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Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics

Key Points

  • Endogenous regeneration seen in animal models provides a template for optimal repair of the human heart following myocardial infarction.

  • In the regenerating heart, new cardiomyocytes are produced by proliferation of the existing cardiomyocyte pool. Understanding and targeting the intrinsic mechanisms that regulate cardiomyocyte cell cycle re-entry could enable therapeutic regeneration in the human heart.

  • Repair is modulated by epicardial activation, neoangiogenesis, the immune response and the extracellular matrix. Biological insights from regenerative models, combined with use of high-throughput phenotypic screens and in vivo discovery approaches, are uncovering novel therapeutic targets and compounds to improve repair.

  • Regenerative strategies that emerge from increased understanding of cardiomyocyte lineage specification include transplantation of in vitro-produced cardiomyocytes and in vivo reprogramming of fibroblasts. Current efforts to improve engraftment, maturation and targeting will enable a next generation of clinical trials.

  • Distinct approaches are required for patients in the immediate post-myocardial infarction period and for those with chronic heart failure, and high-risk strategies should initially be targeted at patients with end-stage heart failure. Clinical trial design should be tailored to incorporate informed biological end points alongside functional end points.

Abstract

Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarction and have provided lessons to guide future efforts towards heart regeneration through cellular reprogramming or cardiomyocyte transplantation.

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Figure 1: Heart failure therapy timeline.
Figure 2: Endogenous mechanisms controlling cardiomyocyte proliferation.
Figure 3: Therapeutic strategies for heart regeneration.

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Acknowledgements

T.J.C. is supported by the Wellcome Trust (grant 106334/Z/14/Z). R.P.C. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford and the British Heart Foundation Centre for Research Excellence, Oxford. P.R.R. is supported by the British Heart Foundation (grants CH/11/1/28798 and RG/13/9/303269).

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Correspondence to Paul R. Riley.

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P.R.R.is co-founder of OxStem Cardio, which is an Oxford University spin-out that seeks to exploit therapeutic strategies stimulating endogenous repair in cardiovascular regenerative medicine. All other authors declare no competing interests.

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Glossary

Heart failure

A pathological state that is defined by the inability of the heart to pump blood to support the requirements of the body. Typical symptoms include shortness of breath, fluid retention and fatigue.

Myocardial infarction

An acute injury to the heart that is caused by occlusion of the coronary blood supply, usually due to atherosclerotic plaque rupture. This process is also commonly known as a heart attack.

Epicardium

The outer layer of the heart; also known as the visceral pericardium.

Fibrosis

A pathological process that is characterized by deposition of interstitial fibrous or scar tissue.

Cytokinesis

Division of the cell cytoplasm to complete the cell cycle and create a membrane barrier between two daughter cells.

Binucleation

Division of the nucleus that leads to the formation of two nuclei within a cell but without division of the cytoplasm.

Ploidy

The number of sets of chromosomes in a cell.

Ventricular remodelling

A process that is characterized by a change in size, shape and structure of the ventricle. After myocardial infarction, pathological remodelling causes the ventricle to enlarge, become spherical in shape and functionally deteriorate.

Embryonic stem cells

(ESCs). Pluripotent stem cells that are derived from the inner cell mass of embryos.

Allogeneic

Derived from genetically different individuals from the same species.

Induced pluripotent stem cell

(iPSC). Pluripotent stem cells that are reprogrammed from somatic cells by introducing pluripotency factors.

Autologous

Derived from cells or tissues of the same individual.

Lymphangiogenesis

The growth of new lymphatic vessels.

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Cahill, T., Choudhury, R. & Riley, P. Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat Rev Drug Discov 16, 699–717 (2017). https://doi.org/10.1038/nrd.2017.106

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