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Splicing Isoforms Associated to TGFβ-Induced Myofibroblast Activation

ABSTRACT: Myofibroblast differentiation is a key process in developmental biology and involved in numerous physiopathology. The gene expression program orchestrating fibroblast to myofibroblast differentiation as well as its recapitulation by TGFβ stimulation in vitro is relatively well characterized. Intriguingly, it is known that the splicing isoform EDA+FN1 is a marker and driver of myofibroblast differentiation but the alternative splicing landscape of myofibroblast is unknown. Here, we performed a high-throughput transcriptomic approach by RNA-Seq in a primary skin fibroblast line and uncover more than 250 splicing isoforms associated to TGFβ-induced myofibroblast using two different bioinformatic pipelines. This splicing profile highlights a distinct layer of regulation when compared to the global gene expression profile of myofibroblast. Surprisingly, TGFβ do not induce an EDA+FN1 splicing shift, although it stimulates global fibronectin expression. A 5 alternative splicing event (ASE) signature was further validated by ddPCR and AS-PCR and retrieved in publicly available RNA-Seq datasets describing other TGFβ-stimulated lung and skin fibroblasts. Thus, we conclude that the 5 ASEs signature may be used as putative universal myofibroblast markers and be of functional significance to myofibroblast formation and biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313078 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of Î± smooth muscle actin (Î±SMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor Î² (TGFÎ²) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of Î±SMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFÎ² activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines Four primary myofibroblast cultures established from adult human colon compared to four skin fibroblast cell lines to identify intestinal myofibroblast specific markers

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Splicing Isoforms Associated to TGFβ-Induced Myofibroblast Activation

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