Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

Abstract

Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

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Figure 1: Repetitive lung injury causes sustained alveolar epithelial cell damage, irreversible pulmonary fibrosis, and persistent Notch signaling in perivascular fibroblasts.
Figure 2: Pro-fibrotic role of the Notch ligand Jag1 in mouse PCECs after bleomycin injury.
Figure 3: The CXCL12 receptor CXCR7 promotes lung repair and suppresses fibrosis after bleomycin injury.
Figure 4: VEGFR1+ perivascular macrophages induce β-catenin–dependent Jag1 upregulation in PCECs.
Figure 5: CXCR7 suppresses VEGFR1+ macrophage–dependent stimulation of the β-catenin/Jag1 pathway in PCECs of chronically injured lungs.
Figure 6: Lung repair and fibrosis in mice after repeated hydrochloric acid aspiration.

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Acknowledgements

We are grateful to S. M. Albelda, M. Beers, and V. R. Muzykantov (University of Pennsylvania) for evaluating our study. Vector 2.2 for the generation of pseudotyped viral particle was a gift from I. Chen and K. Morizono (University of California, Los Angeles). Floxed Cxcr7 mice were kindly provided by Chemocentryx, CA. We would also like to thank R.H. Adams and T. Gridley for offering mouse lines of inducible EC-specific Cdh5(PAC)/VE-cadherin-CreERT2 and floxed Jag1. Z.C. is supported by a Druckenmiller Fellowship from the New York Stem Cell Foundation. B.-S.D. is supported by a National Scientist Development Grant from the American Heart Association (12SDG1213004) and the Ansary Stem Cell Institute. G.-H.F. is supported by the National Eye Institute (2R01EY019721-06A1). T.P.S. receives support for this project from the Robertson Foundation. S.R. is supported by the Ansary Stem Cell Institute, the Empire State Stem Cell Board and New York State Department of Health grants (nos. C024180, C026438, C026878, C028117), and by grants from the National Heart, Lung, and Blood Institute (R01HL097797 and R01HL119872). M.G. is an employee of Angiocrine Bioscience, New York, New York, USA. S.R. is the founder of and a non-paid consultant to the Angiocrine Bioscience, New York.

Author information

Z.C. designed the study, performed the experiments, interpreted the results, and wrote the paper. R.L. and M.G. performed the experiments and analyzed the data. D.C. performed mouse experiments, collected and analyzed the data. K.S. and S.Y.R. helped to collect the data. G.-H.F. generated floxed Vegfr1 mice and interpreted the results. T.P.S. analyzed the data and edited the manuscript. S.R. helped to formulate the hypothesis and edited the manuscript. B.-S.D. conceived the project, performed the experiments, analyzed the data and wrote the paper.

Correspondence to Zhongwei Cao or Shahin Rafii or Bi-Sen Ding.

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Competing interests

S.R. is the founder of and a non-paid consultant to Angiocrine Bioscience, New York, New York, USA. M.G. is an employee of Angiocrine Bioscience, New York, New York, USA.

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Cao, Z., Lis, R., Ginsberg, M. et al. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat Med 22, 154–162 (2016). https://doi.org/10.1038/nm.4035

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