Signals and Molecular Mechanisms Regulating Stem Cell Behavior in Other Systems (e.g., Hematopoietic Stem Cells)

  • Ahmed El-Hashash


Over recent years, many studies of stem cell behavior in different organs have accumulated evidences on the molecular mechanisms and signaling pathways that regulate key aspects of stem/progenitor cell behavior such as self-renewal, differentiation, and apoptosis. These molecular mechanisms include Wnt, TGF beta, and Notch signaling pathways that are well investigated in hematopoietic stem cells. In this chapter, we will discuss the hematopoietic stem/progenitor cell niche and both the molecular mechanisms and signaling pathways that control their behavior since this will improve our understanding of the role of these mechanisms and signals in the behavior of lung stem/progenitor cells that is still not well studied compared to hematopoietic stem/progenitor cells.


Stem cells Cell behavior Cell fate Hematopoietic stem cells Wnt Notch TGF Signaling pathway 


  1. Adams, G. B., Chabner, K. T., Alley, I. R., et al. (2006). Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature, 439, 599–603.CrossRefPubMedGoogle Scholar
  2. Adolfsson, J., Borge, O. J., Bryder, D., et al. (2001). Upregulation of Flt3 expression within the bone marrow Lin(−)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity, 15, 659–669.CrossRefPubMedGoogle Scholar
  3. Audet, J., Miller, C. L., Rose-John, S., Piret, J., & Eaves, C. (2001). Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 98, 1757–1762.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Batard, P., Monier, M. N., Fortunel, N., et al. (2000). TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation. Journal of Cell Science, 113, 383–390.PubMedGoogle 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. Blank, U., & Karlsson, S. (2011). The role of Smad signaling in hematopoiesis and translational hematology. Leukemia, 25, 1379–1388.CrossRefPubMedGoogle Scholar
  7. Borge, O. J., Ramsfjell, V., Veiby, O., Murphy, M. J., Jr., Lok, S., & Jacobsen, S. E. (1996). Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro. Blood, 88, 2859–2870.PubMedGoogle Scholar
  8. Bowie, M. B., McKnight, K. D., Kent, D. G., McCaffrey, L., Hoodless, P. A., & Eaves, C. J. (2006). Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. The Journal of Clinical Investigation, 116, 2808–2816.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Buza-Vidas, N., Antonchuk, J., Qian, H., et al. (2006). Cytokines regulate postnatal hematopoietic stem cell expansion: Opposing roles of thrombopoietin and LNK. Genes & Development, 20, 2018–2023.CrossRefGoogle Scholar
  10. Calvi, L. M., Adams, G. B., Weibrecht, K. W., et al. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 425, 841–846.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Christensen, J. L., & Weissman, I. L. (2001). Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells. Proceedings of the National Academy of Sciences of the United States of America, 98, 14541–14546.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cobas, M., Wilson, A., Ernst, B., et al. (2004). Beta-catenin is dispensable for hematopoiesis and lymphopoiesis. The Journal of Experimental Medicine, 199, 221–229.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Delaney, C., Varnum-Finney, B., Aoyama, K., Brashem-Stein, C., & Bernstein, I. D. (2005). Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood, 106, 2693–2699.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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
  15. Ema, H., Sudo, K., Seita, J., et al. (2005). Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Developmental Cell, 8, 907–914.CrossRefPubMedGoogle Scholar
  16. Enver, T., Heyworth, C. M., & Dexter, T. M. (1998). Do stem cells play dice? Blood, 92, 348–351.PubMedGoogle Scholar
  17. Garbe, A., Spyridonidis, A., Mobest, D., et al. (1997). Transforming growth factor-beta 1 delays formation of granulocyte-macrophage colony-forming cells, but spares more primitive progenitors during ex vivo expansion of CD34+ haemopoietic progenitor cells. British Journal of Haematology, 99, 951–958.CrossRefPubMedGoogle Scholar
  18. Ikuta, K., & Weissman, I. L. (1992). Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proceedings of the National Academy of Sciences of the United States of America, 89, 1502–1506.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ito, K., Hirao, A., Arai, F., et al. (2004). Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature, 431, 997–1002.CrossRefPubMedGoogle Scholar
  20. Ito, K., Hirao, A., Arai, F., et al. (2006). Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Medicine, 12, 446–451.CrossRefPubMedGoogle Scholar
  21. Itoh, F., Itoh, S., Goumans, M. J., et al. (2004). Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. The EMBO Journal, 23, 541–551.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Karanu, F. N., Murdoch, B., Gallacher, L., et al. (2000). The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. The Journal of Experimental Medicine, 192, 1365–1372.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Karanu, F. N., Murdoch, B., Miyabayashi, T., et al. (2001). Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood, 97, 1960–1967.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kaushansky, K., & Drachman, J. G. (2002). The molecular and cellular biology of thrombopoietin: The primary regulator of platelet production. Oncogene, 21, 3359–3367.CrossRefPubMedGoogle Scholar
  25. Kimura, S., Roberts, A. W., Metcalf, D., et al. (1998). Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proceedings of the National Academy of Sciences of the United States of America, 95, 1195–1200.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kirstetter, P., Anderson, K., Porse, B. T., et al. (2006). Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nature Immunology, 7, 1048–1056.CrossRefPubMedGoogle Scholar
  27. Kunisato, A., Chiba, S., Nakagami-Yamaguchi, E., et al. (2003). HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood, 101, 1777–1783.CrossRefPubMedGoogle Scholar
  28. Labbé, E., Letamendia, A., & Attisano, L. (2000). Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proceedings of the National Academy of Sciences of the United States of America, 97, 8358–8363.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Larsson, J., Blank, U., Helgadottir, H., et al. (2003). TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood, 102, 3129–3135.CrossRefPubMedGoogle Scholar
  30. Larsson, J., Blank, U., Klintman, J., Magnusson, M., & Karlsson, S. (2005). Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo. Experimental Hematology, 33, 592–596.CrossRefPubMedGoogle Scholar
  31. Mancini, S. J., Mantei, N., Dumortier, A., et al. (2005). Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood, 105, 2340–2342.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Matsuzaki, Y., Kinjo, K., Mulligan, R. C., et al. (2004). Unexpectedly efficient homing capacity of purified murine hematopoietic stem cells. Immunity, 20, 87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Metcalf, D. (1993). Hematopoietic regulators: Redundancy or subtlety? Blood, 82, 3515–3523.PubMedGoogle Scholar
  34. Miller, C. L., & Eaves, C. J. (1997). Expansion in vitro of adult murine hematopoietic stem cells with transplantable lympho-myeloid reconstituting ability. Proceedings of the National Academy of Sciences of the United States of America, 94, 13648–13653.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Milner, L. A., Kopan, R., Martin, D. I., et al. (1994). A human homologue of the Drosophila developmental gene, Notch, is expressed in CD34+ hematopoietic precursors. Blood, 83, 2057–2062.PubMedGoogle Scholar
  36. Morrison, S. J., & Scadden, D. T. (2014). The bone marrow niche for haematopoietic stem cells. Nature, 505, 327–334.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Morrison, S. J., & Weissman, I. L. (1994). The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity, 1, 661–673.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Nandurkar, H. H., Robb, L., Tarlinton, D., et al. (1997). Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis. Blood, 90, 2148–2159.PubMedGoogle Scholar
  39. Nilsson, S. K., Johnston, H. M., Whitty, G. A., et al. (2005). Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood, 106, 1232–1239.CrossRefPubMedGoogle Scholar
  40. Nishita, M., Hashimoto, M. K., Ogata, S., et al. (2000). Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann’s organizer. Nature, 403, 781–785.CrossRefPubMedGoogle Scholar
  41. Ohishi, K., Varnum-Finney, B., & Bernstein, I. D. (2002). Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(−) cord blood cells. The Journal of Clinical Investigation, 110, 1165–1174.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Okada, S., Nakauchi, H., Nagayoshi, K., et al. (1992). In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood, 80, 3044–3050.PubMedGoogle Scholar
  43. Osawa, M., Hanada, K., Hamada, H., et al. (1996). Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science, 273, 242–245.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Parmar, K., Mauch, P., Vergilio, J. A., et al. (2007). Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 104, 5431–5436.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Pestina, T.I., Cleveland, J., Yang, C., Zambetti, G., & Jackson C (2001). Mpl ligand prevents lethalmyelosuppression by inhibiting p53-dependent apoptosis. Blood, 98, 2084–2090.Google Scholar
  46. Radtke, F., Wilson, A., Mancini, S. J., et al. (2004). Notch regulation of lymphocyte development and function. Nature Immunology, 5, 247–253.CrossRefPubMedGoogle Scholar
  47. Reya, T., Duncan, A. W., Ailles, L., et al. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature, 423, 409–414.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Schofield, R. (1978). The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells, 4, 7–25.PubMedPubMedCentralGoogle Scholar
  49. Seita, J., Ema, H., Ooehara, J., et al. (2007). Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 104, 2349–2354.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Sitnicka, E., Ruscetti, F. W., Priestley, G. V., et al. (1996). Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells. Blood, 88, 82–88.PubMedGoogle Scholar
  51. Solar, G. P., Kerr, W. G., Zeigler, F. C., et al. (1998). Role of c-mpl in early hematopoiesis. Blood, 92, 4–10.PubMedGoogle Scholar
  52. Spangrude, G. J., Heimfeld, S., & Weissman, I. L. (1988). Purification and characterization of mouse hematopoietic stem cells. Science, 241, 58–62.CrossRefPubMedGoogle Scholar
  53. Stier, S., Cheng, T., Dombkowski, D., et al. (2002). Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood, 99, 2369–2378.CrossRefPubMedGoogle Scholar
  54. Stier, S., Ko, Y., Forkert, R., et al. (2005). Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. The Journal of Experimental Medicine, 201, 1781–1791.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Suzuki, A., Raya, A., Kawakami, Y., et al. (2006). Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 103, 10294–10299.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Takaki, S., Sauer, K., Iritani, B. M., et al. (2000). Control of B cell production by the adaptor protein lnk: Definition of a conserved family of signal-modulating proteins. Immunity, 13, 599–609.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Till, J. E., McCulloch, E. A., & Siminovitch, L. (1964). A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells. Proceedings of the National Academy of Sciences of the United States of America, 51, 29–36.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tong, W., Zhang, J., & Lodish, H. F. (2005). Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood, 105, 4604–4612.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Trowbridge, J. J., Xenocostas, A., Moon, R. T., et al. (2006). Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Medicine, 12, 89–98.CrossRefPubMedGoogle Scholar
  60. Varnum-Finney, B., Xu, L., Brashem-Stein, C., et al. (2000). Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nature Medicine, 6, 1278–1281.CrossRefPubMedGoogle Scholar
  61. Varnum-Finney, B., Brashem-Stein, C., & Bernstein, I. D. (2003). Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood, 101, 1784–1789.CrossRefPubMedGoogle Scholar
  62. Vas, V., Szilagyi, L., Paloczi, K., et al. (2004). Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay. Journal of Leukocyte Biology, 75, 714–720.CrossRefPubMedGoogle Scholar
  63. Velazquez, L., Cheng, A. M., Fleming, H. E., et al. (2002). Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. The Journal of Experimental Medicine, 195, 1599–1611.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Willert, K., Brown, J. D., Danenberg, E., et al. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 423, 448–452.CrossRefPubMedGoogle Scholar
  65. Wilson, A., & Trumpp, A. (2006). Bone-marrow haematopoietic-stem-cell niches. Nature Reviews. Immunology, 6, 93–106.CrossRefPubMedGoogle Scholar
  66. Yang, L., Bryder, D., Adolfsson, J., et al. (2005). Identification of Lin(−)Sca1(+)kit(+)CD34(+)Flt3- short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood, 105, 2717–2723.CrossRefPubMedGoogle Scholar
  67. Zheng, J., Huynh, H., Umikawa, M., et al. (2011). Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood, 117, 470–479.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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