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Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair

Key Points

  • In response to myocardial infarction, damaged adult cardiomyocytes are replaced by activated fibroblasts that form a fibrotic scar, leading to reduced cardiac function and heart failure. As the adult heart has limited regenerative capacity, there is a need to develop innovative strategies to enhance cardiac repair and regeneration.

  • Cellular replacement strategies for heart repair, in which stem cells and other cell types are injected directly into the injured heart or into the coronary circulation, have shown modest beneficial effects on cardiac function. An alternative approach is to reprogramme non-muscle cells in the injured heart to adopt a cardiac fate.

  • Positive cell cycle regulators are highly expressed in the embryonic heart and downregulated in the adult heart. Activation of various signalling pathways in the heart can modestly reactivate proliferation in adult cardiomyocytes.

  • Identification of transcription factors and microRNAs that control heart formation has enabled reprogramming of non-muscle cells into cardiomyocytes and other cell types of the heart. Following injury, in vivo reprogramming of non-myocytes into cardiomyocytes has improved heart function in mice.

  • Epicardial cells are activated following cardiac injury and have the potential to differentiate into various cell types, offering a niche that can be targeted with small molecules. This provides an attractive approach for regenerative medicine.

  • The inflammatory response has a role in cardiac repair following injury. Several studies have shed light on both positive and negative roles of the inflammatory response in tissue repair and regeneration.

Abstract

As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through 'reawakening' pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure.

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Figure 1: Regeneration of the mammalian neonatal heart.
Figure 2: Regulation of cardiomyocyte proliferation.
Figure 3: Regulation of cardiomyocyte proliferation by the Hippo pathway.
Figure 4: Reprogramming fibroblasts into cardiomyocytes.
Figure 5: Reprogramming different cardiac cell types.

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Acknowledgements

The authors thank G. Huang, Y.-J. Nam, A. Aurora and K. Song for constructive scientific discussions. They thank J. Cabrera for assistance with figures. Work in the author's laboratory was supported by grants from the National Institutes of Health, the Robert A. Welch Foundation (grant I-0025), the Leducq Foundation-Transatlantic Network of Excellence in Cardiovascular Research Program, the American Heart Association-Jon Holden DeHaan Foundation and the Cancer Prevention and Research Institute of Texas (CPRIT). M.X. was supported by a Beginning Grant-in-Aid from the SouthWest Affiliate of the American Heart Association.

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Glossary

Paracrine effects

The effects of a signalling factor secreted by one cell on a nearby cell.

Cardiogenesis

The development of the embryonic heart.

Myocardial infarction

Interruption of the blood flow to the heart, causing cell death and heart damage. Also known as heart attack.

Lineage tracing

A genetic tool used to trace all progeny originating from a single cell.

Cre–loxP recombination system

Tissue-specific expression of Cre recombinase to carry out targeted gene deletion.

Ventricle apex

Anatomically, the lowest portion of the heart.

Myocardial ischaemia–reperfusion

Restoration of the blood supply to the heart tissue that is ischaemic due to a decrease in this.

Trabecular cardiomyocytes

Highly organized cardiomyocytes that form 'projections' into the lumen of the heart ventricles to increase surface area. They facilitate contractility of the heart.

Locked nucleic acid (LNA)-modified anti-miRNAs

Chemically modified, single-stranded RNA oligonucleotides that contain an extra bridge connecting the 2′ oxygen and 4′ carbon, which 'locks' the ribose in the 3′-endo conformation. This results in high stability and affinity to inactivate specific miRNAs.

Subcompact ventricular myocardial layers

The thick muscular walls of the heart ventricles.

Teratogenicity

The capability of producing congenital anomalies.

Heterokaryons

A cell that contains multiple genetically different nuclei.

Gap junctions

A specialized intercellular connection that directly connects the cytoplasm of two cells, allowing various molecules and ions to pass freely between cells.

Venous plexus

A congregation of multiple veins.

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Xin, M., Olson, E. & Bassel-Duby, R. Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 14, 529–541 (2013). https://doi.org/10.1038/nrm3619

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