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. Author manuscript; available in PMC: 2016 May 24.
Published in final edited form as: Nature. 2016 Jan 21;529(7586):316–325. doi: 10.1038/nature17040

Figure 3. Tissue-specific ECs by supplying membrane-bound and secreted angiocrine factors support regeneration of alveolar epithelial cells and hepatocytes.

Figure 3

(A) At steady state Wnt2 and Wnt9b produced by liver central vein ECs sustains liver mass by replenishing the Axin2+Tbx3+ hepatic stem cell pools. After 70% partial hepatectomy (PH), VEGF-A via AKT activation induces Id 1 in LSECs upregulating HGF and Wnt2. VEGF-A through activation of VEGFR1 upregulates HGF, HB-EGF and CTGF. These angiocrine factors stimulate hepatocyte proliferation without provoking angiogenesis, (inductive phase). Four days after PH, increase in liver initiates proliferative angiogenesis. Upon PH downregulation of Ang2 in LSECs and TGF-β accelerates hepatic recovery. During resolution phase of liver regeneration (days 4–8 post-PH), VEGF-A and restoration of Ang2 stimulates angiogenesis and finalize hepatic reconstitution. Activation of CXCR7 on LSECs triggers pro-regenerative and anti-fibrotic angiocrine factors, including Apelin, follistatin-1-like that facilitates fibrosis-free healing. Chronic injury by persistent CXCR4 activation and CXCR7 suppression stimulates TGF-β and BMP4 leading to fibrosis. Balance of CXCR4 and CXCR7 in LSECs negotiates liver regeneration and fibrosis.

(B) After removal of mice left lung (pneumonectomy, PNX), the PCECs in right lung express membrane-bound MMP14, which unmasks the cryptic EGF-receptor ligands from HB-EGF and Laminin5 γ-2. This inductive phase orchestrates the angiogenesis-independent compensatory alveolar epithelial regeneration. After chemical injury (i.e. bleomycin), BMP4 through engagement of its receptor Bmpr1 sets up NFATc1/Calcineurin-dependent transcription of TSP1. TSP1 facilitates differentiation of lung epithelial progenitors into functional epithelial cells. After PNX, upregulation of the VEGF-A, FGF2 and deposition of platelets on PCECs by production of SDF1 and CXCR4 activation induces MMP14 initiating alveolar regeneration. Increase in lung mass triggers angiogenic phase of lung regeneration.