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Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration

Nature Cell Biology volume 17, pages 123136 (2015) | Download Citation

Abstract

The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that platelets trigger lung regeneration by supplying stromal-cell-derived factor-1 (SDF-1, also known as CXCL12). After PNX, activated platelets stimulate SDF-1 receptors CXCR4 and CXCR7 on pulmonary capillary endothelial cells (PCECs) to deploy the angiocrine membrane-type metalloproteinase MMP14, stimulating alveolar epithelial cell (AEC) expansion and neo-alveolarization. In mice lacking platelets or platelet Sdf1, PNX-induced alveologenesis was diminished. Reciprocally, infusion of Sdf1+/+ but not Sdf1-deficient platelets rescued lung regeneration in platelet-depleted mice. Endothelial-specific ablation of Cxcr4 and Cxcr7 in adult mice similarly impeded lung regeneration. Notably, mice with endothelial-specific Mmp14 deletion exhibited impaired expansion of AECs but not PCECs after PNX, which was not rescued by platelet infusion. Therefore, platelets prime PCECs to initiate lung regeneration, extending beyond their haemostatic contribution. Therapeutic targeting of this haemo-vascular niche could enable regenerative therapy for lung diseases.

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Acknowledgements

We are grateful to T. Hla, R. Nachman and A. Choi (Weill Cornell) and S. Albelda and D. Cines (University of Pennsylvania) for critically evaluating our manuscript. Thpo−/− mice were provided by F. de Sauvage at Genentech. We would also like to thank R. H. Adams, S. J. Weiss and Y-R. Zou for offering inducible EC-specific Cdh5-(PAC)-CreERT2 and floxed Mmp14 and Cxcr4 mouse lines. We are indebted to M. E. Penfold at Chemocentryx for his help in providing floxed Cxcr7 mice. B-S.D. is supported by a National Scientist Development Grant from the American Heart Association (number 12SDG1213004). B-S.D. and Z.C. are both supported by Druckenmiller Fellowships from the New York Stem Cell Foundation. S.Y.R. is supported by Biotime. S.R. and K.S. are supported by Ansary Stem Cell Institute, the Empire State Stem Cell Board and New York State Department of Health grants (C026878, C028117, C029156), and S.R. is supported by the National Heart, Lung, and Blood Institute R01HL097797, R01HL115128, R01HL119872 and R01HL128158, National Cancer Institute U54CA163167 and the National Institute of Diabetes and Digestive and Kidney Diseases R01DK095039.

Author information

Author notes

    • Zhongwei Cao
    • , Raphael Lis
    •  & Ilias I. Siempos

    These authors contributed equally to this work.

Affiliations

  1. Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10065, USA

    • Shahin Rafii
    • , Zhongwei Cao
    • , Raphael Lis
    • , Deebly Chavez
    • , Koji Shido
    • , Sina Y. Rabbany
    •  & Bi-Sen Ding
  2. Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Shahin Rafii
    • , Zhongwei Cao
    • , Raphael Lis
    • , Ilias I. Siempos
    • , Deebly Chavez
    • , Koji Shido
    •  & Sina Y. Rabbany
  3. Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Shahin Rafii
    • , Deebly Chavez
    •  & Bi-Sen Ding
  4. Department of Reproductive Medicine, Weill Cornell Medical College, New York, New York 10065, USA

    • Shahin Rafii
    •  & Raphael Lis
  5. First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens 10675, Greece

    • Ilias I. Siempos
  6. Bioengineering Program, Hofstra University, Hempstead, New York 11549, USA

    • Sina Y. Rabbany

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Contributions

S.R. and Z.C. designed the experiments and wrote the paper. S.R., Z.C., R.L., I.I.S. and D.C. carried out the experiments and analysed the data. K.S. and S.Y.R. interpreted the data. B-S.D. conceived the project, carried out the experiments, analysed the data and wrote the paper. All authors commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bi-Sen Ding.

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https://doi.org/10.1038/ncb3096

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