Therapeutic approaches for cardiac regeneration and repair

Abstract

Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

Key points

  • Preclinical outcomes of cardiac regenerative therapy approaches have not translated effectively to clinical trials.

  • Transplantation of induced pluripotent stem cell-derived cardiomyocytes for cardiac repair has encountered problems related to safety and low engraftment rates.

  • Cell-free-based approaches for heart repair and regeneration involve cardioprotective secretory factors or direct reprogramming of resident cardiac fibroblasts to cardiomyocyte-like cells.

  • Endogenous cardiomyocyte proliferation can be evoked by modulating cell cycle regulators, the Hippo signalling pathway, and the cardiac microenvironment.

  • Genome editing can correct underlying mutations causing heart disease in animals and offers a state-of-the-art therapeutic approach for cardiac repair.

  • The therapeutic potential of cardiac regeneration approaches can be improved by optimizing the delivery method of the therapeutic factors.

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Fig. 1: Response and therapeutic approaches to myocardial injury.
Fig. 2: Contributions of secretory factors to cardiac repair and regeneration.
Fig. 3: Direct reprogramming of fibroblasts into cardiomyocytes.
Fig. 4: Approaches to stimulate endogenous regenerative capacity for heart repair.
Fig. 5: Genome editing as a therapeutic approach to heart disease.

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Acknowledgements

The authors thank L. Amoasii and Y.-L. Min (University of Texas Southwestern Medical Center, USA) and S. Tohyama (Keio University School of Medicine, Japan) for constructive scientific discussions, J. Cabrera (University of Texas Southwestern Medical Center, USA) for assistance with figures, and A. McKenzie (University of Texas Southwestern Medical Center, USA) for help with editing. Work in the authors’ laboratory is supported by grants from the NIH (AR-067294, HL-130253, HD-087351, and HL-138426), Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research, and the Robert A. Welch Foundation (grant 1–0025 to E.N.O.). H.H. is supported by the Uehara Memorial Foundation Postdoctoral Fellowship and the Kanae Foreign Study Grant.

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Nature Reviews Cardiology thanks T. Eschenhagen and the other, anonymous reviewers for their contribution to the peer review of this work.

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Glossary

Left ventricular assist devices

(LVADs). Electromechanical devices to support circulation of a failing heart.

Cardiac resynchronization therapy

Therapy that uses an electromechanical device to resynchronize ventricular contraction in patients with heart failure.

Lineage tracing

A method to identify all progeny originating from a single cell.

MerCreMer

A fusion protein containing Cre recombinase flanked at both ends with a mutated murine oestrogen receptor (Mer) ligand binding domain. MerCreMer generates an inducible Cre recombinase activation system that can gain access to the nuclear compartment only with exposure to tamoxifen.

Hydrogels

Colloid gels composed of a network of hydrophilic polymer chains.

Paracrine effects

The effects on a cell that are induced by secreted factors from another cell.

Synthetic modified RNA

Chemically synthesized RNA with changes to the chemical composition that alter function or stability of the RNA.

Xenotransplantation

Cell, tissue, or organ transplantation across different species.

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Hashimoto, H., Olson, E.N. & Bassel-Duby, R. Therapeutic approaches for cardiac regeneration and repair. Nat Rev Cardiol 15, 585–600 (2018). https://doi.org/10.1038/s41569-018-0036-6

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