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Science 343 (6169): 416-419

Copyright © 2014 by the American Association for the Advancement of Science

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

Junhao Hu,1,* Kshitij Srivastava,1,2,* Matthias Wieland,1,2 Anja Runge,1,2 Carolin Mogler,1,3 Eva Besemfelder,1 Dorothee Terhardt,1 Marion J. Vogel,1 Liji Cao,4 Claudia Korn,1 Susanne Bartels,1 Markus Thomas,1,2,{dagger} Hellmut G. Augustin1,2,5,{ddagger}

Abstract: 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.

1 Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), DKFZ–Center for Molecular Biology Alliance, 69120 Heidelberg, Germany.
2 Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, Germany.
3 Department of Pathology, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
4 Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, 69120 Heidelberg, Germany.
5 German Cancer Consortium, 69120 Heidelberg, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, 82372 Penzberg, Germany.

{ddagger} Corresponding author. E-mail: augustin{at}

Vascular Niche Controls Organ Regeneration.
Y. Manavski, R. A. Boon, and S. Dimmeler (2014)
Circ. Res. 114, 1077-1079
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