PT  - JOURNAL ARTICLE
AU  - Darrian Bugg
AU  - Ross Bretherton
AU  - Kylie Beach
AU  - Anna Reese
AU  - Jagadambika Gunaje
AU  - Galina Flint
AU  - Cole A. DeForest
AU  - April Stempien-Otero
AU  - Jennifer Davis
TI  - Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair
AID  - 10.1101/2021.01.26.428279
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.26.428279
4099  - http://biorxiv.org/content/early/2021/01/26/2021.01.26.428279.short
4100  - http://biorxiv.org/content/early/2021/01/26/2021.01.26.428279.full
AB  - Dynamic fibroblast state transitions are responsible for the heart’s fibrotic response to injury, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by the RNA binding protein Muscleblind Like 1 (MBNL1) has emerged as a potential driver of differentiated cell states. Here genetic lineage tracing of myofibroblasts in the injured heart demonstrated that gains in MBNL1 function corresponded to profibrotic fibroblast states. Similarly, in mice cardiac fibroblast specific MBNL1 overexpression induced a transcriptional myofibroblast profile in healthy cardiac fibroblasts that prevented the fibroproliferative phase of cardiac wound healing. By contrast loss of MBNL1 reverted cardiac fibroblasts to a pro-proliferative epicardial progenitor state that limited cardiac fibrosis following myocardial infarction. This progenitor state transition was associated with an MBNL1-dependent destabilization of the mesenchymal transition gene, Sox9. These findings suggest that MBNL1 regulation of the fibroblast transcriptome drives state transitions underlying cardiac fibrosis and repair.Competing Interest StatementThe authors have declared no competing interest.