Elsevier

Developmental Biology

Volume 399, Issue 1, 1 March 2015, Pages 27-40
Developmental Biology

A dual epimorphic and compensatory mode of heart regeneration in zebrafish

https://doi.org/10.1016/j.ydbio.2014.12.002Get rights and content
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Highlights

  • Mitotic index suggests a dual regenerative mechanism in the zebrafish heart.

  • Embryonic myosin is reactivated in the adult ventricle around the injured area.

  • Undifferentiated cardiac cells integrate with the fibrotic tissue and the original myocardium.

  • A transient cardiac blastema resolves during the advanced regeneration phase.

  • Compensatory proliferation of mature cells contributes to ventricle restoration.

Abstract

Zebrafish heart regeneration relies on the capacity of cardiomyocytes to proliferate upon injury. To understand the principles of this process after cryoinjury-induced myocardial infarction, we established a spatio-temporal map of mitotic cardiomyocytes and their differentiation dynamics. Immunodetection of phosphohistone H3 and embryonic ventricular heavy chain myosin highlighted two distinct regenerative processes during the early phase of regeneration. The injury-abutting zone comprises a population of cardiac cells that reactivates the expression of embryo-specific sarcomeric proteins and it displays a 10-fold higher mitotic activity in comparison to the injury-remote zone. The undifferentiated cardiomyocytes resemble a blastema-like structure between the original and wound tissues. They integrate with the fibrotic tissue through the fibronectin-tenascin C extracellular matrix, and with the mature cardiomyocytes through upregulation of the tight junction marker, connexin 43. During the advanced regenerative phase, the population of undifferentiated cardiomyocytes disperses within the regenerating myocardium and it is not detected after the termination of regeneration. Although the blastema represents a transient landmark of the regenerating ventricle, the remaining mature myocardium also displays an enhanced mitotic index when compared to uninjured hearts. This suggests an unexpected contribution of a global proliferative activity to restore the impaired cardiac function. Based on these findings, we propose a new model of zebrafish heart regeneration that involves a combination of blastema-dependent epimorphosis and a compensatory organ-wide response.

Abbreviations

CM
cardiomyocyte
reg My
regenerated myocardium
ori My
original myocardium
embCMHC
embryonic cardiac myosin heavy chain, ECM, extracellular matrix
PIT
post-infarcted tissue
dpci
days post cryoinjury
CI
cryoinjury
MyoC
myocardium

Keywords

Heart regeneration
Epimorphic regeneration
Blastema
Compensatory growth
Cell cycle
N2.261
Phosphohistone H3
Cardiac undifferentiated cells
Embryonic ventricular myosin
Zebrafish

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Equal contribution.