Smad2 and Smad3 Play Different Roles in Rat Hepatic Stellate Cell Function and α-Smooth Muscle Actin Organization
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Published:2005-09
Issue:9
Volume:16
Page:4214-4224
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ISSN:1059-1524
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Container-title:Molecular Biology of the Cell
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language:en
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Short-container-title:MBoC
Author:
Uemura Masayuki1, Swenson E. Scott2, Gaça Marianna D.A.1, Giordano Frank J.2, Reiss Michael3, Wells Rebecca G.1
Affiliation:
1. The University of Pennsylvania School of Medicine, Philadelphia, PA 19104 2. Yale University School of Medicine, New Haven, CT 06520 3. Robert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903
Abstract
Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis, transdifferentiating in chronic liver disease from “quiescent” HSC to fibrogenic myofibroblasts. Transforming growth factor-β (TGF-β), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF-β signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3. Smad3-overexpressing cells exhibited increased deposition of fibronectin and type 1 collagen, increased chemotaxis, and decreased proliferation compared with uninfected cells and those infected with Smad2 or either dominant negative, demonstrating different biological functions for the two Smads. Additionally, coinfection experiments suggested that Smad2 and Smad3 signal via independent pathways. Smad3-overexpressing cells as well as TGF-β-treated cells demonstrated more focal adhesions and increased α-smooth muscle actin (α-SMA) organization in stress fibers, although all cells reached the same level of α-SMA expression, indicating that Smad3 also regulates cytoskeletal organization in HSC. We suggest that TGF-β, signaling via Smad3, plays an important role in the morphological and functional maturation of hepatic myofibroblasts.
Publisher
American Society for Cell Biology (ASCB)
Subject
Cell Biology,Molecular Biology
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