Mode of Cell Division as a Regulatory Mechanism for Lung Stem Cell Behavior Compared to Other Systems

  • Ahmed El-Hashash


Over the last decade, new insights have been accumulated on the cell fate, behavior, and mode of division of stem/progenitor cells in the respiratory system and many other systems. The balance between symmetric and asymmetric divisions of tissue-specific stem cells is essential for proper organ formation, development, function, and repair/regeneration and, therefore, is tightly controlled. Improper asymmetric cell division can disrupt the tightly regulated morphogenesis of organs, while uncontrolled symmetrical cell division can promote tumor formation. In this chapter, we describe recently accumulated data on the division mode (symmetric vs. asymmetric) of lung stem/progenitor cells. In addition, we describe and compare these division modes and their regulatory mechanisms between the lung and other tissue-specific stem cells in mammals and other organisms, in which these processes are well investigated.


Lung Stem cell Cell behavior Symmetric Asymmetric Cell division Muscle stem cells Epidermal stem cells Neural stem cells 


  1. Ajduk, A., & Zernicka-Goetz, M. (2016). Polarity and cell division orientation in the cleavage embryo: from worm to human. Molecular Human Reproduction, 22, 691–703.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alexson, T. O., Hitoshi, S., Coles, B., Bernstein, A., & van der Kooy, D. (2006). Notch signaling is required to maintain all neural stem cell populations–irrespective of spatial or temporal niche. Developmental Neuroscience, 28, 34–48.CrossRefPubMedGoogle Scholar
  3. Berdnik, D., Török, T., González-Gaitán, M., & Knoblich, J. A. (2002). The endocytic protein alpha-Adaptin is required for numb-mediated asymmetric cell division in Drosophila. Developmental Cell, 3, 221–231.CrossRefPubMedGoogle Scholar
  4. Berika, M., Elgayyar, M., & El-Hashash, A. H. (2014). Asymmetric cell divisions of stem cells in the lung and other systems. Frontiers in Cell and Development Biology, 2, 33–42.CrossRefGoogle Scholar
  5. Berika, M., Ku, J., Huang, H., & El-Hashash, A. H. (2016). Gene and signals regulating stem cell fate. In A. El-Hashash (Ed.), Developmental and stem cell biology in health and disease (pp. 36–48). Madison: Bentham Science Publisher, USA.CrossRefGoogle Scholar
  6. Betschinger, J., & Knoblich, J. A. (2004). Dare to be different: Asymmetric cell division in Drosophila, C. elegans and vertebrates. Current Biology, 14, R674–R685.CrossRefPubMedGoogle Scholar
  7. Boitano, S., Safdar, Z., Welsh, D., Bhattacharya, J., & Koval, M. (2004). Cell-cell interactions in regulating lung function. American Journal of Physiology. Lung Cellular and Molecular Physiology, 287, L455–L459.CrossRefPubMedGoogle Scholar
  8. Cayouette, M., & Raff, M. (2002). Asymmetric segregation of Numb: A mechanism for neural specification from Drosophila to mammals. Nature Neuroscience, 5, 1265–1269.CrossRefPubMedGoogle Scholar
  9. Cayouette, M., & Raff, M. (2003). The orientation of cell division influences cell-fate choice in the developing mammalian retina. Development, 130, 2329–2339.CrossRefPubMedGoogle Scholar
  10. Chen, K., Huang, Y., & Chen, J. (2013). Understanding and targeting cancer stem cells: Therapeutic implications and challenges. Acta Pharmacologica Sinica, 34, 732–740.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chen, C., Fingerhut, J. M., & Yamashita, Y. M. (2016). The ins(ide) and outs(ide) of asymmetric stem cell division. Current Opinion in Cell Biology, 43, 1–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Daynac, M., & Petritsch, C. K. (2017). Regulation of asymmetric cell division in mammalian neural stem and cancer precursor cells. In J. P. Tassan & J. Kubiak (Eds.), Asymmetric cell division in development, differentiation and cancer. Results and problems in cell differentiation (Vol. 61). Cham: Springer.Google Scholar
  13. Dewey, E. B., Taylor, D. T., & Johnston, C. A. (2015). Cell fate decision making through oriented cell division. Journal of Developmental Biology, 3, 129–157.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Doe, C. Q. (2008). Neural stem cells: Balancing self-renewal with differentiation. Development, 135, 1575–1587.CrossRefPubMedGoogle Scholar
  15. Drummond, M. L., & Prehoda, K. E. (2016). Molecular control of atypical Protein Kinase C: Tipping the balance between self-renewal and differentiation. Journal of Molecular Biology, 428, 1455–1464.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Duncan, A. W., Rattis, F. M., DiMascio, L. N., et al. (2005). Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nature Immunology, 6, 314–322.CrossRefPubMedGoogle Scholar
  17. El-Hashash, A. H. (2013). Lung stem cells: Mechanisms of behavior, development and regeneration. Anatomy and Physiology, 3, 119–128.CrossRefGoogle Scholar
  18. El-Hashash, A. H. (2015). Asymmetric cell divisions of stem/progenitor cells. In D. David Warburton (Ed.), Stem cells, tissue engineering and regenerative medicine (pp. 41–58). New Jersey: World Scientific Publishing.CrossRefGoogle Scholar
  19. El-Hashash, A. H., & Warburton, D. (2011). Cell polarity and spindle orientation in the distal epithelium of embryonic lung. Developmental Dynamics, 240, 441–445.CrossRefPubMedPubMedCentralGoogle Scholar
  20. El-Hashash, A. H., & Warburton, D. (2012). Numb expression and asymmetric versus symmetric cell division in embryonic distal lung epithelium. Journal of Histochemistry and Cytochemistry, 60, 675–682.CrossRefPubMedPubMedCentralGoogle Scholar
  21. El-Hashash, A., Turcatel, G., Alam, D., Buckley, S., Bellusci, S., & Warburton, D. (2011c). Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development, 138, 1395–1407.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Elshahawy, S., Ibrahim, A., Soliman, S., Berika, M., & El-Hashash, A. H. (2016). Behavior and asymmetric cell divisions of stem cells. In A. El-Hashash (Ed.), Developmental and stem cell biology in health and disease (pp. 81–104). Madison: Bentham Science Publisher, USA.Google Scholar
  23. Florian, M. C., & Geiger, H. (2010). Concise review: Polarity in stem cells, disease, and aging. Stem Cells (Dayton, Ohio), 28(9), 1623–1629.CrossRefGoogle Scholar
  24. Frise, E., Knoblich, J. A., Younger-Shepherd, S., et al. (1996). The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proceedings of the National Academy of Sciences of the United States of America, 93, 11925–11932.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Fu, Y., Li, H., & Hao, X. (2017). The self-renewal signaling pathways utilized by gastric cancer stem cells. Tumor Biology, 1–7.Google Scholar
  26. Giebel, B., & Wodarz, A. (2012). Notch signaling: Numb makes the difference. Curr Biol, 22, R133–R135.CrossRefPubMedGoogle Scholar
  27. Goldstein, B., & Macara, I. G. (2007). The PAR proteins: Fundamental players in animal cell polarization. Developmental Cell, 13, 609–622.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Gómez-López, S., Lerner, R. G., & Petritsch, C. (2014). Asymmetric cell division of stem and progenitor cells during homeostasis and cancer. Cellular and Molecular Life Sciences, 71, 575–597.CrossRefPubMedGoogle Scholar
  29. Gulino, A., Di Marcotullio, L., & Screpanti, I. (2010). The multiple functions of Numb. Experimental Cell Research, 316, 900–906.CrossRefPubMedGoogle Scholar
  30. Guo, M., Jan, L. Y., & Jan, Y. N. (1996). Control of daughter cell fates during asymmetric division: Interaction of Numb and Notch. Neuron, 17, 27–41.CrossRefPubMedGoogle Scholar
  31. Haydar, T. F., Ang, E., Jr., & Rakic, P. (2003). Mitotic spindle rotation and mode of cell division in the developing telencephalon. Proceedings of the National Academy of Sciences of the United States of America, 100, 2890–2895.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Homem, C. C., & Knoblich, J. A. (2012). Drosophila neuroblasts: A model for stem cell biology. Development, 139, 4297–4310.CrossRefPubMedGoogle Scholar
  33. Huttner, W. B., & Kosodo, Y. (2005). Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Current Opinion in Cell Biology, 17, 648–657.CrossRefPubMedGoogle Scholar
  34. Ibrahim, A., & El-Hashash, A. H. (2015). Lung stem cell behavior in development and regeneration. Edorium Journal of Stem Cell Research and Therapy, 1, 1–13.Google Scholar
  35. Juven-Gershon, T., Shifman, O., Unger, T., et al. (1998). The Mdm2 oncoprotein interacts with the cell fate regulator Numb. Molecular and Cellular Biology, 18, 3974–3982.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Knoblich, J. A. (2001). Asymmetric cell division during animal development. Nature Reviews. Molecular Cell Biology, 2, 11–20.CrossRefPubMedGoogle Scholar
  37. Knoblich, J. A. (2010). Asymmetric cell division: Recent developments and their implications for tumour biology. Nature Reviews. Molecular Cell Biology, 11, 849–860.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kosodo, Y., Röper, K., Haubensak, W., et al. (2004). Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. The EMBO Journal, 23, 2314–2324.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Ku, J., & El-Hashash, A. H. (2016). Molecular control of the mode of cell division: A view from mammalian lung epithelial stem cells. A Journal of Anatomy, 3, 3–6.Google Scholar
  40. Lechler, T., & Fuchs, E. (2005). Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature, 437, 275–280.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Liu, K., Lin, Q., Wei, Y., et al. (2015). Gαs regulates asymmetric cell division of cortical progenitors by controlling Numb mediated Notch signaling suppression. Neuroscience Letters, 597, 97–103.CrossRefPubMedGoogle Scholar
  42. Lu, Y., Okubo, T., Rawlins, E., et al. (2008). Epithelial progenitor cells of the embryonic lung and the role of microRNAs in their proliferation. Proceedings of the American Thoracic Society, 5, 300–304.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Nelson, W. J. (2003a). Epithelial cell polarity from the outside looking in. News in Physiological Sciences, 18, 143–146.PubMedPubMedCentralGoogle Scholar
  44. Nelson, W. J. (2003b). Adaptation of core mechanisms to generate cell polarity. Nature, 422, 766–774.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Noctor, S. C., Martínez-Cerdeño, V., Ivic, L., et al. (2004). Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neuroscience, 7, 136–144.CrossRefPubMedGoogle Scholar
  46. Overeem, A. W., Bryant, D. M., & van IJzendoorn, S. C. (2015). Mechanisms of apical-basal axis orientation and epithelial lumen positioning. Trends in Cell Biology, 25, 476–485.CrossRefPubMedGoogle Scholar
  47. Pece, S., Confalonieri, S. R., Romano, P., et al. (2011). NUMB-ing down cancer by more than just a NOTCH. Biochimica et Biophysica Acta, 1815, 26–43.PubMedGoogle Scholar
  48. Peng, Y., & Axelrod, J. D. (2012). Asymmetric protein localization in planar cell polarity: Mechanisms, puzzles and challenges. Current Topics in Developmental Biology, 101, 33–53.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rawlins, E. L. (2008). Lung epithelial progenitor cells: Lessons from development. Proceedings of the American Thoracic Society, 5, 675–681.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Rawlins, E. L., & Hogan, B. L. (2006). Epithelial stem cells of the lung: Privileged few or opportunities for many? Development, 133, 2455–2465.CrossRefPubMedGoogle Scholar
  51. Rawlins, E. L., Clark, C. P., Xue, Y., et al. (2009a). The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development, 136, 3741–3745.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Rawlins, E. L., Okubo, T., Xue, Y., et al. (2009b). The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell, 4, 525–534.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Roignot, J., Peng, X., & Mostov, K. (2013). Polarity in mammalian epithelial morphogenesis. Cold Spring Harbor Perspectives in Biology, 5, a013789.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Shi, W., Xu, J., & Warburton, D. (2009). Development, repair and fibrosis: What is common and why it matters. Respirology, 14, 656–655.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Shinin, V., Gayraud-Morel, B., Gomes, D., & Tajbakhsh, S. (2006). Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nature Cell Biology, 8, 677–687.CrossRefPubMedGoogle Scholar
  56. Tepass, U. (2012). The apical polarity protein network in Drosophila epithelial cells: Regulation of polarity, junctions, morphogenesis, cell growth, and survival. Annual Review of Cell and Developmental Biology, 28, 655–685.CrossRefPubMedGoogle Scholar
  57. Tuncay, H., & Ebnet, K. (2016). Cell adhesion molecule control of planar spindle orientation. Cellular and Molecular Life Sciences, 73, 1195–1207.CrossRefPubMedGoogle Scholar
  58. Vorhagen, S., & Niessen, C. M. (2014). Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate. Experimental Cell Research, 328, 296–302.CrossRefPubMedGoogle Scholar
  59. Wang, C., Chang, K. C., Somers, G., et al. (2009). Protein phosphatase 2A regulates self-renewal of Drosophila neural stem cells. Development, 136, 2287–2296.CrossRefPubMedGoogle Scholar
  60. Warburton, D. (2008). Developmental biology: Order in the lung. Nature, 453, 73–75.CrossRefGoogle Scholar
  61. Warburton, D., Schwarz, M., Tefft, D., et al. (2000). The molecular basis of lung morphogenesis. Mech Dev, 92, 55–81.CrossRefPubMedGoogle Scholar
  62. Warburton, D., Perin, L., Defilippo, R., et al. (2008). Stem/progenitor cells in lung development, injury repair, and regeneration. Proceedings of the American Thoracic Society, 5, 703–706.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Warburton, D., El-Hashash, A., Carraro, G., et al. (2010). Lung organogenesis. Current Topics in Developmental Biology, 90, 73–158.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Wodarz, A. (2002). Establishing cell polarity in development. Nature Cell Biology, 4, E39–E44.CrossRefPubMedGoogle Scholar
  65. Woods, D. F., Wu, J. W., & Bryant, P. J. (1997). Localization of proteins to the apico-lateral junctions of Drosophila epithelia. Developmental Genetics, 20, 111–118.CrossRefPubMedGoogle Scholar
  66. Yamashita, Y. M., Yuan, H., Cheng, J., et al. (2010). Polarity in stem cell division: Asymmetric stem cell division in tissue homeostasis. Cold Spring Harbor Perspectives in Biology, 2, a001313.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Yan, B., Omar, F. M., Das, K., et al. (2008). Characterization of Numb expression in astrocytomas. Neuropathology, 28, 479–484.CrossRefPubMedGoogle Scholar
  68. Yang, S., Ma, K., Geng, Z., et al. (2015). Oriented cell division: New roles in guiding skin wound repair and regeneration. Bioscience Reports, 35, 6.CrossRefGoogle Scholar
  69. Zhou, Q., Law, A. C., Rajagopal, J., et al. (2007). A multipotent progenitor domain guides pancreatic organogenesis. Developmental Cell, 13, 103–114.CrossRefPubMedGoogle Scholar
  70. Zimdahl, B., Ito, T., Blevins, A., et al. (2014). Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nature Genetics, 46, 245–252.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ahmed El-Hashash
    • 1
  1. 1.The University of Edinburgh-Zhejiang International campus (UoE-ZJU Institute), and Centre of Stem Cell and Regenerative Medicine Schools of Medicine & Basic Medicine, Zhejiang UniversityHainingChina

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