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Grhl3 Downregulation Drives Extracellular Matrix Adaptation to Cell Fate Commitment from Fibroblasts to Induced Cardiomyocytes

ABSTRACT: Myocardial infarction (MI) remains as one of the leading causes of heart failure. Following MI, excessive extracellular matrix (ECM) deposition forms a rigid fibrotic scar, leading to pathological remodeling and functional adaptation, which drives heart failure and the onset of arrhythmia. Changes of myocardial ECM have been reported to diversely regulate tissue repair, supporting the notion that remodeling ECM proteins would be a critical strategy to enhance heart regeneration. Direct cardiac reprogramming holds promising translational potential for heart regeneration by converting fibroblasts directly into induced cardiomyocytes (iCMs), and the field is now starting to unveil how the ECM and cellular microenvironment affects iCM generation. Through ECM related pathway activity analysis, we observed that integrin related pathways were dysregulated in iCMs, and identified integrin alpha-8 (Itga8) as the critical ECM receptor that suppresses iCMs reprogramming. A loss-of-function screen showed that grainyhead-like protein 3 homolog (Grhl3) was a key regulator of integrins, including Itga8, which impairs iCM generation. Integrative analysis using RNA sequencing and CUT&Tag profiling histone 3 lysine 27 acetylation revealed that loss of Grhl3 remodels ECM composition to a more CM-like state that enhances iCM conversion. In addition, Grhl3 deficiency further enhanced functional improvement and reduced scar size after myocardial injury. Our work highlights the indispensable roles of ECM in regulating iCM conversion.

ORGANISM(S): Mus Musculus

SUBMITTER: Li Wang

PROVIDER: PXD069415 | iProX | Tue Oct 14 00:00:00 BST 2025

REPOSITORIES: iProX

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