MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response
Citations Over TimeTop 10% of 2015 papers
Abstract
The differentiation of fibroblasts into myofibroblasts mediates tissue wound healing and fibrotic remodelling, although the molecular programme underlying this process remains poorly understood. Here we perform a genome-wide screen for genes that control myofibroblast transformation, and identify the RNA-binding protein muscleblind-like1 (MBNL1). MBNL1 overexpression promotes transformation of fibroblasts into myofibroblasts, whereas loss of Mbnl1 abrogates transformation and impairs the fibrotic phase of wound healing in mouse models of myocardial infarction and dermal injury. Mechanistically, MBNL1 directly binds to and regulates a network of differentiation-specific and cytoskeletal/matrix-assembly transcripts to promote myofibroblast differentiation. One of these transcripts is the nodal transcriptional regulator serum response factor (SRF), whereas another is calcineurin Aβ. CRISPR-Cas9-mediated gene-editing of the MBNL1-binding site within the Srf 3'UTR impairs myofibroblast differentiation, whereas in vivo deletion of Srf in fibroblasts impairs wound healing and fibrosis. These data establish a new RNA-dependent paradigm for myofibroblast formation through MBNL1.
Related Papers
- → The myofibroblast in wound healing and fibrosis: answered and unanswered questions(2016)287 cited
- → Factors influencing myofibroblast differentiation during wound healing and fibrosis.(1995)265 cited
- → Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology(2021)22 cited
- → 50 Years of Myofibroblasts: How the Myofibroblast Concept Evolved(2021)20 cited
- → Temporal elevation of type VI collagen and cardiac myofibroblast differentiation during post‐infarction remodeling(2006)