We have identified TSP-1 as a novel immediate early gene derived from ECs, showing that the expression level of TSP-1 was immediately PARP cancer up-regulated and returned to basal levels by 24 hours in response to PH hepatectomy. Our findings and the previous report28 suggest that ECs may play two distinct roles in hepatocyte proliferation after PH hepatectomy: One is an antiproliferative role by activating the TSP-1/TGF-β1 axis within 24 hours, and the other is a proproliferative role by activating VEGFR-2 after 24 hours. This finding is consistent with the evidence that TSP-1 inhibits the activation of VEGFR-2

through its receptor, CD47, in ECs,23 and suggests that the reduction of TSP-1 expression may be required for the functional shift in ECs from an anti- to a proproliferative role in hepatocytes. Microvascular rearrangement is important for tissue remodeling, and the antiangiogenic action is one of the well-recognized functions of TSP-1.29 Selleck Olaparib However, the expression of CD31 mRNA for monitoring angiogenesis did not show any significant difference between WT and TSP-1-null mice at 24, 48, and 72 hours after PH hepatectomy (Hayashi H, and Sakai T;

unpublished data), suggesting that TSP-1 does not affect vascularization during liver regeneration after PH hepatectomy. TGF-β1 is known to be a potent inhibitor of mitogen-stimulated DNA synthesis in cultured hepatocytes.3 p21 is important for inhibiting hepatocyte proliferation in vivo, especially at the G1/S transition of the cell cycle,20 and the expression of p21 is up-regulated by TGF-β1.30 There is evidence that TGF-β1 mRNA induction occurs within 4 hours and remains elevated until 72 hours after PH hepatectomy.5, 6 In contrast, we found the only limited activation of TGF-β signaling in an earlier phase (within 24 hours), with a peak at ∼12 hours. It is known that TGF-β is secreted as latent forms and

selleck chemicals llc they are converted into active TGF-β in response to injury. There are several mechanisms for activation, such as by proteases, integrins (e.g., αvβ6 and αvβ8), and TSP-1, all of which are likely to be tissue specific.31 Whereas the complete lack of TGF-β-mediated signal in hepatocyte-specific TGF-β type II receptor knockout mice accelerates hepatocyte proliferation in the later phase (∼36-48 hours) after hepatectomy,7 the role of TGF-β signaling in the earlier phase (within 24 hours) remains to be elucidated. Our present findings provide compelling evidence that locally activated TGF-β1 mediated by TSP-1 as an immediate early gene is critical in the early phase (within 24 hours) post PH posthepatectomy to initiate the inhibitory effect on hepatocyte proliferation, and this TGF-β signaling has a functional link to the G1/S-phase transition by modulating p21 protein expression. A major downstream target of TGF-β1, PAI-1,21 is a negative regulator of liver regeneration, and PAI-1-null mice show acceleration of liver regeneration after Fas-mediated massive hepatocyte death.