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Intact signaling by transforming growth factor β is not required for termination of liver regeneration in mice
Author(s) -
Oe Shoshiro,
Lemmer Eric R.,
Conner Elizabeth A.,
Factor Valentina M.,
Levéen Per,
Larsson Jonas,
Karlsson Stefan,
Thorgeirsson Snorri S.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20426
Subject(s) - liver regeneration , follistatin , hepatocyte , smad , transforming growth factor , endocrinology , medicine , biology , signal transduction , conditional gene knockout , microbiology and biotechnology , growth factor , regeneration (biology) , chemistry , receptor , in vitro , phenotype , biochemistry , gene
Transforming growth factor β (TGF‐β) is a potent inhibitor of hepatocyte proliferation in vitro and is suggested to be a key negative regulator of liver growth. To directly address the role of TGF‐β signaling in liver regeneration in vivo , the TGF‐β type II receptor gene ( Tgfbr2 ) was selectively deleted in hepatocytes by crossing “floxed” Tgfbr2 conditional knockout mice with transgenic mice expressing Cre under control of the albumin promoter. Hepatocytes isolated from liver‐specific Tgfbr2 knockout (R2LivKO) mice were refractory to the growth inhibitory effects of TGF‐β1. The peak of DNA synthesis after 70% partial hepatectomy occurred earlier (36 vs. 48 hours) and was 1.7‐fold higher in R2LivKO mice compared with controls. Accelerated S‐phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver. Regenerating R2LivKO liver showed evidence of increased signaling by activin A and persistent activity of the Smad pathway. Blockage of activin A signaling by the specific inhibitor follistatin resulted in increased hepatocyte proliferation at 120 hours, particularly in R2LivKO livers. In conclusion , TGF‐β regulates G 1 to S phase transition of hepatocytes, but intact signaling by TGF‐β is not required for termination of liver regeneration. Increased signaling by activin A may compensate to regulate liver regeneration when signaling through the TGF‐β pathway is abolished, and may be a principal factor in the termination of liver regeneration. (H EPATOLOGY 2004.)