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

TY - JOUR

T1 - Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration

AU - de Bakker, Dennis E M

AU - Bouwman, Mara

AU - Dronkers, Esther

AU - Simões, Filipa C

AU - Riley, Paul R

AU - Goumans, Marie-José

AU - Smits, Anke M

AU - Bakkers, Jeroen

N1 - © 2021. Published by The Company of Biologists Ltd.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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, such as 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 homeobox-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 where it restricts TGFβ ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal epicardial-derived cells 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. This article has an associated 'The people behind the papers' interview.

AB - 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, such as 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 homeobox-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 where it restricts TGFβ ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal epicardial-derived cells 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. This article has an associated 'The people behind the papers' interview.

KW - Animals

KW - Cell Line

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cells, Cultured

KW - Collagen/metabolism

KW - Fibroblasts/metabolism

KW - Fibrosis

KW - Heart/physiology

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Myocytes, Cardiac/metabolism

KW - Neuregulin-1/metabolism

KW - Regeneration

KW - Transforming Growth Factor beta/metabolism

KW - Zebrafish

KW - Zebrafish Proteins/genetics

U2 - 10.1242/dev.198937

DO - 10.1242/dev.198937

M3 - Article

C2 - 34486669

SN - 0950-1991

VL - 148

JO - Development (Cambridge)

JF - Development (Cambridge)

IS - 19

ER -