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Reconstruction of Extracellular Matrix by Grhl3 Modulates Cell Fate Commitment from Fibroblasts to Induced Cardiomyocytes

ABSTRACT: Direct cardiac reprogramming provides a promising therapeutic strategy for heart regeneration by leveraging the endogenous fibroblast population to restore myocardial structure and function. While cardiac transcription factors such as Mef2c, Gata4 and Tbx5 (MGT) drive the generation of induced cardiomyocyte (iCM), the role of extracellular matrix (ECM) components during this process remain largely unexplored. Here, we investigated ECM dynamics during iCM reprogramming and identified integrin subunit alpha 8 (Itga8) as a critical ECM component that suppresses iCM conversion. A loss-of-function screen revealed grainyhead-like protein 3 homolog (Grhl3) as a transcriptional regulator of ECM, including Itga8. Multi-omics analyses demonstrated that Grhl3 efficiency remodels ECM composition to a cardiomyocyte-like state, enhancing iCM reprogramming efficiency and functional maturation. In a mouse model of myocardial infarction, removing Grhl3 enhanced in vivo cardiac reprogramming, and contributed to reduced scar size and improved heart function. These findings establish ECM remodeling as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE285223 | GEO | 2026/01/09

REPOSITORIES: GEO

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Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

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Reconstruction of Extracellular Matrix by Grhl3 Modulates Cell Fate Commitment from Fibroblasts to Induced Cardiomyocytes

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