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The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [CUT&RUN]

ABSTRACT: Smooth muscle-derived Sca1+ adventitial progenitor cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and matrix tissue. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the differentiation trajectory of AdvSca1-SM cells to myofibroblasts are unclear. Here we show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells in vivo after acute vascular injury and pharmacological inhibition of the Brg1 bromodomain by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness-related genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; Brg1 inhibition blocked TGF-β1-induced phenotypic transition. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal regulatory sequences of stemness-related genes and recruitment of Brg1 to promoters of myofibroblast-related genes. This recruitment of Brg1 to myofibroblast genes was blocked in the presence of PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit.

ORGANISM(S): Mus musculus

PROVIDER: GSE211422 | GEO | 2023/03/28

REPOSITORIES: GEO

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The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [RNA-seq]

Project description:Smooth muscle-derived Sca1+ adventitial progenitor cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and matrix tissue. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the differentiation trajectory of AdvSca1-SM cells to myofibroblasts are unclear. Here we show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells in vivo after acute vascular injury and pharmacological inhibition of the Brg1 bromodomain by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness-related genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; Brg1 inhibition blocked TGF-β1-induced phenotypic transition. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal regulatory sequences of stemness-related genes and recruitment of Brg1 to promoters of myofibroblast-related genes. This recruitment of Brg1 to myofibroblast genes was blocked in the presence of PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit.

2023-03-28 | GSE211421 | GEO

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Genome-wide transcript profiling for native porcine valvular interstitial cells and those cultured on TCPS and treated with TGF-β1

Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.

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Smooth muscle-derived progenitor cell myofibroblast differentiation through KLF4 downregulation promotes arterial remodeling and fibrosis

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Genome-wide transcript profiling for native porcine valvular interstitial cells and those cultured on TCPS and treated with TGF-β1

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Transcription profiling of human IMR-90 cells in response to TGF-I?1

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