Yap is required for scar formation but not myocyte proliferation during heart regeneration in zebrafish. Cardiovasc Res 2019 Mar 01;115(3):570-577
Date
10/09/2018Pubmed ID
30295714DOI
10.1093/cvr/cvy243Scopus ID
2-s2.0-85061983162 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
AIMS: The Hippo signalling pathway regulates multiple cellular processes during organ development and maintenance by modulating activity of the transcriptional cofactor Yap. Core components of this pathway are required for neonatal mouse heart regeneration, however, investigations to date have typically focused on expression and activity in cardiomyocytes. Due to the regenerative capacity of zebrafish and the fact that global loss of Yap is not fully embryonic lethal in zebrafish, we leveraged a yap null mutant to investigate the impact of constitutive Yap deletion during zebrafish heart regeneration.
METHODS AND RESULTS: Following cryoinjury in adult hearts, myocyte proliferation was not decreased in yap mutants, contrary to expectations based on mouse data. Experiments in larval zebrafish (Danio rerio) revealed that deletion of either Yap or Taz had a modest effect on heart growth, reducing gross organ size, while their combined deletion was synergistic; thus, Yap and Taz share some overlapping roles in zebrafish heart development. Surprisingly, adult yap mutants exhibited decreased collagen composition at 7 days post-injury, suggesting a critical role for Yap in scar formation during heart regeneration. siRNA-mediated Yap knockdown in primary rat (Rattus norvegicus) cardiac cells revealed a fibroblast-specific role for Yap in controlling the expression of cytoskeletal and myofibroblast activation genes, as well as pro-inflammatory cyto/chemokines. Corroborating these RNAseq data, we observed increased macrophage infiltration in the scars of yap mutants at 7 days post-injury.
CONCLUSION: These results suggest that Yap deletion has minimal effect on myocyte proliferation in adults, but significantly influences scar formation and immune cell infiltration during zebrafish heart regeneration. Collectively, these data suggest an unexpected role for Yap in matrix formation and macrophage recruitment during heart regeneration.
Author List
Flinn MA, Jeffery BE, O'Meara CC, Link BAAuthors
Michael Andrew Flinn Research Scientist I in the Physiology department at Medical College of WisconsinBrian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Apoptosis Regulatory Proteins
Cell Proliferation
Cells, Cultured
Cicatrix
Cold Temperature
Disease Models, Animal
Fibroblasts
Fibrosis
Gene Expression Regulation
Heart Injuries
Macrophages
Myocytes, Cardiac
Rats
Regeneration
Signal Transduction
Trans-Activators
Ventricular Remodeling
Zebrafish
Zebrafish Proteins
