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Inhibition of transforming growth factor‐β/Smad signaling improves regeneration of small‐for‐size rat liver grafts
Author(s) -
Zhong Zhi,
Tsukada Shigeki,
Rehman Hasibur,
Parsons Christopher J.,
Theruvath Tom P.,
Rippe Richard A.,
Brenner David A.,
Lemasters John J.
Publication year - 2010
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.21966
Subject(s) - liver regeneration , smad , medicine , liver transplantation , transplantation , andrology , bilirubin , transforming growth factor , transforming growth factor beta , endocrinology , regeneration (biology) , biology , microbiology and biotechnology
Transforming growth factor‐β (TGF‐β) is a potent inhibitor of cell proliferation. This study investigated whether overexpression of Smad7, which blocks TGF‐β–induced activation of Smad2/3, could prevent the suppression of regeneration of small‐for‐size liver grafts. Rats were intravenously given adenoviruses (2 × 10 10 pfu/rat) carrying the LacZ gene or the Smad7 gene (Ad‐ Smad7 ) 3 days prior to liver harvesting. Half‐size livers were implanted into recipients of the same weight or twice the donor weight, and this resulted in half‐size or quarter‐size liver grafts. Cell proliferation, detected by 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation, increased to 23% in half‐size grafts at 38 hours after implantation but was only 4% in quarter‐size grafts. Graft weight did not increase after 38 hours in full‐size and quarter‐size grafts but increased 28% in half‐size grafts. Ad‐ Smad7 restored BrdU labeling to 32%, and the graft weight increased to 43% in quarter‐size grafts. Serum total bilirubin increased approximately 30‐fold after the implantation of quarter‐size grafts. Ad‐ Smad7 blunted hyperbilirubinemia by 80%. The basal hepatic TGF‐β 1 level was 7 ng/g of liver wet weight, and this increased to 30 ng/g at 1.5 hours after the transplantation of full‐size grafts but decreased rapidly afterwards. After the transplantation of quarter‐size grafts, however, TGF‐β 1 progressively increased to 159 ng/g in 38 hours. Nuclear phosphorylated Smad2/3 was barely detectable, and p21Cip1 expression was negligible in full‐size grafts but increased markedly in quarter‐size grafts. Ad‐ Smad7 blocked Smad2/3 activation and expression of p21Cip1. Together, these data show that TGF‐β is responsible, at least in part, for the defective liver regeneration in small‐for‐size grafts by activating the Smad signaling pathway. Liver Transpl 16:181–190, 2010. © 2010 AASLD.