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

ABSTRACT: 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-?1) complexes into their biologically active form. TGF-? plays significant roles in cell-cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF-?1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF-?1 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-?-mediated signaling during the repair process after hepatectomy. We show here that TSP-1-mediated TGF-?1 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-?/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-?/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.We have identified TSP-1 as an inhibitory element in regulating liver regeneration by TGF-?1 activation. Our work defines TSP-1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration.

SUBMITTER: Hayashi H 

PROVIDER: S-EPMC3295913 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature