Skip to main content
SpringerLink
Log in

Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Human airway basal cells (BC) function as stem/progenitor cells of the human airway epithelium, capable of differentiating into ciliated and secretory cells during turnover and repair. The positioning of BC along the basement membrane allows for potential paracrine signaling from non-epithelial cells in the mesenchyme to regulate BC function. Based on the knowledge that interaction between the airway epithelium and mesenchyme is critical for proper maintenance of both tissues, and that endothelial cells (EC) can regulate multiple functions of BC, the present study was designed to help understand the role of BC and EC cross-talk in regulating BC stem/progenitor function. Using an in vitro co-culture system that mimics the in vivo physical separation of these cell types, we assessed the impact of primary lung microvascular EC on differentiation of primary BC into a mucociliated epithelium. The data demonstrate that co-culture of BC and lung microvasculature EC results in increased ciliated cell differentiation of BC via activation of insulin (INS) and insulin-like growth factor 1 (IGF1) receptor (INSR and IGF1R) mediated signaling in BC. Consistent with this data, siRNA mediated knockdown of INSR and IGF1R in BC suppressed ciliated cell differentiation. Together these findings identify an important signaling pathway required for differentiation of BC into a ciliated cells and demonstrate the importance of BC-EC cross-talk in regulating normal airway epithelial structure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Crystal, R. G., Randell, S. H., Engelhardt, J. F., Voynow, J., & Sunday, M. E. (2008). Airway epithelial cells: current concepts and challenges. Proceedings of the American Thoracic Society, 5(7), 772–777.

    Article  PubMed  Google Scholar 

  2. Knight, D. A., & Holgate, S. T. (2003). The airway epithelium: structural and functional properties in health and disease. Respirology, 8(4), 432–446.

    Article  PubMed  Google Scholar 

  3. Tam, A., Wadsworth, S., Dorscheid, D., Man, S. F., & Sin, D. D. (2011). The airway epithelium: more than just a structural barrier. Therapeutic Advances in Respiratory Disease, 5(4), 255–273.

    Article  PubMed  Google Scholar 

  4. Tilley, A. E., Walters, M. S., Shaykhiev, R., & Crystal, R. G. (2015). Cilia dysfunction in lung disease. Annual Review of Physiology, 77, 379–406.

    Article  CAS  PubMed  Google Scholar 

  5. Evans, M. J., Van Winkle, L. S., Fanucchi, M. V., & Plopper, C. G. (2001). Cellular and molecular characteristics of basal cells in airway epithelium. Experimental Lung Research, 27(5), 401–415.

    Article  CAS  PubMed  Google Scholar 

  6. Hackett, N. R., Shaykhiev, R., Walters, M. S., Wang, R., Zwick, R. K., Ferris, B., et al. (2011). The human airway epithelial basal cell transcriptome. PLoSOne., 6(5), e18378.

    Article  CAS  Google Scholar 

  7. Hackett, T. L., Shaheen, F., Johnson, A., Wadsworth, S., Pechkovsky, D. V., Jacoby, D. B., et al. (2008). Characterization of side population cells from human airway epithelium. Stem Cells, 26(10), 2576–2585.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hajj, R., Baranek, T., Le, N. R., Lesimple, P., Puchelle, E., & Coraux, C. (2007). Basal cells of the human adult airway surface epithelium retain transit-amplifying cell properties. Stem Cells, 25(1), 139–148.

    Article  CAS  PubMed  Google Scholar 

  9. Hogan, B. L., Barkauskas, C. E., Chapman, H. A., Epstein, J. A., Jain, R., Hsia, C. C., et al. (2014). Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell, 15(2), 123–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rock, J. R., Onaitis, M. W., Rawlins, E. L., Lu, Y., Clark, C. P., Xue, Y., et al. (2009). Basal cells as stem cells of the mouse trachea and human airway epithelium. Proceedings of the National Academy of Sciences of the United States of America, 106(31), 12771–12775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rock, J. R., Randell, S. H., & Hogan, B. L. (2010). Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Disease Models Mechanisms, 3(9–10), 545–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaykhiev, R., Zuo, W. L., Chao, I., Fukui, T., Witover, B., Brekman, A., et al. (2013). EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 12102–12107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Staudt, M. R., Buro-Auriemma, L. J., Walters, M. S., Salit, J., Vincent, T., Shaykhiev, R., et al. (2014). Airway basal stem/progenitor cells have diminished capacity to regenerate airway epithelium in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine, 190(8), 955–958.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Warner, S. M., Hackett, T. L., Shaheen, F., Hallstrand, T. S., Kicic, A., Stick, S. M., et al. (2013). Transcription factor p63 regulates key genes and wound repair in human airway epithelial basal cells. American Journal of Respiratory Cell and Molecular Biology, 49(6), 978–988.

    Article  CAS  PubMed  Google Scholar 

  15. McCulley, D., Wienhold, M., & Sun, X. (2015). The pulmonary mesenchyme directs lung development. Current Opinion in Genetics & Development, 32, 98–105.

    Article  CAS  Google Scholar 

  16. Ojo, O., Lagan, A. L., Rajendran, V., Spanjer, A., Chen, L., Sohal, S. S., et al. (2014). Pathological changes in the COPD lung mesenchyme--novel lessons learned from in vitro and in vivo studies. Pulmonary Pharmacology & Therapeutics, 29(2), 121–128.

    Article  CAS  Google Scholar 

  17. Tadokoro, T., Wang, Y., Barak, L. S., Bai, Y., Randell, S. H., & Hogan, B. L. (2014). IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proceedings of the National Academy of Sciences of the United States of America, 111(35), E3641–E3649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Curradi, G., Walters, M. S., Ding, B. S., Rafii, S., Hackett, N. R., & Crystal, R. G. (2012). Airway basal cell vascular endothelial growth factor-mediated cross-talk regulates endothelial cell-dependent growth support of human airway basal cells. Cellular and Molecular Life Sciences, 69(13), 2217–2231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ding, B. S., Gomi, K., Rafii, S., Crystal, R. G., & Walters, M. S. (2015). Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells. Journal of Cell Science, 128(16), 2983–2988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Franzdottir, S. R., Axelsson, I. T., Arason, A. J., Baldursson, O., Gudjonsson, T., & Magnusson, M. K. (2010). Airway branching morphogenesis in three dimensional culture. Respiratory Research, 11, 162.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gomi, K., Arbelaez, V., Crystal, R. G., & Walters, M. S. (2015). Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoSOne., 10(2), e0116507.

    Article  Google Scholar 

  22. Walters, M. S., Gomi, K., Ashbridge, B., Moore, M. A., Arbelaez, V., Heldrich, J., et al. (2013). Generation of a human airway epithelium derived basal cell line with multipotent differentiation capacity. Respiratory Research, 14, 135.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fidler, M. J., Shersher, D. D., Borgia, J. A., & Bonomi, P. (2012). Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls. Therapeutic Advances Medical Oncology, 4(2), 51–60.

    Article  CAS  Google Scholar 

  24. Iams, W. T., & Lovly, C. M. (2015). Molecular pathways: clinical applications and future direction of insulin-like growth factor-1 receptor pathway blockade. Clinical Cancer Research, 21(19), 4270–4277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Malaguarnera, R., & Belfiore, A. (2014). The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells. Front Endocrinol (Lausanne), 5, 10.

    Google Scholar 

  26. Singh, P., Alex, J. M., & Bast, F. (2014). Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Medical Oncology, 31(1), 805.

    Article  PubMed  Google Scholar 

  27. Tahimic, C. G., Long, R. K., Kubota, T., Sun, M. Y., Elalieh, H., Fong, C., et al. (2016). Regulation of ligand and shear stress-induced insulin-like growth factor 1 (IGF1) signaling by the integrin pathway. The Journal of Biological Chemistry, 291(15), 8140–8149.

    Article  CAS  PubMed  Google Scholar 

  28. Moreno-Barriuso, N., Lopez-Malpartida, A. V., de Pablo, F., & Pichel, J. G. (2006). Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF-I double deficient embryos. Developmental Dynamics, 235(8), 2040–2050.

    Article  CAS  PubMed  Google Scholar 

  29. Pais, R. S., Moreno-Barriuso, N., Hernandez-Porras, I., Lopez, I. P., De Las Rivas, J., & Pichel, J. G. (2013). Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation. PloS One, 8(12), e83028.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Pichel, J. G., Fernandez-Moreno, C., Vicario-Abejon, C., Testillano, P. S., Patterson, P. H., & de Pablo, F. (2003). Developmental cooperation of leukemia inhibitory factor and insulin-like growth factor I in mice is tissue-specific and essential for lung maturation involving the transcription factors Sp3 and TTF-1. Mechanisms of Development, 120(3), 349–361.

    Article  CAS  PubMed  Google Scholar 

  31. Galvis, L. A., Holik, A. Z., Short, K. M., Pasquet, J., Lun, A. T., Blewitt, M. E., et al. (2015). Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung. Development, 142(8), 1458–1469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gunschmann, C., Stachelscheid, H., Akyuz, M. D., Schmitz, A., Missero, C., Bruning, J. C., et al. (2013). Insulin/IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition. Developmental Cell, 26(2), 176–187.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Stachelscheid, H., Ibrahim, H., Koch, L., Schmitz, A., Tscharntke, M., Wunderlich, F. T., et al. (2008). Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation. The EMBO Journal, 27(15), 2091–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ding, B. S., Nolan, D. J., Guo, P., Babazadeh, A. O., Cao, Z., Rosenwaks, Z., et al. (2011). Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell, 147(3), 539–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, J. H., Bhang, D. H., Beede, A., Huang, T. L., Stripp, B. R., Bloch, K. D., et al. (2014). Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell, 156(3), 440–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ramasamy, S. K., Kusumbe, A. P., & Adams, R. H. (2015). Regulation of tissue morphogenesis by endothelial cell-derived signals. Trends in Cell Biology, 25(3), 148–157.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank N. Mohamed for help in preparing this manuscript. These studies were supported, in part, by R01 HL107882, P20 HL113443. KG was supported, in part by a NYSTEM Fellowship. Research reported in this publication was supported by NIH and the Family Smoking Prevention and Tobacco Control Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration.

Author information

Author notes

  1. Matthew S. Walters

    Present address: Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, 800 N. Research Parkway, Building 800, 4th Floor, Rm 410, Oklahoma City, OK, 73104, USA

Authors and Affiliations

  1. Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 164, New York, NY, 10065, USA

    Kazunori Gomi, Yongjiang Tang, Vanessa Arbelaez, Ronald G. Crystal & Matthew S. Walters

Authors
  1. Kazunori Gomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongjiang Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vanessa Arbelaez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronald G. Crystal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew S. Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthew S. Walters.

Ethics declarations

Conflict of Interest

The authors declare no potential conflict of interest.

Role of Sponsor/Funder

The funders of this study had no role in the design and conduct of the study; not in the collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gomi, K., Tang, Y., Arbelaez, V. et al. Endothelial Cell Mediated Promotion of Ciliated Cell Differentiation of Human Airway Basal Cells via Insulin and Insulin-Like Growth Factor 1 Receptor Mediated Signaling. Stem Cell Rev and Rep 13, 309–317 (2017). https://doi.org/10.1007/s12015-016-9707-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-016-9707-z

Keywords

Search

Navigation