03-05

Issue

Section

Articles

How to Cite

Cardiac Progenitor Cell Transplantation and Functional Recovery in Ischaemic Models. (2025). Annals of Stem Cell Research, 8(1), 9-16. https://doi.org/10.5281/zenodo.22274693