Endothelial Cell-Derived Angiopoietin-2 Controls Liver Regeneration as a Spatiotemporal Rheostat

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Science  24 Jan 2014:
Vol. 343, Issue 6169, pp. 416-419
DOI: 10.1126/science.1244880

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Liver regeneration requires spatially and temporally precisely coordinated proliferation of the two major hepatic cell populations, hepatocytes and liver sinusoidal endothelial cells (LSECs), to reconstitute liver structure and function. The underlying mechanisms of this complex molecular cross-talk remain elusive. Here, we show that the expression of Angiopoietin-2 (Ang2) in LSECs is dynamically regulated after partial hepatectomy. During the early inductive phase of liver regeneration, Ang2 down-regulation leads to reduced LSEC transforming growth factor–β1 production, enabling hepatocyte proliferation by releasing an angiocrine proliferative brake. During the later angiogenic phase of liver regeneration, recovery of endothelial Ang2 expression enables regenerative angiogenesis by controlling LSEC vascular endothelial growth factor receptor 2 expression. The data establish LSECs as a dynamic rheostat of liver regeneration, spatiotemporally orchestrating hepatocyte and LSEC proliferation through angiocrine- and autocrine-acting Ang2, respectively.

Vascular Endothelium and Tissue Regeneration

The vascular endothelium is increasingly being recognized to play a role during organogenesis and tissue regeneration. Hu et al. (p. 416) found that rapid down-regulation of endothelial-derived Angiopoietin-2 following partial hepatectomy releases an endogenous transforming growth factor β1–driven paracrine proliferative brake on hepatocytes. Later, recovery of endothelial Angiopoetin-2 expression facilitates angiogenesis in the regenerating liver in a vascular endothelial growth factor receptor 2–dependent manner. Thus, the vascular endothelium may help to orchestrate tissue regeneration through the control of inhibitory and stimulatory pathways in parenchymal and nonparenchymal cells.

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