Phenotypic change in portal fibroblasts in biliary fibrosis

Tang, Liang; Tanaka, Yujiro; Marumo, Fumiaki; Sato, Chifumi

doi:10.1111/j.1600-0676.1994.tb00051.x

Cited by 55 publications

(21 citation statements)

References 16 publications

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“…Although the role of aPFs in the development of portal fibrosis has been discussed (42, 61), our study is the first to our knowledge to quantify the myofibroblast populations over a time course. Consistent with previous studies (62,63), we demonstrate that aPFs play an important role at early stages of BDL-induced liver fibrosis (13) by contributing >70% of myofibroblasts. Moreover, even at later stages (BDL, 17-20 d), aPFs contribute ∼50% of myofibroblasts and exhibit a more activated phenotype than aHSCs.…”

Section: Ahscs and Apfs Contribute Differently To Liver Fibrosis Of Dsupporting

confidence: 93%

Origin of myofibroblasts in the fibrotic liver in mice

Iwaisako

Jiang

Zhang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

450

461

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Significance Liver resident activated hepatic stellate cells (aHSCs), and activated portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury, whereas fibrosis in hepatotoxic liver injury is attributed to aHSCs. However, the contribution of aPFs to cholestatic fibrosis is not well characterized because of difficulties in cell purification and the lack of identified aPF-specific markers. We have developed a novel flow cytometry-based method of aPFs purification from the nonparenchymal cell fraction of collagen-α1(I)-GFP mice and have identified potential aPF-specific markers. The goal of this study is to determine whether aPFs contribute to cholestatic liver fibrosis and identify the mechanism(s) of their activation.

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Section: Ahscs and Apfs Contribute Differently To Liver Fibrosis Of Dsupporting

confidence: 93%

Origin of myofibroblasts in the fibrotic liver in mice

Iwaisako

Jiang

Zhang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

450

461

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“…Although hepatic stellate cells are well established as the predominant source of ECM in parenchymal fibrosis, portal mesenchymal cells play an important role in biliary fibrosis 28–31 . In agreement with these reports, we found that, while there were many αSMA-expressing myofibroblasts in the portal region following bile duct ligation (Supplemental Figure 10A), there were few hepatic stellate cells (as determined by staining for desmin, red) (Supplemental Figure 10B).…”

Section: Resultsmentioning

confidence: 99%

“…Instead, it enhances motility in hepatic stellate cells but not portal fibroblasts, a phenotype that specifically requires EIIIA and integrin α 9 β 1 . Male EIIIA−/− mice are protected from thioacetamide-induced fibrosis, which primarily affects the sinusoids, but not from bile duct ligation-induced fibrosis, which affects the portal area and may depend more on portal fibroblasts 28–31 . The data provide proof of concept that subtle changes in the ECM can have large effects on myofibroblast behavior and liver fibrosis, and they highlight a previously unappreciated function of EIIIA+ cFN in promoting stellate cell motility rather than myofibroblast differentiation.…”

Section: Discussionmentioning

confidence: 99%

Fibronectin Extra Domain-A Promotes Hepatic Stellate Cell Motility but Not Differentiation Into Myofibroblasts

et al. 2012

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Background & Aims Myofibroblasts are the primary cell type involved in physiologic wound healing and its pathologic counterpart, fibrosis. Cellular fibronectin that contains the alternatively spliced extra domain A (EIIIA) is upregulated during these processes, and is believed to promote myofibroblast differentiation. We sought to determine the requirement for EIIIA in fibrosis and differentiation of myofibroblasts in rodent livers. Methods We used a mechanically tunable hydrogel cell culture system to study differentiation of primary hepatic stellate cells and portal fibroblasts from rats into myofibroblasts. Liver fibrosis was induced in mice by bile duct ligation or administration of thioacetamide. Results EIIIA was not required for differentiation of rat hepatic stellate cells or portal fibroblasts into fibrogenic myofibroblasts. Instead, hepatic stellate cells cultured on EIIIA-containing cellular fibronectin formed increased numbers of lamellipodia; their random motility and chemotaxis also increased. These increases required the receptor for EIIIA, the integrin α9β1. In contrast, the motility of portal fibroblasts did not increase on EIIIA and these cells expressed little α9β1. Male EIIIA−/− mice were modestly protected from thioacetamide-induced fibrosis, which requires motile hepatic stellate cells, but not from bile duct ligation-induced fibrosis, in which portal fibroblasts are more important. Notably, myofibroblasts developed during induction of fibrosis with either thioacetamide or bile duct ligation in EIIIA−/− mice. Conclusions EIIIA is dispensable for differentiation of hepatic stellate cells and portal fibroblasts to myofibroblasts, both in culture and in mouse models of fibrosis. These findings indicate a role for EIIIA in promoting stellate cell motility and parenchymal liver fibrosis.

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“…11 There is evidence, in particular, to indicate that mesenchymal cells in the portal tract, which include fibroblasts located around bile ducts 11 give rise to myofibroblasts in biliary-type liver fibrosis. [12][13][14][15][16][17] As the portal area is a prominent location of fibrosis development not only in biliary diseases, but in virtually all types of chronic liver diseases, including viral and alcohol-related diseases, 18,19 the implication of portal mesenchymal cells in the formation of liver fibrosis may be more important than what has been generally assumed. However, no marker(s) has been identified that allows, so far, to fully discriminate these cells from HSCs at the stage of myofibroblasts, 14,[20][21][22][23] and to what extent these cells compared with HSCs may actually contribute to liver fibrogenesis is at present largely unknown.…”

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confidence: 97%

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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Phenotypic change in portal fibroblasts in biliary fibrosis

Cited by 55 publications

References 16 publications

Origin of myofibroblasts in the fibrotic liver in mice

Origin of myofibroblasts in the fibrotic liver in mice

Fibronectin Extra Domain-A Promotes Hepatic Stellate Cell Motility but Not Differentiation Into Myofibroblasts

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

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