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Effect of Misexpression of Sox9 on Gastric Differentiation

ABSTRACT: To determine if Sox9 was sufficient to drive mucous differentiation in the gastric epithelium, we bred mice carrying alleles for ROSA26rtTA.IRES.EGFP, TetO-Sox9, and Fgf20Cre.GFP. In these mice, cells expressing Cre will induce rtTA from the ROSA26rtTA.IRES.EGFP allele. To explore transcriptional changes following adult misexpression of Sox9, we isolated RNA from the corpus of Fgf20Cre.GFP/Cre.GFP; ROSA26rtTA.IRES.EGFP/rtTA.IRES.EGFP; TetO-Sox9 pup (misexpression animals) and ROSA26rtTA.IRES.EGFP/rtTA.IRES.EGFP; TetO-Sox9 pup (control) animals and performed RNA-sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE230101 | GEO | 2023/08/30

REPOSITORIES: GEO

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Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.

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Effect of Misexpression of Sox9 on Gastric Differentiation

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