Inhibition of transforming growth factor-β/Smad signaling improves regeneration of small-for-size rat liver grafts

✍ Scribed by Zhi Zhong; Shigeki Tsukada; Hasibur Rehman; Christopher J. Parsons; Tom P. Theruvath; Richard A. Rippe; David A. Brenner; John J. Lemasters

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 440 KB
• Volume: 16
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.21966

✦ Synopsis

Transforming growth factor-␤ (TGF-␤) is a potent inhibitor of cell proliferation. This study investigated whether overexpression of Smad7, which blocks TGF-␤-induced activation of Smad2/3, could prevent the suppression of regeneration of small-for-size liver grafts. Rats were intravenously given adenoviruses (2 ϫ 10 9 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-2Ј-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-␤ 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-␤ 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-␤ is responsible, at least in part, for the defective liver regeneration in small-for-size grafts by activating the Smad signaling pathway.