Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined. Here, we provide evidence that the pro-fibrotic growth factor, TGF-␤1, induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of epithelial to mesenchymal transition (EMT). We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL 4 -induced liver fibrosis. Furthermore, we demonstrate that bone morphogenic protein-7 (BMP7), a member of the TGF␤ superfamily, which is known to antagonize TGF␤ signaling, significantly inhibits progression of liver fibrosis in these mice. BMP7 treatment abolishes EMT-derived fibroblasts, suggesting that the therapeutic effect of BMP7 was at least partially due to the inhibition of EMT. These results provide direct evidence for the functional involvement of adult hepatocytes in the accumulation of activated fibroblasts in the fibrotic liver. Furthermore, our findings suggest that EMT is a promising therapeutic target for the attenuation of liver fibrosis.Liver cirrhosis is still the sixth most common cause of death among United States citizens from ages 25 to 64 (1). Cirrhosis of the liver and its functional loss, which is caused by a progressive fibrosis, occurs due to a variety of insults, such as viral hepatitis, metabolic or autoimmune diseases, toxic injury, or congenital abnormalities (1-3). Fibrosis in the liver, as with fibrosis in other organs such as lung, kidney, heart, or skin, is described as excessive deposition of extracellular matrix (ECM), 6 which leads to the destruction of organ structure and impairment of organ function. Activated fibroblasts are key mediators of organ fibrosis. In the fibrotic liver, such activated fibroblasts are considered to derive via activation and proliferation of resident stellate cells and periportal fibroblasts (1, 2, 4 -9). Because specific treatments to halt progressive fibrosis of the liver are not yet available, further understanding of the underlying pathogenic mechanisms involved in the accumulation of scar-forming fibroblasts is required.Evidence is evolving that fibroblasts are more heterogeneous than traditionally thought (10) and recent studies reveal additional mechanisms such as recruitment of bone marrow-derived cells and conversion of resident epithelia as contributors to the accumulation of activated fibroblasts in fibrotic tissues (10,11). In this study, we attempted to gain further insights into the role of adult hepatocytes, the parenchymal epithelial cells of the liver, in the accumulation of fibroblasts in the inflamed liver. A direct contribution of hepatocytes to liver fibr...

Whereas the roles of proangiogenic factors in carcinogenesis are well established, those of endogenous angiogenesis inhibitors (EAIs) remain to be fully elaborated. We investigated the roles of three EAIs during de novo tumorigenesis to further test the angiogenic balance hypothesis, which suggests that blood vessel development in the tumor microenvironment can be governed by a net loss of negative regulators of angiogenesis in addition to the well-established principle of up-regulated angiogenesis inducers. In a mouse model of pancreatic neuroendocrine cancer, administration of endostatin, thrombospondin-1, and tumstatin peptides, as well as deletion of their genes, reveal neoplastic stage-specific effects on angiogenesis, tumor progression, and survival, correlating with endothelial expression of their receptors. Deletion of tumstatin and thrombospondin-1 in mice lacking the p53 tumor suppressor gene leads to increased incidence and reduced latency of angiogenic lymphomas associated with diminished overall survival. The results demonstrate that EAIs are part of a balance mechanism regulating tumor angiogenesis, serving as intrinsic microenvironmental barriers to tumorigenesis.integrins | cell biology

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