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Abstract: Mechanical forces are essential to the development and progression of fibrosis, and are likely to be as important as soluble factors. These forces regulate the phenotype and proliferation of myofibroblasts and other cells in damaged tissues, the activation of growth factors, the structure and mechanics of the matrix, and, potentially, tissue patterning. Better understanding of the variety and magnitude of forces, the characteristics of those forces in biological tissues, and their impact on fibrosis in multiple tissues is needed and may lead to identification of important new therapeutic targets. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. [Copyright &y& Elsevier]

Abstract: The Type III TGF-β receptor, betaglycan, is a widely expressed proteoglycan co-receptor for TGF-β superfamily ligands. The full-length protein undergoes ectodomain cleavage with release of a soluble ectodomain fragment. The fate of the resulting transmembrane–cytoplasmic fragment, however, has never been explored. We demonstrate here that the transmembrane–cytoplasmic fragment is stable in transfected cells and in cell lines expressing endogenous betaglycan. Production of this fragment is inhibited by the ectodomain shedding inhibitor TAPI-2. Treatment of cells with inhibitors of the intramembrane protease γ-secretase stabilizes this fragment, suggesting that it is a substrate of γ-secretase. Expression of the transmembrane–cytoplasmic fragment as well as γ-secretase inhibitor stabilization are independent of TGF-β1 or -β2 and are unaffected by mutation of the cytoplasmic domain serines that undergo phosphorylation. γ-Secretase inhibition or the expression of a transmembrane–cytoplasmic fragment in HepG2 cells blunted TGF-β2 signaling. Our findings thus suggest that the transmembrane–cytoplasmic fragment remaining after betaglycan ectodomain cleavage is stable and a substrate of γ-secretase, which may have significant implications for the TGF-β signaling response. [ABSTRACT FROM AUTHOR]

Abstract: Transforming growth factor-β (TGF-β) has potent, cell phenotype restricted effects. In bone, it controls multiple activities by osteoblasts through three predominant receptors. Of these, the relative amounts of TGF-β receptor I (TβRI) vary directly with TGF-β sensitivity. The rat TβRI gene promoter includes cis-acting elements for transcription factor Runx2. Here we show conservation and selective partitioning of TβRI and retention of TGF-β activity with osteoblast differentiation, Runx2 binding to the TβRI gene promoter on osteoblast chromatin, and decreased promoter activity by Runx2 binding site mutation. Furthermore, in contrast to the stimulatory effects induced by single or limited exposure to TGF-β, we found that osteoblasts became resistant to TGF-β after high dose and repetitive treatment. TβRI protein, mRNA, and gene promoter activity all decreased after three daily TGF-β treatments, in parallel with a reduction in Runx2 protein and Runx dependent gene expression. In this way, sustained TGF-β exposure can limit its own effectiveness by suppressing the expression of its primary signaling receptor. This tightly controlled system may constitute a feedback loop to protect against TGF-β excess, and impose important limitations that are required for the progression of events during skeletal growth, remodeling and repair. [Copyright &y& Elsevier]

Studies activation of the transforming growth factor-beta downstream signaling molecules Smads, 2,3, and 4 in hepatic stellate cells (HSC) cultured in vitro with several phenotypes. Unchanged total levels of Smad4 in the transdifferentiation of HSC; Mediation of the activation of Smad2 by the transforming growth factor-beta (TGF-beta); Difference in TGF-beta-mediated signaling pathways in quiescent and in vitro transdifferentiated HSC.

Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen. [Display omitted] • The majority of CAF in ICC are derived from hepatic stellate cells • Inflammatory CAF promote ICC through HGF and its receptor MET • myCAF promote ICC through Has2 /hyaluronic acid • CAF-derived type I collagen contributes to stiffness but does not promote ICC growth Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily stiff liver tumor due to abundant scar-forming cancer-associated fibroblasts (CAF). Here, Affo et al. determine the origin and functions of CAF, and uncover distinct CAF subsets, promoting ICC growth via different therapeutically targetable mediators. Thus, CAF and their mediators may serve as therapeutic targets for ICC. [ABSTRACT FROM AUTHOR]