Key result
In mice, cardiac fibroblast-specific MBNL1 overexpression induced a profibrotic state, whereas loss of MBNL1 reverted fibroblasts to a progenitor state that limited cardiac fibrosis after MI.
Why the study?
Dynamic fibroblast state transitions drive the heart's fibrotic response to injury, raising the question of whether controlling these transitions can alter maladaptive fibrosis.
MBNL1 regulates cardiac fibroblast state transitions, and its deletion limits cardiac fibrosis by reverting fibroblasts to a pro-proliferative progenitor state, highlighting a potential therapeutic target for cardiac repair.
MBNL1 gains mark profibrotic fibroblast states; hypothesis-generating for targeted antifibrotic strategies in patients.
SUMMARY 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.
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Bugg et al. (2021) studied Cardiac fibrosis and myocardial infarction. MBNL1 overexpression and loss of function was evaluated on Fibroblast state transitions and cardiac fibrosis. In mice, cardiac fibroblast-specific MBNL1 overexpression induced a profibrotic state, whereas loss of MBNL1 reverted fibroblasts to a progenitor state that limited cardiac fibrosis after MI.
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