Molecular Neurobiology

, Volume 31, Issue 1–3, pp 231–242 | Cite as

Effects of hypoxia on the proliferation and differentiation of NSCs

  • Ling-Ling Zhu
  • Li-Ying Wu
  • David Tai Yew
  • Ming FanEmail author


Oxygen is vital to nearly all forms of life on Earth via its role in energy homeostasis and other cell functions. Until recently, the effects of oxygen on the proliferation and differentiation of neural stem cells (NSCs) have been largely ignored. Some studies have been carried out on the basis of the fact that NSCs exists within a “physiological hypoxic” environment at 1 to 5% O2 in both embryonic and adult brains. The results showed that hypoxia could promote the growth of NSCs and maintain its survival in vitro. In vivo studies also showed that ischemia/hypoxia increased the number of endogenous NSCs in the subventricular zone and dentate gyrus. In addition, hypoxia could influence the differentiation of NSCs. More neurons, especially more doparminergic neurons, were produced under hypoxic condition. The effects of hypoxia on the other kind of stem cell were briefly introduced as additional evidence. The mechanism of these responses might be primarily involved in the hypoxic inducible factor-1 (HIF-1) signal pathway. The present review summarizes recent works on the role of hypoxia in the proliferation and differentiation of NSCs both in vitro and in vivo, and the mechanism involved in HIF-1 signaling pathway behind this response was also discussed.

Index Entries

Hypoxia NSCs proliferation differentiation HIF-1 


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  1. 1.
    Yun Z., Maecker H.L., Johnson R.S., and Giaccia A.J. (2002) Inhibition of PPARγ2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev. Cell 2, 331–341.PubMedCrossRefGoogle Scholar
  2. 2.
    Gage F.H. (2002) Neurogenesis in the adult brain. J. Neurosci. 22, 612–613.PubMedGoogle Scholar
  3. 3.
    Genbacev O. (2001) To proliferate or to divide—to be or not to be. Early Pregn. 5, 63–64.Google Scholar
  4. 4.
    Mitchell J.A. and Yochim J.M. (1968) Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity. Endocrinology 83, 701–715.PubMedCrossRefGoogle Scholar
  5. 5.
    Rodesch F., Simon P., Donner C., and Jauniaux X. (1992) Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet. Gynecol. 80, 283–285.PubMedGoogle Scholar
  6. 6.
    Burton G.J. and Jaunaiux E. (2001) Maternal vascularisation of the human placenta: does the embryo develop in a hypoxia environment. Gynecol. Obstet. Fertil. 29, 503–508.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee Y.M., Jeong C.H., Koo S.Y., Son M.J., Song H.S., and Bae S.K. (2001) Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev. Dynam. 220, 175–186.CrossRefGoogle Scholar
  8. 8.
    Goda F., O’Hara J.A., Liu K.J., Rhodes E.S., Dunn J.F., and Swartz H.J. (1997) Comparisons of measurements of pO2 in tissue in vivo by EPR oximetry and microelectrodes. Adv. Exp. Med. Biol. 411, 543–549.PubMedGoogle Scholar
  9. 9.
    Liu K.J., Hoopes P.J., Rolett E.L., Beerle B.J., Azzawi A., and Goda F. (1997) Effect of anesthesia on cerebral tissue oxygen and cardiopulmonary parameters in rats. Adv. Exp. Med. Biol. 411, 33–39.PubMedGoogle Scholar
  10. 10.
    Tammela O., Song D., Olano M., Delivoria-Papadopoulos M., Wilson D.F., and Pastuszko A. (1997) Response of cortical oxygen and striatal extracellular dopamine to metabolic acidosis in newborn piglets. Adv. Exp. Med. Biol. 411, 103–111.PubMedGoogle Scholar
  11. 11.
    Koos B.J. and Power G.C. (1987) Predit fetal brain PO2 during hypoxaemia and anemia in sheep. J. Dev. Physiol. 9, 517–526.PubMedGoogle Scholar
  12. 12.
    Silver I. and Erecinska M. (1988) Oxygen and ion concentrations in normoxic and hypoxic brain cells. Adv. Exp. Med. Biol. 454, 7–16.Google Scholar
  13. 13.
    Morrison S.J., Csete M., Groves A.K., Melega W., Wold B., and Anderson D.J. (2000) Culture in reduced levels of oxygen promotes clonogenic sympathoadrenal differentiation by isolated neural crest stem cells. J. Neurosci. 20, 7370–7376.PubMedGoogle Scholar
  14. 14.
    Storch A., Paul G., Csete M., et al. (2001) Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells. Exp. Neurol. 170, 317–325.PubMedCrossRefGoogle Scholar
  15. 15.
    Studer L., Csete M., Lee S.H., Kabbani N., Walikonis J., and Wold B. (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J. Neurosci. 20, 7377–7383.PubMedGoogle Scholar
  16. 16.
    Storch A., Lester H.A., Boehm B.O., and Schwarz J. (2003) Functional characterization of dopaminergic neurons derived from rodent mesencephalic progenitor cells. J. Chem. Neuroanat. 26, 133–142.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhu L.L., Zhao T., Zhao H.Q., Li H.S., Wu L.Y., and Fan M. (2004) Effects of hypoxia on the proliferation and differentiation of neural stem Cells. ISN Satellite Meeting on Oxidative Stress in Neurodegenerative Disorders, p. 44.Google Scholar
  18. 18.
    Kennea N.L. and Mehmet H. (2002) Neural stem cells. J. Pathol. 197, 536–550.PubMedCrossRefGoogle Scholar
  19. 19.
    Kokaia Z. and Lindvall O. (2003) Neurogenesis after ischaemic brain insults (review). Curr. Opin. Neurobiol. 13, 127–132.PubMedCrossRefGoogle Scholar
  20. 20.
    Liu J., Solway K., Messing R.O., and Sharp F.R. (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbilis. J. Neurosci. 18, 7768–7778.PubMedGoogle Scholar
  21. 21.
    Takagi Y., Nozaki K., Takahashi J., Yodoi J., Ishikawa M., and Hashimoto N. (1999) Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res. 831, 283–287.PubMedCrossRefGoogle Scholar
  22. 22.
    Kee N.J., Preston E., and Wojtowicz J.M. (2001) Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Exp. Brain Res. 136, 313–320.PubMedCrossRefGoogle Scholar
  23. 23.
    Yagita Y., Kitagawa K., Ohtsuki T., Takasawa K., Miyata T., and Okano H. (2001) Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke 32, 1890–1896.PubMedGoogle Scholar
  24. 24.
    Jin K., Mao X.O., Sun Y., Xie L., and Greenberg D.A. (2001) Stem cell factor stimulates neurogenesis in vitro and in vivo. J. Clin. Invest. 110, 311–319.CrossRefGoogle Scholar
  25. 25.
    Iwai M. (2002) Three steps of neural stem cells development in gerbil dentate gyrus after transient ischemia. J. Cereb. Blood Flow Metab. 22, 411–419.PubMedCrossRefGoogle Scholar
  26. 26.
    Tonchev A.B., Yamashima T., Zhao L., Okano H.J., and Okano H. (2003) Proliferation of neural and neuronal progenitors after global brain ischemia in young adult macaque monkeys. Mol. Cell. Neurosci. 23, 292–301.PubMedCrossRefGoogle Scholar
  27. 27.
    Shingo T., Sorokan S.T., Shimazaki T., and Weiss S. (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J. Neurosci. 21, 9733–9743.PubMedGoogle Scholar
  28. 28.
    Zigova T., Pencea V., Wiegand S.J., and Luskin M.B. (1998) Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol. cell. Neurosci. 11, 234–245.PubMedCrossRefGoogle Scholar
  29. 29.
    Pencea V., Bingaman K.D., Wiegand S.J., and Luskin M.B. (2002) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J. Neurosci. 21, 6706–6717.Google Scholar
  30. 30.
    Benrasis A., Chmielnicki E., Lerner K., Roh D., and Goldman S.A. (2001) Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci. 21, 6718–6731.Google Scholar
  31. 31.
    Nakatomi H., Kuriu T., Okabe S., Yamamoto S., Hatano O., and Kawahara N. (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429–441.PubMedCrossRefGoogle Scholar
  32. 32.
    Ramirez-Bergeron D. and Simon M.C. (2001) Hypoxia-inducible factor and the development of stem cells of the cardiovascular system (review). Stem Cells 19, 279–286.PubMedCrossRefGoogle Scholar
  33. 33.
    Cipolleschi M.G., Dello Sbarba P., and Olivotto M. (1993) The role of hypoxia in the maintaince of hematopietic stem cells. Blood 82, 2031–2037.PubMedGoogle Scholar
  34. 34.
    Ivanovic Z., Dello Sbarba P.D., and Trimoreau F. (2000) Primitive human HPCs are better maintained and expanded in vitro at 1 percent oxygen than at 20 percent. Transfusion 40, 1482–1488.PubMedCrossRefGoogle Scholar
  35. 35.
    Ivanovic Z., Belloc F., and Faucher J.L. (2002) Hypoxia maintains and interleukin-3 reduces the pre-colony-forming cell potential of dividing CD34+ muring bone marrow cells. Exp. Hematol. 30, 67–73.PubMedCrossRefGoogle Scholar
  36. 36.
    Mostafa S.M., Papoutsakis E.T., and Miller W.M. (2000) Oxygen tension has significant effects on human megakaryocyte maturation. Exp. Hematol. 28, 1498.CrossRefGoogle Scholar
  37. 37.
    Caniggia I., Mostachfi H., Winter J., Gassmann M., Lye S.J., and Kuliszewski M. (2000) Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophblast differentiation through TGF β 3. J. Clin. Invest. 105, 577–587.PubMedGoogle Scholar
  38. 38.
    Genbacev O., Zhou Y., Ludlow J.W., and Fisher S.L. (1997) Regulation of human placental development by oxygen tension. Science 277, 1669–1672.PubMedCrossRefGoogle Scholar
  39. 39.
    Emura M., Ochiai A., Gobert-Bohlen A., Panning B., and Dungworth D.L. (1994) Neuroendocrine phenotype differentiation in a hamster lung epithelial cell line under low oxygen pressure or after transformation by diethylnitrosamine. Toxicol. Lett. 72, 59–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Csete M., Walikonis J., Slawny N., et al. (2001) Oxygen-mediated regulation of skeletal muscle satellite cell proliferation and adipogenesis in culture. J. Cell Physiol. 189, 189–196.PubMedCrossRefGoogle Scholar
  41. 41.
    Hollenberg M., Honbo N., Ghani Q.P., and Samorodin A.J. (1981) Oxygen enhances fusion of cultured chick embryo myoblasts. J. Cell Physiol. 106, 209–213.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhao T., Zhu L.L., Zhao H.Q., Li H.S., and Fan M. (2003) Effects of hypoxia on the proliferation of rat myoblast in vitro. Proceedings of 5th Congress of Chinese Society for Neuroscience, p. 290.Google Scholar
  43. 43.
    Carlo A.D., Mori R.D., Martelli F., Pompilio G., Capogrossi M.C., and German A. (2004) Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation. J. Biol. Chem. 279, 16,332–16,338.CrossRefGoogle Scholar
  44. 44.
    Roy S., Khanna S., Bickerstaff A.A., Subramanian S.V., Atalay M., and Bierl M. (2003) Oxygen sensing by primary cardiac fibroblasts: a key role of p21(Waf1/Cip1/Sdi1). Circ. Res. 92, 264–271.PubMedCrossRefGoogle Scholar
  45. 45.
    Lennon D.P., Edmison J.M., and Caplan A.I. (2001) Cultivation of rat marrow-derived mesenchymal stem cells in reduced oxygen tension: effects on in vitro and in vivo osteochondrogenesis. J. Cell Physiol. 187, 345–355.PubMedCrossRefGoogle Scholar
  46. 46.
    Li H.S., Zhao H.Q., Zhu L.L., et al. (2003) Effect of hypoxia on proliferation of human mesenchymal stem cells in vitro. Proceedings of 5th Congress of Chinese Society for Neuroscience, p. 287.Google Scholar
  47. 47.
    Wu L.Y., Wu Y., Zhu L.L., et al. (2004) Hypoxia regulates the proliferation and neuronal differentiation of P19 cells. ISN Satellite Meeting on Oxidative Stress in Neurodegenerative Disorders, p. 54.Google Scholar
  48. 48.
    Sun B., Bai C.X., Feng K., Li L., Zhao P., and Pei X.T. (2000) Effects of hypoxia on the proliferation and differentiation of CD34(+) hematopoietic stem/progenitor cells and their response to cytokines Sheng Li Xue Bao. 52, 143–146.PubMedGoogle Scholar
  49. 49.
    Adelman D.M., Maltepe E., and Simon M.C. (1999) Multilineage embryonic hematopoiesis requires hypoxic ARNT activity. Genes Dev. 13, 2478–2483.PubMedCrossRefGoogle Scholar
  50. 50.
    Caniggia I., Mostachfi H., Winter J., et al. (2000) Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J. Clin. Invest. 105, 577–587.PubMedCrossRefGoogle Scholar
  51. 51.
    Gassmann M., Fandrey J., Bichet S., et al. (1996) Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc. Natl. Acad. Sci. USA 93, 2867–2872.PubMedCrossRefGoogle Scholar
  52. 52.
    Semenza G.L. (2002) Molecular responses to hypoxia in tumor cells. Biochem. Pharmacol. 64, 993–998.PubMedCrossRefGoogle Scholar
  53. 53.
    Jain S., Maltepe E., Lu M.M., Simon C., and Bradfield C.A. (1998) Expression of ARNT, ARNT2, HIF1a, HIF2a and Ah receptor mRNA in the developing mouse. Mech. Dev. 73, 117–123.PubMedCrossRefGoogle Scholar
  54. 54.
    Iyer N.V., Kotch L.E., Agani F., Leung S.W., Laugher E., and Wenger R.H. (1998) Cellular and development control of O2 homeostasis by hypoxia-inducible factor1a. Genes Dev. 12, 149–162.PubMedGoogle Scholar
  55. 55.
    Kotch L.E., Iyer N.V., Laughner E., and Semenza G.L. (1999) Defective vascularization of HIF-1a-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev. Biol. 209, 254–267.PubMedCrossRefGoogle Scholar
  56. 56.
    Adelman D.M., Gertsrnstein M., Nagy A., Simon M.C., and Maltepe E. (2000) Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191–3203.PubMedCrossRefGoogle Scholar
  57. 57.
    Yin Z., Haynie J., Yang X.M., Han B.G., Kiatchoosakun S., and Restivo J. (2002) The essential role of Cited2, a negative regulator for HIF-1α, in heart development and neurulation. PNAS 99, 488–493.Google Scholar
  58. 58.
    Yu X., Shacka J.J., Eells J.B., Suarez-Quian C., Przygodzki R.M., and Beleslin-Cokic B. (2002) Erythropoietin receptor signalling is required for normal brain development. Development 129, 505–516.PubMedGoogle Scholar
  59. 59.
    Tomita S., Ueno M., Sakamoto M., Kitahama Y., Ueki M., and Maekawa N. (2003) Defective brain development in mice lacking the Hif-1α gene in neural cells. Mol. Cell. Biol. 23, 6739–6749.PubMedCrossRefGoogle Scholar
  60. 60.
    Carmeliet P., Dor Y., Herbert J.M., Fukumura D., Brusselmans K., and Dewerchin. (1998) Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490.PubMedCrossRefGoogle Scholar
  61. 61.
    Brusselman K., Bono F., Maxwell P., Dor Y., Dewerchin M., and Collen D. (2001) Hypoxia-inducible factor-2α (HIF-2α) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J. Biol. Chem. 276, 39,192–39,196.Google Scholar
  62. 62.
    Rose F., Grimminger F., Appel J., Heller M., Pies V., and Weissmann N. (2002) Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: role of hypoxia-inducible transcription factors. FASEB J. 16, 1660–1661.PubMedGoogle Scholar
  63. 63.
    Jögi A., tOra I., Nilsson H., Poellinger L., Axelson H., and Påhlman S. (2003) Hypoxiainduced dedifferentiation in neuroblastoma cells. Cancer Lett. 197, 145–150.PubMedCrossRefGoogle Scholar
  64. 64.
    Carmeliet P., Dor Y., Herbert J.M., Fukumura D., Brusselmans K., and Dewerchin M. (1998) Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Ling-Ling Zhu
    • 1
  • Li-Ying Wu
    • 1
  • David Tai Yew
    • 2
  • Ming Fan
    • 1
    Email author
  1. 1.Department of Brain Protection and PlasticityInstitute of Basic Medical ScienceBeijingChina
  2. 2.Department of AnatomyMedical College of Hong Kong Chinese UniversityHong Kong

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