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Maintenance of Fibroblast Identity During Cardiac Reprogramming and Heart Repair [ATAC-seq]

ABSTRACT: Direct cardiac reprogramming (CR) of fibroblasts into induced cardiomyocytes represents a promising therapeutic avenue to treat heart failure as it would use the injury by-product and transform fibroblasts into new cardiac muscle thereby achieving the unmet medical need of cardiac regeneration. However, low reprogramming efficiency limits its clinical potential. Our lab identified four transcription factors playing a conserved role as barriers to CR. Knock-down of these barriers increase CR five-fold compared to MGT (MEF2C; GATA4; TBX5) overexpression alone. Exploration of direct downstream targets of these barriers identified proteoglycan sulfation as potential pathway regulating cell fate stability. Proteoglycan sulfation, specifically Carbohydrate Sulfotransferase 7 (CHST7), was identified as a conserved barrier to CR. Knockdown of Chst7 in mouse and human fibroblasts significantly enhances CR, increasing expression of cardiac-specific markers and promoting sarcomeric organization. Functional screening of proteoglycan core proteins identifies CD44 as a conserved barrier to reprogramming. Additionally, Chst7 and Cd44 functionally interact to mediate cell fate stability. RNA sequencing and transcription factor analysis identify Junb as the main TF mediating Chst7-regulated transcription during CR. Mechanistic studies of Chst7-regulated pathway genes demonstrate that Chst7 knockdown reduces Pip4k2c expression, establishing a novel regulatory axis between Chst7/Cd44/Junb and Pip4k2c. In vivo, shRNA-mediated Pip4k2c knockdown significantly enhances MGT-mediated CR, increasing cardiac muscle content and reducing fibrosis after myocardial infarction. These findings establish proteoglycan sulfation as a key regulator of cell fate stability, offering new opportunities to improve CR therapies. Thus, proteoglycan sulfation-associated genes might represent an innovative target space to enhance CR for therapeutic purposes.

ORGANISM(S): Mus musculus

PROVIDER: GSE305166 | GEO | 2025/08/19

REPOSITORIES: GEO

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Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

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Maintenance of Fibroblast Identity During Cardiac Reprogramming and Heart Repair [ATAC-seq]

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