Journal
DEVELOPMENT
Volume 148, Issue 19, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.198937
Keywords
Prrx1; Neuregulin; Zebrafish; Heart regeneration; Fibrosis; Fibroblasts
Categories
Funding
- Netherlands CardioVascular Research Initiative (CVON)
- Dutch Heart Foundation (Hartstichting)
- Dutch Federation of University Medical Centres (Nederlandse Federatie van Universitair Medische Centra)
- Netherlands Organisation for Health Research and Development (ZonMw)
- Royal Netherlands Academy of Sciences (Koninklijke Nederlandse Akademie van Wetenschappen)
- Dekker fellowship of the Dutch Heart Foundation [2017T059]
- British Heart Foundation personal chair award [CH/11/1/28798]
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The homeobox-containing transcription factor Prrx1b is essential for scar-free regeneration of the zebrafish heart by regulating fibrosis and cardiomyocyte proliferation. Prrx1b is activated in epicardial-derived cells where it inhibits TGF beta ligand expression and collagen production while promoting Nrg1 expression to stimulate cardiomyocyte proliferation, maintaining a balance between fibrosis and regeneration in the injured zebrafish heart.
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 TGF beta 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.
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