Adult humans have a hard time regenerating damaged hearts, and scientists have sought inspiration from more-proficient animal models for clues as how to induce regeneration. Zebrafish regenerate injured myocardium in a manner reliant on cardiomyocyte (CM) proliferation, and have emerged as a particularly powerful model for cardiac regeneration, as exemplified in Chinmoy Patra and colleagues’ new paper. A screen to find pro-regenerative extracellular matrix (ECM) genes identifies ccn2a, which encodes a secreted matricellular protein. After heart injury, ccn2a expression is prominently upregulated in the injured tissue, predominantly in endocardial cells. ccn2a mutants show minimal heart regeneration and a persistent collagenous scar. In these mutants, although coronary angiogenesis is unaffected, CMs fail to repopulate the wound site (in controls, CMs track along new coronary vessels to infiltrate the wound site) and CMs also fail to proliferate normally. In both loss-of-function and gain-of-function contexts, ccn2a positively regulates expression of ECM genes encoding collagens and fibronectins, and promotes nuclear localisation of pSmad3 (a marker of TGFβ signalling activity). Moreover, pharmacological inhibition of the TGFβ pathway phenocopies the ccn2a mutant CM phenotype. Taken together, Ccn2a promotes the innate regenerative response of the adult zebrafish heart, and may be a promising therapeutic target for humans.
Heartbroken zebrafish rejuvenate with Ccn2a
Heartbroken zebrafish rejuvenate with Ccn2a. Development 15 January 2021; 148 (2): e148_e0201. doi:
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