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

Living donor and split liver transplantation (LT) has become more widely used in recent years to alleviate the mortality resulting from the scarcity of suitable liver grafts for transplantation.1,2 Donor-recipient graft size disparity leading to small-for-size graft dysfunction and failure is an important issue limiting the wider use of partial LT for adults.3 The mechanisms underlying the dysfunction and failure of small-for-size grafts remain unclear. Previous studies have indicated that liver regeneration is markedly suppressed in small-for-size liver grafts, and this appears to contribute to graft failure.4–6 Growth factors such as hepatic growth factor (HGF), transforming growth factor-α (TGF-α), epidermal growth factor (EGF), and vascular endothelial growth factor and the cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) stimulate liver regeneration.7–9 TGF-β is a potent inhibitor of hepatocyte proliferation that counterbalances the stimulatory effects of mitogens during liver regeneration.10–12 In many cell types, TGF-β is the most potent growth-inhibitory polypeptide currently known.13 However, whether TGF-β plays a role in the suppression of small-for-size liver graft regeneration remains unclear. TGF-β elicits its biological effects by signaling through a heteromeric receptor complex consisting of type I and type II receptors. The binding of TGF-β to type II receptors leads to the recruitment, phosphorylation, and activation of type I receptors, which subsequently phosphorylate proteins of the Smad family, particularly Smad2 and Smad3.14,15 Phosphorylated Smad2 and Smad3 form a complex with Smad4, move into the nucleus, and activate target genes expressing regulatory proteins for cell proliferation, differentiation, and cell death.14,16 TGF-β also regulates mitogen-activated protein kinase–mediated signaling pathways and other signaling proteins, such as protein kinase A, protein kinase C, phospholipase C, and nuclear factor-κB, in different cell types.17,18 Another Smad family member, Smad7, associates stably with the TGF-β receptor complex, which inhibits TGF-β–induced phosphorylation of Smad2 and Smad3 and blocks TGF-β–dependent signaling.19 This study examined the effect of the adenoviral delivery of Smad7 on liver regeneration after LT with small-for-size grafts. Our results show that TGF-β1 increases sharply after the transplantation of small-for-size liver grafts in association with Smad2/3 phosphorylation and nuclear translocation. Smad7 adenoviral expression blocks Smad2/3 activation, promotes liver regeneration, and improves graft function.