Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration

Abstract

Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, like zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here we show that the homeo-box containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA-sequencing we find that Prrx1b is activated in epicardial-derived cells (EPDCs) where it restricts TGF-β ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal EPDCs and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart.

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

“…The epicardium serves as a cell source and signaling hub for heart regeneration (Cao and Poss, 2018). Paracrine signals from the epicardium that support CM proliferation include the growth factor neuregulin 1 (Nrg1) and follistatin-like 1 (Fstl1) (de Bakker et al, 2021;Gemberling et al, 2015;Wei et al, 2015). We analyzed the genomic regions that included nrg1, fstl1a or fstl1b to help understand their regulation.…”

Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells

“…Proliferation and differentiation of intracardiac C-kit+CD45- [ 5 ] and Side Population (SP) [ 6 – 8 ] progenitor cell populations have for example been explored as possible sources for cardiomyocyte renewal. Cardiomyocyte dedifferentiation and proliferation has however subsequently been established as the main mechanism for cardiomyocyte renewal in adult zebrafish [ 9 , 10 ], rodents [ 11 , 12 ] and possibly humans [ 1 ].…”

Chitosan Scaffolds for Cardiac Tissue Engineering

“…Mammalian hearts, as opposed to amphibians, lack from regenerative capabilities that can revert the fibrotic scar and replenish CM population and cardiac function. The mechanisms of differences are still not well understood [9]. In zebrafishes, transcription factor Prrx1b promotes Neuregulin 1 that acts as a mitogen and activates CM proliferation [10].…”