Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells

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• 作者：Erica Novo¹ ; ^† ; ; Chiara Busletta¹ ; ^† ; ; Lorenzo Valfrè ; di Bonzo¹ ; Davide Povero¹ ; Claudia Paternostro¹ ; Katia Mareschi² ; ³ ; Ivana Ferrero² ; ³ ; Ezio David⁴ ; Cristiana Bertolani⁵ ; Alessandra Caligiuri⁵ ; Stefania Cannito¹ ; Elena Tamagno¹ ; Alessandra Compagnone¹ ; Sebastiano Colombatto¹ ; Fabio Marra⁵ ; Franca Fagioli² ; Massimo Pinzani⁵ ; Maurizio Parola¹ ; ^{maurizio.parola@unito.it}
• 关键词：Hepatic stellate cells ; Mesenchymal stem cells ; Liver fibrogenesis ; Reactive oxygen species ; Chemotaxis
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：May 2011
• 年：2011
• 卷：54
• 期：5
• 页码：964-974
• 全文大小：3154 K

文摘

ass=""h4"">Background & Aims

Liver fibrogenesis is sustained by myofibroblast-like cells originating from hepatic stellate cells (HSC/MFs), portal fibroblasts or bone marrow-derived cells, including mesenchymal stem cells (MSCs). Herein, we investigated the mechanistic role of intracellular generation of reactive oxygen species (ROS) and redox-sensitive signal transduction pathways in mediating chemotaxis, a critical profibrogenic response for human HSC/MFs and for MSC potentially engrafting chronically injured liver.

ass=""h4"">Methods

Intracellular generation of ROS and signal transduction pathways were evaluated by integrating morphological and molecular biology techniques. Chemokinesis and chemotaxis were evaluated by wound healing assay and modified Boyden’s chamber assay, respectively. Additional in vivo evidence was obtained in human specimens from HCV-related cirrhosis.

ass=""h4"">Results

Human MSCs and HSC/MFs migrate in response to a panel of polypeptide chemoattractants and extracellularly generated superoxide anion. All polypeptides induced a NADPH-oxidase-dependent intracellular rise in ROS, resulting in activation of ERK1/2 and JNK1/2. Moreover, menadione or 2,3-dimethoxy-1,4-naphthoquinone, which generate intracellular superoxide anion or hydrogen peroxide, respectively, induced ERK1/2 and JNK1/2 activation and migration. JNK1 activation was predominant for migration as shown by specific silencing. Finally, activation of ERK1/2 and JNK1/2 was found in extracts obtained from HSC/MFs during the course of an oxidative stress-mediated model of liver injury and phosphorylated JNK1/2 isoforms were detected in α-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhotic livers.

ass=""h4"">Conclusions

Intracellular generation of ROS, through activation of specific signaling pathways, is a critical event for directional migration of HSC/MFs and MSCs.