Review Article | Published:

The epicardium as a hub for heart regeneration


After decades of directed research, no effective regenerative therapy is currently available to repair the injured human heart. The epicardium, a layer of mesothelial tissue that envelops the heart in all vertebrates, has emerged as a new player in cardiac repair and regeneration. The epicardium is essential for muscle regeneration in the zebrafish model of innate heart regeneration, and the epicardium also participates in fibrotic responses in mammalian hearts. This structure serves as a source of crucial cells, such as vascular smooth muscle cells, pericytes, and fibroblasts, during heart development and repair. The epicardium also secretes factors that are essential for proliferation and survival of cardiomyocytes. In this Review, we describe recent advances in our understanding of the biology of the epicardium and the effect of these findings on the candidacy of this structure as a therapeutic target for heart repair and regeneration.

Key points

  • The epicardium is a layer of mesothelial tissue that envelops the heart in all vertebrates.

  • The epicardium contributes essential cells and signals during heart development and regeneration.

  • The epicardium comprises a heterogeneous cell population and is a highly regenerative tissue.

  • The epicardium is required for normal myocardial regeneration in zebrafish.

  • Current research approaches aim to activate the adult epicardium to promote heart regeneration.

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The authors thank A. Dickson (Duke University, Durham, NC, USA) for assistance with artwork and R. Karra (Duke University, Durham, NC, USA) and J. Kang (University of Wisconsin-Madison, USA) for comments on the manuscript. The authors apologize to their colleagues whose work they could not discuss owing to space limitations. J.C. was supported by AHA postdoctoral fellowships (14POST20230023 and 16POST30230005). K.D.P. acknowledges grant support from the National Heart, Lung, and Blood Institute (NHLBI) (HL081674, HL131319, and HL136182), an AHA Merit Award, and Fondation Leducq.

Reviewer information

Nature Reviews Cardiology thanks M. J. Goumans, P. Riley, and B. Zhou for their contribution to the peer review of this work.

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Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Jingli Cao or Kenneth D. Poss.



Containing two complete sets of chromosomes.


A genetic engineering method to insert an exogenous sequence or to replace the endogenous sequence in a given locus of the genome.

Mitogenic factors

Factors that promote cell proliferation.

In situ hybridization

A biochemical method that uses labelled complementary nucleic acids to visualize specific nucleic acid sequences in tissues.

Gene-trap line

A high-throughput method that captures the readouts of gene regulatory sequences in transgenic animals.

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Further reading

Fig. 1: Cellular contributions of epicardial cells during heart repair and regeneration.
Fig. 2: Epicardial signals in heart repair and regeneration.
Fig. 3: Ex vivo epicardial regeneration.
Fig. 4: Epicardium-based strategy for heart repair.