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Thrombospondin‐1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor‐beta1 activation in mice

The matricellular protein, thrombospondin‐1 (TSP‐1), is prominently expressed during tissue repair. TSP‐1 binds to matrix components, proteases, cytokines, and growth factors and activates intracellular signals through its multiple domains. TSP‐1 converts latent transforming growth factor‐beta1 (TGF‐β1) complexes into their biologically active form. TGF‐β plays significant roles in cell‐cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF‐β1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF‐β1 during liver regeneration remains to be defined in vivo. We generated a TSP‐1‐deficient mouse model of a partial hepatectomy (PH) and explored TSP‐1 induction, progression of liver regeneration, and TGF‐β‐mediated signaling during the repair process after hepatectomy. We show here that TSP‐1‐mediated TGF‐β1 activation plays an important role in suppressing hepatocyte proliferation. TSP‐1 expression was induced in endothelial cells (ECs) as an immediate early gene in response to PH. TSP‐1 deficiency resulted in significantly reduced TGF‐β/Smad signaling and accelerated hepatocyte proliferation through down‐regulation of p21 protein expression. TSP‐1 induced in ECs by reactive oxygen species (ROS) modulated TGF‐β/Smad signaling and proliferation in hepatocytes in vitro, suggesting that the immediately and transiently produced ROS in the regenerating liver were the responsible factor for TSP‐1 induction. Conclusions: We have identified TSP‐1 as an inhibitory element in regulating liver regeneration by TGF‐β1 activation. Our work defines TSP‐1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration. (HEPATOLOGY 2011)