Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart

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 ECM-producing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation.H.S.-I. and N.M. were funded by the Spanish Ministry of Economy and Competitiveness (MINECO) by Grants FPU12/03007 and BFU2014–56970–P, Plan Estatal 2013–2016, Programa Estatal de I+D+i: Proyectos I+D+i 2016, and Fondo Europeo de Desarrollo Regional. N.M. is supported by Swiss National Science Foundation Grant 31003A_159721 and ERC Starting Grant 337703–Zebra–Heart. A.E. is funded through ANR-SNF Project 320030E-164245 (to N.M.). The CNIC is supported by MINECO and the ProCNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO Award SEV-2015-0505).Peer reviewe