Maintenance of Fibroblast Identity During Cardiac Reprogramming and Heart Repair [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1304539 | ENA |
REPOSITORIES: ENA
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Project description:Maintenance of Fibroblast Identity During Cardiac Reprogramming and Heart Repair [ATAC-seq]
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Project description: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.
2025-08-19 | GSE305170 | GEO
Project description: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.
2025-08-19 | GSE305166 | GEO
Project description:Here, we engineered functional EV-like nanovesicles (NVs) from human-induced pluripotent stem cells and highlight their potential as a functional surrogate for natural EVs for tissue repair. Proteome profiling of target cells further identified pathways implicated in angiogenesis (MYH10, AAMP, SLC3A2), cell survival (CCN2, RHEB, IGF2R, MFGE8), and fibroblast activation (CCN2, STAT3, COL1A1/2/4A2/12A1, ACTN1/4, ACTC1). This study demonstrates scalable generation of functional NVs and highlights their potential as a functional surrogate for natural EVs for tissue repair.
2023-01-15 | PXD036654 | Pride
Project description:Fibroblast-derived TGFb1 regulates skin repair and fibrosis
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Project description:Fibroblast-derived osteoglycin promotes alveolar epithelial cell repair
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Project description:Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment. Loosely defined based on their mesenchymal origin, capacity to adhere to plastic and to secrete extracellular matrix, cardiac fibroblasts have been largely neglected due to heterogeneity and lack of proper markers. Objective: To identify genes uniquely expressed in the cardiac fibroblast pool, we performed an unbiased comparative analysis between cardiac and tail fibroblasts, and tracked cardiac fibroblasts after injury to determine their contribution to myocardial regeneration. Methods and Results: High-throughput cell surface and intracellular profiling identified homogeneously expressed MSC markers in cardiac fibroblasts, as well as a surprising number of cardiogenic markers, some expressed at higher levels than in cardiomyocytes. Genetically marked fibroblasts contributed to interstitial but not cardiomyocyte compartments in infarcted hearts. Conclusions: The core transcriptional identity of cardiac fibroblasts reflects their embryological origin, provoking novel interpretations for studies on more specialized cardiac progenitors, and offering a novel perspective for reinterpreting cardiac regenerative therapies 3 biological replicates plated over 5 days after isolation pooled out of 2 animals were used for both tail and heart fibroblasts (6 total samples analysed)
2014-05-20 | E-GEOD-50531 | biostudies-arrayexpress
Project description:Fibroblast-derived CSF1 is essential for intestinal macrophage maintenance
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Project description:Inhibition of fibroblast activation protein promotes cardiac repair by stabilizing brain natriuretic peptide after myocardial infarction
2023-01-26 | GSE184986 | GEO
Project description:There is an increasing need for pharmacological treatments that target defective epithelial repair in chronic diseases, such as chronic obstructive pulmonary disease. The mesenchymal niche plays a major regulatory role in guiding epithelial progenitor cell activation during repair. We persuaded that the secreted factors involved in this interaction hold potential as drug targets. In this study, we utilized a proteomics-guided drug discovery strategy, leveraging the secretome of lung fibroblasts, aimed to uncover drug targets affecting epithelial progenitor behavior. Using lung organoids, we identified several ligands with regenerative potential. Surprisingly, the matrix protein osteoglycin (OGN) had the most profound effect. RNA sequencing revealed that OGN promoted alveolar epithelial type II cell differentiation, whilst increasing reactive oxygen species detoxification, reducing senescence, and enhancing growth factor-mediated fibroblast-epithelial crosstalk. The idea that OGN protein plays a role in COPD was further substantiated by the finding that the expression was reduced in lung tissue of COPD patients and in smoke-exposed mice. Additionally, we found an active fragment of OGN comprising the leucine-rich repeat regions 4-7 to have comparable regenerative potential in regulating lung organoid formation. The active fragment of OGN ameliorated elastase-induced lung injury in murine precision-cut lung slices (PCLS) and improved lung function in mice. These findings identify lung fibroblast-derived OGN as a matrix protein supporting alveolar epithelial growth and its active fragment as a promising therapeutic target for epithelial cell repair in individuals with accelerated tissue damage.
2025-04-15 | PXD053766 | Pride