QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 16, Issue 9, 4214-4224, September 2005

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E05-02-0149v1 16/9/4214    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Uemura, M. Articles by Wells, R. G. Search for Related Content PubMed PubMed Citation Articles by Uemura, M. Articles by Wells, R. G.

Smad2 and Smad3 Play Different Roles in Rat Hepatic Stellate Cell Function and -Smooth Muscle Actin Organization

Masayuki Uemura ^*, E. Scott Swenson , Marianna D.A. Gaça ^*, Frank J. Giordano , Michael Reiss , and Rebecca G. Wells ^*

^* The University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Yale University School of Medicine, New Haven, CT 06520; and Robert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903

Submitted February 23, 2005; Revised June 13, 2005; Accepted June 16, 2005
Monitoring Editor: Asma Nusrat

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- (TGF-), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF- 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--treated cells demonstrated more focal adhesions and increased -smooth muscle actin (-SMA) organization in stress fibers, although all cells reached the same level of -SMA expression, indicating that Smad3 also regulates cytoskeletal organization in HSC. We suggest that TGF-, signaling via Smad3, plays an important role in the morphological and functional maturation of hepatic myofibroblasts.

Abbreviations used: -SMA, -smooth muscle actin; Gal, -galactosidase; HSC, hepatic stellate cells; HSP, heat shock protein; MOI, multiplicity of infection; pSmad, phosphorylated Smad; pFAK, phosphorylated FAK; TGF-, transforming growth factor-.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Rebecca G. Wells (rgwells{at}mail.med.upenn.edu).

This article has been cited by other articles:

				C. V. Esguerra, L. Nelles, L. Vermeire, A. Ibrahimi, A. D. Crawford, R. Derua, E. Janssens, E. Waelkens, P. Carmeliet, D. Collen, et al. Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination Development, December 15, 2007; 134(24): 4381 - 4393. [Abstract] [Full Text] [PDF]

				L. L. Burger, D. J. Haisenleder, G. M. Wotton, K. W. Aylor, A. C. Dalkin, and J. C. Marshall The regulation of FSHbeta transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E277 - E285. [Abstract] [Full Text] [PDF]

				Y Inagaki and I Okazaki Emerging insights into Transforming growth factor {beta} Smad signal in hepatic fibrogenesis Gut, February 1, 2007; 56(2): 284 - 292. [Full Text] [PDF]

				B. Hu, Z. Wu, T. Liu, M. R. Ullenbruch, H. Jin, and S. H. Phan Gut-Enriched Kruppel-Like Factor Interaction with Smad3 Inhibits Myofibroblast Differentiation Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 78 - 84. [Abstract] [Full Text] [PDF]

				S. Zheng and A. Chen Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-{gamma} in rat hepatic stellate cells Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G113 - G123. [Abstract] [Full Text] [PDF]

				N. C. Henderson, A. C. Mackinnon, S. L. Farnworth, F. Poirier, F. P. Russo, J. P. Iredale, C. Haslett, K. J. Simpson, and T. Sethi Galectin-3 regulates myofibroblast activation and hepatic fibrosis PNAS, March 28, 2006; 103(13): 5060 - 5065. [Abstract] [Full Text] [PDF]