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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: In response to liver injury or loss of liver mass, proliferation of mature liver cells is the first-line defense to restore liver homeostasis. In the setting of chronic liver disease, however, the ability of hepatocytes and cholangiocytes to proliferate is blocked and small bipotential progenitor cells are activated. Recent studies have established the role of these facultative progenitor cells in injury repair and fibrosis in patients with chronic liver disease and in experimental models. Several signaling pathways linking progenitor cell activation and fibrosis have been identified, and there is increasing evidence that cross-talk (both physical and via soluble factors) between progenitor cells and myofibroblasts is essential for both fibrosis and parenchymal regeneration. Even more exciting are new data examining the cellular components of the progenitor cell niche, demonstrating that both resident liver cells and circulating cells from the bone marrow can function as stem cells, suggesting that there is a surprising degree of phenotypic plasticity such that progenitor cells can contribute to the myofibroblast population and vice versa. We highlight here recent findings from the literature demonstrating the cellular and functional complexity of the progenitor cell niche, and emphasize some of the important questions that remain to drive future research. [ABSTRACT FROM AUTHOR]

• A novel regulatory role for a cysteine-rich domain of Type III collagen was examined • CR peptide binds to TGFβ with high affinity and in a dose dependent manner • The CR peptide attenuates TGFβ signaling in fibroblasts and breast cancer cells • CR peptide tempers myofibroblast activation and function • In vivo studies support CR's potential to control scarring, fibrosis and tumor activities TGFβ is a key regulator of the dynamic reciprocity between cells and the extracellular matrix that drives physiologic and pathologic responses in both tissue repair and tumor microenvironments. Our studies define type III Collagen (Col3) as a suppressor of scar formation and desmoplasia through its effects, in part, on myofibroblasts. TGFβ stimulates activation of myofibroblasts, and here, we demonstrate that cultured Col3-deficient fibroblasts have increased TGFβ signaling compared to wild-type fibroblasts. Moreover, kinetic binding studies show that a synthetic peptide containing a Col3 cysteine-rich (CR) domain found within its N-propeptide binds in a dose-dependent manner to TGFβ1, while a CR control peptide with mutated cysteines does not, suggesting that Col3 attenuates TGFβ signaling in part through the N-propeptide CR domain. Consistent with this hypothesis, the CR peptide attenuates TGFβ signaling in fibroblasts and 4T1 breast cancer cells and suppresses fibroblast activation and contraction, as assessed by α-smooth-muscle actin staining, cell wrinkling of deformable silicone, and stressed-fibroblast populated collagen lattice contraction assays. Finally, CR peptide treatment of orthotopically injected breast cancer cells (4T1) suppresses intratumoral fibroblast activation and inhibits primary tumor growth compared to CR control. Treatment with the CR peptide decreases both intratumoral canonical and non-canonical downstream TGFβ signaling targets, consistent with its extracellular binding to TGFβ. Taken together, our results suggest that the Col3 N-propeptide CR domain binds TGFβ1 and attenuates (but importantly does not eliminate) TGFβ signaling in fibroblasts and cancer cells. Expanding on our previous work, this study demonstrates an additional mechanism by which Col3 regulates cell behaviors in post-injury and tumor microenvironments and suggests that novel Col3-targeted strategies could effectively control biologic responses in vivo and improve anti-scarring/fibrosis and oncologic therapies. [ABSTRACT FROM AUTHOR]