354 Growth arrest-specific protein 6 (GAS6) promotes liver tissue repair after an acute toxic injury

Lafdil, Fouad; Deveaux, Vanessa; Chobert, M.N.; Brouillet, Arthur; Zafrani, Es; Mavier, Philippe; Nakano, Tameo; Laperche, Yannick

doi:10.1016/s0168-8278(06)80354-5

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“…44 It has been shown these cells also secreted the Growth arrest specific gene protein 6 (Gas6), 45 which is able to protect myofibroblasts from apoptosis, 46 while the inactivation of Gas6 gene prevents the accumulation of myofibroblats in liver injury. 47 Conversely, it has been proposed that peribiliary myofibroblasts could regulate cholangiocyte proliferation via their expression of ecto-nucleoside triphosphate diphosphohydrolase. 48 Finally, cholangiocytes may directly act on matrix accumulation, for example through the release of Tissue Inhibitor Metalloprotease 1.…”

Section: Discussionmentioning

confidence: 99%

Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries

Beaussier

Wendum

Schiffer

et al. 2007

Laboratory Investigation

137

111

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Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/ resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of a-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of a-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.

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