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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

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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.

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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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