During embryogenesis, endothelial cells induce organo-genesis before the development of circulation. These findings suggest that endothelial cells not only form passive conduits to deliver nutrients and oxygen, but also establish an instructive vascular niche, which through elaboration ofparacrine trophogens stimulates organ regeneration, in a manner similar to endothelial-cell-derived angio-crine factors that support hematopoiesis. However, the precise mechanism by which tissue-specific subsets of endothelial cells promote organogenesis in adults is unknown. Here we demonstrate that liver sinusoidal endothelial cells (LSECs) constitute a unique population of phenotypically and functionally defined VEGFR3(+)CD34(-)VEG-FR2(+)VE-cadherin(+)FactorVIU(+)CD45(-) endothelial cells, which through the release of angiocrine trophogens initiate and sustain liver regeneration induced by 70% partial hepatectomy. After partial hepatectomy, residual liver vasculature remains intact without experiencing hypoxia or structural damage, which allows the study of _ physiological liver regeneration. Using this model, we show that indudble genetic ablation of vascular endothelial growth factor (VEGF)-A receptor-2 (VEGFR2) in the LSECs impairs the initial burst ofhepatocyte proliferation (days 1-3 after partial hepatectomy) and subsequent reconstitution of the hepatovoscular mass (days 4-8 after partial hepatectomy) by inhibiting upregulation of the endothe-lial-cell-specific transcription factor Idl. Accordingly, ldl-deficient mice also manifest defects throughout liver regeneration, owing to diminished expression of LSEC-derived angiocrine factors, including hepatocyte growth factor (HGF) and Wnt2. Notably, in in vitro co-cultures, VEGFR2-Idl activation in LSECs stimulates hepatocyte proliferation. Indeed, intrasplenic transplantation of Idl(+/+)or Idl(-I-) LSECs transduced with Wnt2 and HGF (Idl(-/-)Wnt2(+)HGF(+) LSECs) re-establishes an inductive vascular niche in the liver...
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