Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart
Sánchez-Iranzo, Héctor (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Galardi-Castilla, María (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Sanz-Morejón, Andrés (Universität Bern)
González-Rosa, Juan Manuel (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Costa, Ricardo (Centre de Recerca en Agrigenòmica)
Ernst, Alexander (Universität Bern)
Sainz de Aja, Julio (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Langa, Xavier (Universität Bern)
Mercader, Nadia (Universität Bern)
Institut de Recerca i Tecnologia Agroalimentàries

Fecha:	2018
Resumen:	After myocardial infarction in the mammalian heart, millions of cardiomyocytes are lost and replaced by fibrotic scar tissue. While fibrosis is persistent in adult mammals, there are some vertebrates, including zebrafish, with the capacity for regeneration. This process does not occur in the absence of fibrosis. Here we studied subpopulations of collagen-producing cells and analyzed their fate after complete regeneration of the zebrafish myocardium. Our data show that fibroblasts persisted in the regenerated heart but shut down the profibrotic program. While fibrosis could be considered as detrimental to the regeneration process, our study reveals a positive effect on cardiomyocyte proliferation. Accordingly, a fibrotic response can be beneficial for heart regeneration. 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.
Ayudas:	European Commission 337703 Ministerio de Economía y Competitividad SEV-2015-0505 Ministerio de Economía y Competitividad BFU2014-56970-P Ministerio de Economía y Competitividad FPU12/03007
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Heart regeneration ; Fibroblast inactivation ; Zebrafish ; Fibrosis ; Cardiomyocyte proliferation
Publicado en:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, issue 16 (April 2018) , p. 4188-4193, ISSN 1091-6490

DOI: 10.1073/pnas.1716713115
PMID: 29610343

6 p, 1.8 MB

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