Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 16, Pages 4188-4193Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716713115
Keywords
heart regeneration; fibroblast inactivation; zebrafish; fibrosis; cardiomyocyte proliferation
Categories
Funding
- Spanish Ministry of Economy and Competitiveness (MINECO) [FPU12/03007, BFU2014-56970-P]
- Fondo Europeo de Desarrollo Regional
- Swiss National Science Foundation [31003A_159721]
- ERC Starting Grant [337703-Zebra-Heart]
- ANR-SNF Project [320030E-164245]
- MINECO
- ProCNIC Foundation
- MINECO [SEV-2015-0505]
- Swiss National Science Foundation (SNF) [31003A_159721] Funding Source: Swiss National Science Foundation (SNF)
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In the zebrafish (Danio rerio), regeneration and fibrosis after cardiac injury are not mutually exclusive responses. Upon cardiac cryoinjury, collagen and other extracellular matrix (ECM) proteins accumulate at the injury site. However, in contrast to the situation in mammals, fibrosis is transient in zebrafish and its regression is concomitant with regrowth of the myocardial wall. Little is known about the cells producing this fibrotic tissue or how it resolves. Using novel genetic tools to mark periostin b- and collagen 1alpha2 (col1a2)-expressing cells in combination with transcriptome analysis, we explored the sources of activated fibroblasts and traced their fate. We describe that during fibrosis regression, fibroblasts are not fully eliminated but become inactivated. Unexpectedly, limiting the fibrotic response by genetic ablation of col1a2-expressing cells impaired cardiomyocyte proliferation. We conclude that ECMproducing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation.
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