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

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.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…As previously mentioned, Ang-1 is produced by pericytes and smooth muscle cells, which activates endothelial Tie-2, increasing the strength of the peg and socket interaction between EC and pericytes. Ang-2 is expressed by ECs, particularly during tissue regeneration (Hu et al, 2014); it binds competitively with Ang-1 for Tie-2 and acts as an opposing factor in pericyte-EC interactions. Furthermore, increased Ang-2 expression dissociates pericytes from vessels (Ziegler et al, 2013).…”

Vessels of rejuvenation

“…The different structural and metabolic requirements of organs and tissues prompt the formation of specialized blood vessels during development 1 , which deliver molecules that instruct tissues on their fates 2,3 . This process requires crosstalk between organs and the vasculature: organs generate local growth factors that attract blood vessels toward metabolically active regions, and the vessels release molecules (known as angiocrine signals) that affect cell differentiation in the developing organs.…”

“…It is becoming increasingly clear that these interactions are influenced by the endothelial cells that line the inner surface of blood vessels. In two papers 4,5 in this issue, Adams and colleagues demonstrate that the bone vasculature contains specialized endothelial cells with signalling properties that support bone maturation and regeneration. As well as providing insight into the tissue specificity of angiocrine signalling, the findings have direct clinical relevance.…”

“…In the first paper, Kusumbe et al 4 (page 323) began by mapping gene expression, metabolic activity and cellsurface markers in the developing postnatal bone vasculature of mice. The authors distinguished two new subpopulations of endothelial cell (EC) that they term type H and type L ECs.…”

“…In addition to prompting these biological questions, Adams and colleagues' work 4,5 has important clinical implications. Bone is continually deposited by osteoblasts, which are activated by bone fractures.…”