Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat.
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.
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), DKFZ-Center for Molecular Biology Alliance, 69120 Heidelberg, Germany.
Junhao
J
Hu
Kshitij
K
Srivastava
Matthias
M
Wieland
Anja
A
Runge
Carolin
C
Mogler
Eva
E
Besemfelder
Dorothee
D
Terhardt
Marion J
MJ
Vogel
Liji
L
Cao
Claudia
C
Korn
Susanne
S
Bartels
Markus
M
Thomas
Hellmut G
HG
Augustin
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D042702:Angiopoietin-2; D016212:Transforming Growth Factor beta