Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation

Carpino, Guido; Morini, Sergio; Corradini, Stefano Ginanni; Franchitto, Antonio; Merli, Manuela; Siciliano, M.; Gentili, F.; Muda, Andrea Onetti; Berloco, P.B.; Rossi, Massimo; Attili, Adolfo Francesco; Gaudio, Eugenio

doi:10.1016/j.dld.2004.11.009

Cited by 262 publications

(181 citation statements)

References 38 publications

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“…26 The loss of a-SMA-positive cells in residual fibrotic septa is consistent with previous demonstrations that after cessation of CCL 4 intoxication in rats, residual septa are characterized by relative hypocellularity and matrix cross-linking, 40 and that in humans with chronic hepatitis C, a-SMA and fibrosis correlate positively at early stage, but negatively at advanced stage. 41 A strong correlation between fibrosis and ductular reaction, evident in the present study, has been recently reported in patients with chronic hepatitis C. 19 A relationship between ductular proliferation and fibrosis has also been previously reported in primary biliary cirrhosis. 42 Different potential mechanism(s) whereby cholangiocytes may promote fibrogenesis have been envisioned.…”

Section: Discussionsupporting

confidence: 48%

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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Section: Discussionsupporting

confidence: 48%

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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“…Activation of HSC induced by over-expressed TGF-β1 results in increased synthesis and decreased degradation of ECM which transdifferentiates HSC into α-SMA-positive myofibroblasts (Carpino et al, 2005;Li & Friedman, 1999;Meindl-Beinker & Dooley, 2008). In the present study, baicalin significantly reduced the elevated mRNA levels of TGFβ1-related proteins both in serum and liver induced by CCl 4 which was in a dose-dependent manner.…”

Section: Tgfβ1supporting

confidence: 54%

Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFβ1

Qiao

Han

Hong

et al. 2010

Pharmaceutical Biology

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“…Prior to incorporation in 3D bioprinted tissues, HSCs were propagated through multiple population doublings and serial passages in 2D culture. HSCs typically reside in a quiescent state in uninjured liver but undergo activation in response to injury or 2D culture (ie, culture activation on collagen or plastic surfaces) as demonstrated by increased expression levels of activation markers, such as a-SMA (Carpino et al, 2005;Friedman, 2008). When cultured in a 3D context, HSCs embedded within the tissue architecture exhibited a more quiescent-like phenotype as illustrated by the retention of desmin and lack of a-SMA positivity ( Fig.…”

Section: Bioprinted Constructs Exhibit Key Features Of Native Livermentioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation

Cited by 262 publications

References 38 publications

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

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

Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFβ1

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

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