Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration
By B. Ding, D. Nolan, J. Butler, D. James, Alexander O. Babazadeh, Z. Rosenwaks, V. Mittal, Hideki Kobayashi, K. Shido, D. Lyden and 3 more. Nature, 2010
818 citations recorded by the source corpus.
During embryogenesis, endothelial cells induce organogenesis before the development of circulation. 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 haematopoiesis. 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.
Subfields: Hepatology, Surgery
View Paper: https://www.semanticscholar.org/paper/b391dad51c5353b18caa6f6e5be5881848c38c23
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Citations in the corpus
- Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. (2011, background): “Recent studies on liver regeneration indicate the active role of liver endothelial cells and hepatic stellate cells in hepatocyte proliferation (Ding et al., 2010; Passino et al., 2007).”
- Basic and therapeutic aspects of angiogenesis. (2011, neutral): “Notably, besides their role in supplying nutrients, ECs themselves can also promote growth and repair of metabolically active tissues independent of perfusion by secreting angiocrine factors (Butler et al., 2010; Ding et al., 2010).”
- Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology (2017, background): “Angiocrine signals including HGF and Wnt2, secreted from LSECs before the induction of angiogenesis, stimulate hepatocyte proliferation (118, 119).”
- Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver (2015, methodology): “Interestingly, Wnt2 produced by sinusoidal endothelial cells is known to be important for hepatocyte regeneration after injury[26].”
- Liver sinusoidal endothelial cells: Physiology and role in liver diseases. (2017, background): “17 growth factor (HGF), through the up-regulation of the transcription factor Id1 via the VEGFR2/VEGFA pathways [57].”
- Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, neutral): “2007) and signals from endothelial cells also play a crucial role in liver regeneration after partial hepatectomy (Ding et al. 2010).”