Post-transcriptional Fibroblast Fate Switching By MBNL1 Regulates Fibrotic and Myocardial Remodeling During Cardiac Wound Healing

Dynamic fibroblast state transitions underlie the heart's fibrotic response, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by Muscleblind-like 1 (MBNL1) has emerged as a driver of differentiated cell states. Indeed, MBNL1 expression is elevated in conjunction with profibrotic transcripts in lineage traced myofibroblasts and modeling this gain in function by fibroblast-specific overexpression of an MBNL1 transgene induced a myofibroblast transcriptional identity in healthy hearts and promoted maladaptive myocyte remodeling and scar maturation following injury. Both fibroblast-specific and myofibroblast-specific loss of MBNL1 limited scar production and maturation, which was ascribed to negligible myofibroblast activity. MBNL1 deletion drove expansion of all quiescent cardiac fibroblast states and promoted mesenchymal stem cell characteristics while forced MBNL1 expression restricted state diversity by transitioning most fibroblasts to the most mature myofibroblast identity. These data suggest MBNL1 is a post-transcriptional switch controlling quiescent to myofibroblast transitions during cardiac wound healing. Overall design: Examination of single cell gene expression in isolated cardiac fibroblasts in SHAM and myocardial infarction (MI) conditions in Wild Type/Non-transgenic (NTG), MBNL1 knockout (Fl-Tcf21iCre), and MBNL1 overexpression (Tg-Tcf21iCre) mice.