Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis (original) (raw)

Nature volume 505, pages 97–102 (2014)Cite this article

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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 (_Cxcr7_iΔEC/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 (_Fgfr1_iΔEC/iΔEC) or Cxcr4 (_Cxcr4_iΔEC/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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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-Cre_ERT2) 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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Author notes

  1. Bi-Sen Ding and Zhongwei Cao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetic Medicine, Ansary Stem Cell Institute, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, 10065, New York, USA
    Bi-Sen Ding, Zhongwei Cao, Raphael Lis, Daniel J. Nolan, Peipei Guo, Koji Shido, Sina Y. Rabbany & Shahin Rafii
  2. Angiocrine Bioscience, New York, 10065, New York, USA
    Daniel J. Nolan
  3. Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, 06510, Connecticut, USA
    Michael Simons
  4. ChemoCentryx, Inc., Mountain View, 94043, California, USA
    Mark E. Penfold
  5. Bioengineering Program, Hofstra University, Hempstead, 11549, New York, USA
    Sina Y. Rabbany

Authors

  1. Bi-Sen Ding
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  2. Zhongwei Cao
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  3. Raphael Lis
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  4. Daniel J. Nolan
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  5. Peipei Guo
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  6. Michael Simons
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  7. Mark E. Penfold
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  8. Koji Shido
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  9. Sina Y. Rabbany
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  10. Shahin Rafii
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Contributions

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 toBi-Sen Ding or Shahin Rafii.

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The authors declare no competing financial interests.

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Ding, BS., 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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Editorial Summary

CXCR7/CXCR4 balance and liver repair

Shahin Rafii and colleagues show that the balance between two stromal-derived factor-1 receptors, CXCR7 and CXCR4, determines whether liver injury results in a regenerative or fibrotic response in liver sinusoidal endothelial cells (LSECs). Activation of a pro-regenerative CXCR7/Id1 pathway predominates after acute injury, whereas chronic liver injury induces sustained activation of FGFR1 in LSECs, which augments expression of CXCR4, interfering with protective CXCR7 signalling and shifting the response towards fibrogenesis. These results suggest possible strategies for developing therapeutics that facilitate the promotion of liver repair without provoking fibrosis.

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