Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis

Abstract

Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration1,2,3,4,5. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined6,7,8. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration9,10,11,12,13,14,15. Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis16,17. Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18, 19, 20, 21), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells (Cxcr7iΔEC/iΔEC) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors9,10,11. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin+ hepatic stellate-like cells22,23 and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 (Fgfr1iΔEC/iΔEC) or Cxcr4 (Cxcr4iΔEC/iΔEC) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1–CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis1,2,4.

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Figure 1: After acute liver injury, upregulation of SDF-1 receptor CXCR7 in LSECs stimulates angiocrine-mediated regeneration.
Figure 2: Iterative hepatotoxic injury perturbs CXCR7 pro-regenerative pathway in LSECs and forces the generation of a pro-fibrotic vascular niche.
Figure 3: Cholestatic liver injury by FGFR1 overactivation in LSECs shifts CXCR7-dependent pro-regenerative response to a CXCR4-dominated pro-fibrotic vascular niche.
Figure 4: FGFR1 activation of CXCR4 in LSECs provokes pro-fibrotic angiocrine signals in liver repair.

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Acknowledgements

We are grateful to T. Hla for reading the manuscript, R. Berahovich and K. Eggan for their suggestions on CXCR7 signalling for liver repair, R. H. Adams for providing mouse inducible endothelial-cell-specific Cre (Cdh5-PAC-CreERT2) line and Y.-R. Zou for offering the floxed Cxcr4 mouse line. B.-S.D. is supported by a National Scientist Development Grant from the American Heart Association (number 12SDG1213004) and a Druckenmiller Fellowship from the New York Stem Cell Foundation. S.R. is supported by the Ansary Stem Cell Institute, the Howard Hughes Medical Institute, Empire State Stem Cell Board and New York State Department of Health grants (C024180, C026438, C026878, C028117), National Heart, Lung, and Blood Institute grants R01HL097797, R01HL119872 and RC2HL101846, National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK095039, National Cancer Institute grant U54CA163167, Qatar National Priorities Research Foundation grant NPRP08-663-3-140 and the Qatar Foundation BioMedical Research Program. R.L., P.G. and K.S. are supported by Empire State Stem Cell Board and New York State Department of Health training grants (C026878). D.N. is supported by the Tri-Institutional Weill Cornell Starr Stem Cell Scholar Program. M.S. is supported by National Heart, Lung, and Blood Institute grant R01 HL053793.

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B.-S.D. and Z.C. conceived the project, performed experiments and wrote the paper. R.L., D.N. and P.G. performed the experiments and analysed the data. M.E.P., M.S., K.S. and S.Y.R. interpreted the data. S.R. designed the project, analysed the data and wrote the paper. All authors commented on the manuscript.

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Correspondence to Bi-Sen Ding or Shahin Rafii.

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Ding, B., Cao, Z., Lis, R. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014). https://doi.org/10.1038/nature12681

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