Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration

Abstract

There is growing evidence to suggest that endothelial cells are not simply passive conduits for delivering oxygen and nutrients. During embryogenesis, for instance, they induce organogenesis before the circulation has developed. Experiments in a 70% partial hepatectomy liver regeneration model in mice now reveal a molecular pathway by which endothelial cells can sustain liver regeneration after surgical resection. VEGFR2 activation in a defined subpopulation of liver endothelial cells leads to the upregulation of the endothelial-specific transcription factor Id1, which in turn induces the secretion of Wnt2 and hepatocyte growth factor (HGF), which trigger hepatocyte proliferation. This suggests that vascular niche-derived inductive signals that promote liver regeneration could be utilized to initiate and accelerate liver recovery after these surgical procedures. These authors describe a molecular pathway by which endothelial cells sustain liver regeneration after surgical resection. Activation of vascular endothelial growth factor-A receptor-2 in a defined subpopulation of liver endothelial cells leads to the upregulation of the endothelial-specific transcription factor Id1, which in turn induces Wnt2 and hepatocyte growth factor, which are secreted from the endothelial cells and trigger hepatocyte proliferation. During embryogenesis, endothelial cells induce organogenesis before the development of circulation1,2,3,4. 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 of paracrine trophogens stimulates organ regeneration, in a manner similar to endothelial-cell-derived angiocrine factors that support haematopoiesis5,6,7. 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−VEGFR2+VE-cadherin+FactorVIII+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 study of physiological liver regeneration. Using this model, we show that inducible genetic ablation of vascular endothelial growth factor (VEGF)-A receptor-2 (VEGFR2) in the LSECs impairs the initial burst of hepatocyte proliferation (days 1–3 after partial hepatectomy) and subsequent reconstitution of the hepatovascular mass (days 4–8 after partial hepatectomy) by inhibiting upregulation of the endothelial-cell-specific transcription factor Id1. Accordingly, Id1-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-Id1 activation in LSECs stimulates hepatocyte proliferation. Indeed, intrasplenic transplantation of Id1+/+ or Id1−/− LSECs transduced with Wnt2 and HGF (Id1−/−Wnt2+HGF+ LSECs) re-establishes an inductive vascular niche in the liver sinusoids of the Id1−/− mice, initiating and restoring hepatovascular regeneration. Therefore, in the early phases of physiological liver regeneration, VEGFR2-Id1-mediated inductive angiogenesis in LSECs through release of angiocrine factors Wnt2 and HGF provokes hepatic proliferation. Subsequently, VEGFR2-Id1-dependent proliferative angiogenesis reconstitutes liver mass. Therapeutic co-transplantation of inductive VEGFR2+Id1+Wnt2+HGF+ LSECs with hepatocytes provides an effective strategy to achieve durable liver regeneration.