Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myofibroblasts

被引:61
作者
Dooley, S [1 ]
Streckert, M [1 ]
Delvoux, B [1 ]
Gressner, AM [1 ]
机构
[1] Rhein Westfal TH Aachen, Univ Klinikum, Inst Klin Chem & Pathobiochem, D-52074 Aachen, Germany
关键词
liver fibrogenesis; TGF beta signal transduction; Smad; hepatic stellate cells;
D O I
10.1006/bbrc.2001.4811
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
TGF beta is of crucial importance during transdifferentiation of resting retinoid-storing hepatic stellate cells (HSC) to extracellular matrix producing myofibroblasts (MFB) and consequently, inhibition of TGF beta signal transduction is an effective means for preventing experimental fibrosis. We have shown that isolated HSC lose TGF beta -dependent growth control during in vitro activation and that alpha2 (I) collagen production in transdifferentiated MFB is TGF beta -independent, Furthermore, Smad complexes with SEE binding activity were only detected in early cultures of HSC, although TGF beta receptor types I and II were significantly expressed in HSC and MFB. In the present report, we compared the expression pattern of TGF beta downstream mediators, i.e., the Smads, in TGF beta responsive HSC versus nonresponding MFB. The transdifferentiation process was monitored by morphology and increasing expression of TGF beta and alpha -smooth muscle actin, and TGF beta signaling was investigated by (CAGA)(9)-MLP-Luc. The expression level of all Smads remained essentially unchanged both during the activation process and after TGF beta -treatment. Smad7 was transiently upregulated upon TGF beta stimulation in quiescent HSC, indicating a negative feed back loop in responsive cells. In contrast, MFB neither displayed TGF beta -inducible nor constitutively upregulated Smad7 expression. Instead, Smad3 mRNA was increased in MFB. Our data indicate that abrogation of the TGF beta response in RIFE versus HSC is not based on different regulation of Smad expression. (C) 2001 Academic Press.
引用
收藏
页码:554 / 562
页数:9
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