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Surrogate Measures of Adult Stem Cell Self-Renewal: The Neural Stem Cell Paradigm

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Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Since the discovery that neural stem cells (NSCs) reside within specific neurogenic regions of the adult brain, much effort has been devoted to delineating their unique biology and evaluating their therapeutic potential to treat injury and disease. This chapter provides an overview of NSC biology and examines in detail methods used to study the biology and function of these cells. Emphasis is placed on in vitro assays, such as the neurosphere and neural colony-forming assays develo­ped to propagate and enumerate NSCs. The physical and metaphysical limitations of these assays with respect to their capacity to delineate between stem, progenitor, and nonstem cells are discussed together with obstacles associated with developing in vivo assays to measure stem cell function and potency.

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Abbreviations

EGF:

Epidermal growth factor

HSC:

Hematopoietic stem cell

NCFCA:

Neural colony-forming cell assay

NSA:

Neurosphere assay

NSC:

Neural stem cell

RMS:

Rostral migratory stream

SGZ:

Subgranular zone

SVZ:

Subventricular zone

References

  • Altman J (1962) Are new neurons formed in the brains of adult mammals? Science 135:1127–1128.

    Article  CAS  PubMed  Google Scholar 

  • Arvidsson A, Collin T, Kirik D et al (2002) Neuronal replacement from endogeneous precursors in the adult brain after stroke. Nat Med 8:963–970.

    Article  CAS  PubMed  Google Scholar 

  • Bull ND, Bartlett PF (2005) The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci 25:10815–10821.

    Article  CAS  PubMed  Google Scholar 

  • Calza L, Giardino L, Pozza M et al (1998) Proliferation and phenotype regulation in the ­subventricular zone during experimental allergic encephalomyelitis: in vivo evidence of a role for nerve growth factor. Proc Natl Acad Sci USA 95:3209–3214.

    Article  CAS  PubMed  Google Scholar 

  • Cameron HA, McKay RD (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 435:406–417.

    Article  CAS  PubMed  Google Scholar 

  • Carlen M, Cassidy RM, Brismar H et al (2002) Functional integration of adult-born neurons. Curr Biol 12:606–608.

    Article  CAS  PubMed  Google Scholar 

  • Carlen M, Meletis K, Goritz C et al (2009) Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci 12:259–267.

    Article  CAS  PubMed  Google Scholar 

  • Coulombel L (2004) Identification of hematopoietic stem/progenitor cells: strength and drawbacks of functional assays. Oncogene 23:7210–7222.

    Article  CAS  PubMed  Google Scholar 

  • Curtis MA, Kam M, Nannmark U et al (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315:1243–1249.

    Article  CAS  PubMed  Google Scholar 

  • Deleyrolle LP, Reynolds BA (2009a) Identifying and enumerating neural stem cells: application to aging and cancer. Prog Brain Res 175:43–51.

    Article  PubMed  Google Scholar 

  • Deleyrolle LP, Reynolds BA (2009b) Isolation, expansion, and differentiation of adult mammalian neural stem cells and progenitor cells using the neurosphere assay. Methods Mol Biol 549:91–101.

    Article  CAS  PubMed  Google Scholar 

  • Doetsch F, Caille I, Lim DA et al (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716.

    Article  CAS  PubMed  Google Scholar 

  • Enwere E, Shingo T, Gregg C et al (2004) Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24:8354–8365.

    Article  CAS  PubMed  Google Scholar 

  • Eriksson PS, Perfilieva E, Björk-Eriksson T et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317.

    Article  CAS  PubMed  Google Scholar 

  • Foroni C, Galli R, Cipelletti B et al (2007) Resilience to transformation and inherent genetic and functional stability of adult neural stem cells ex vivo. Cancer Res 67:3723–3733.

    Article  Google Scholar 

  • Franke RH, Kaul JD (1978) The Hawthorne experiments: first statistical interpretation. Am Soc Rev 43:623–642.

    Article  Google Scholar 

  • Gheusi G, Cremer H, McLean H et al (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci USA 97:1823–1828.

    Article  CAS  PubMed  Google Scholar 

  • Gould E, McEwen BS, Tanapat P et al (1997) Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17:2492–2498.

    CAS  PubMed  Google Scholar 

  • Gould E, Tanapat P, McEwen BS et al (1998) Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci USA 95:3168–3171.

    Article  CAS  PubMed  Google Scholar 

  • Gritti A, Cova L, Parati EA et al (1995) Basic fibroblast growth factor supports the proliferation of epidermal growth factor-generated neuronal progenitor cells of the adult mouse CNS. Neurosci Lett 185:151–154.

    Article  CAS  PubMed  Google Scholar 

  • Gross CG (2000) Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 1:67–73.

    Article  CAS  PubMed  Google Scholar 

  • Hall PA, Watt FM (1989) Stem cells: the generation and maintenance of cellular diversity. Development 106:619–633.

    CAS  PubMed  Google Scholar 

  • Hastings NB, Gould E (1999) Rapid extension of axons into the CA3 region by adult-generated granule cells. J Comp Neurol 413:146–154.

    Article  CAS  PubMed  Google Scholar 

  • Heisenberg W (1927) Über den anschulichen Inhalt der quantentheoretischen Kinematik und Mechanik. Z Phys 43:172–198.

    Article  Google Scholar 

  • Hitoshi S, Tropepe V, Ekker M et al (2002) Neural stem cell lineages are regionally specified, but not committed, within distinct compartments of the developing brain. Development 129:233–244.

    CAS  PubMed  Google Scholar 

  • Ivanova NB, Dimos JT, Schaniel C et al (2002) A stem cell molecular signature. Science 298:601–604.

    Article  CAS  PubMed  Google Scholar 

  • Johansson CB, Momma S, Clarke DL et al (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96:25–34.

    Article  CAS  PubMed  Google Scholar 

  • Lie DC, Dziewczapolski G, Willhoite AR et al (2002) The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 22:6639–6649.

    CAS  PubMed  Google Scholar 

  • Lie DC, Song H, Colamarino SA et al (2004) Neurogenesis in the adult brain: new strategies for central nervous system diseases. Annu Rev Pharmacol Toxicol 44:399–421.

    Article  CAS  PubMed  Google Scholar 

  • Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193.

    Article  CAS  PubMed  Google Scholar 

  • Louis SA, Rietze RL, Deleyrolle L et al (2008) Enumeration of neural stem and progenitor cells in the neural colony-forming cell assay. Stem Cells 26:988–996.

    Article  PubMed  Google Scholar 

  • Lu F, Wong CS (2005) A clonogenic survival assay of neural stem cells in rat spinal cord after exposure to ionizing radiation. Radiat Res 163:63–71.

    Article  CAS  PubMed  Google Scholar 

  • Machon O, Backman M, Krauss S et al (2005) The cellular fate of cortical progenitors is not maintained in neurosphere cultures. Mol Cell Neurosci 30:388–397.

    Article  CAS  PubMed  Google Scholar 

  • Markakis EA, Gage FH (1999) Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol 406:449–460.

    Article  CAS  PubMed  Google Scholar 

  • Marshall GP II, Scott EW, Zheng T et al (2005) Ionizing radiation enhances the engraftment of transplanted in vitro-derived multipotent astrocytic stem cells. Stem Cells 23:1276–1285.

    Article  PubMed  Google Scholar 

  • Marshall GP II, Laywell ED, Zheng T et al (2006) In vitro-derived “neural stem cells” function as neural progenitors without the capacity for self-renewal. Stem Cells 24:731–738.

    Article  CAS  PubMed  Google Scholar 

  • Maslov AY, Barone TA, Plunkett RJ et al (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733.

    Article  CAS  PubMed  Google Scholar 

  • Matsuzaki Y, Kinjo K, Mulligan RC et al (2004) Unexpected efficient homing capacity of purified hematopoietic stem cells. Immunity 20:87–93.

    Article  CAS  PubMed  Google Scholar 

  • Mayo E (1933) The human problems of an industrialized civilization. Macmillan Press, New York.

    Google Scholar 

  • McCulloch EA, Till JE (1964) Proliferation of hemopoietic colony-forming cells transplanted into irradiated mice. Radiat Res 22:383–397.

    Article  CAS  PubMed  Google Scholar 

  • McCulloch EA, Till JE, Siminovitch L (1965) The role of independent and dependent stem cells in the control of hematopoietic and immunologic responses. Wistar Inst Symp Monogr 4:61–68.

    CAS  PubMed  Google Scholar 

  • Morshead CM, Reynolds BA, Craig CG et al (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082.

    Article  CAS  PubMed  Google Scholar 

  • Morshead CM, Craig CG, van der Kooy D (1998) In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development 125:2251–2261.

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Nabeshima Y, Yoshida S (2007) Functional identification of the actual potential stem cell compartments in mouse spermatogenesis. Dev Cell 12:195–206.

    Article  CAS  PubMed  Google Scholar 

  • Neumeister B, Grabosch A, Basak O et al (2009) Neural progenitors of the postnatal and adult mouse forebrain retain the ability to self-replicate, form neurospheres, and undergo multipotent differentiation in vivo. Stem Cells 27:714–723.

    Article  PubMed  Google Scholar 

  • Nottebohm F (1985) Neuronal replacement in adulthood. Ann N Y Acad Sci 457:143–161.

    Article  CAS  PubMed  Google Scholar 

  • Nottebohm F (2004) The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann N Y Acad Sci 1016:628–658.

    Article  PubMed  Google Scholar 

  • Ohab JJ, Fleming S, Blesch A et al (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016.

    Article  CAS  PubMed  Google Scholar 

  • Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9:115–128.

    Article  CAS  PubMed  Google Scholar 

  • Ostenfeld T, Joly E, Tai YT et al (2002) Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res 134:43–55.

    Article  CAS  PubMed  Google Scholar 

  • Palmer TD, Markakis EA, Willhoite AR et al (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 19:8487–9497.

    CAS  PubMed  Google Scholar 

  • Parent JM, Vexler ZS, Gong C et al (2002a) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813.

    Article  PubMed  Google Scholar 

  • Parent JM, Valentin VV, Lowenstein DH (2002b) Prolonged seizures increases proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. J Neurosci 22:3174–3188.

    CAS  PubMed  Google Scholar 

  • Parmar M, Skogh C, Bjorklund A et al (2002) Regional specification of neurosphere cultures derived from subregions of the embryonic telencephalon. Mol Cell Neurosci 21:645–656.

    Article  CAS  PubMed  Google Scholar 

  • Petreanu L, Alvarez-Buylla A (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J Neurosci 22:6106–6113.

    CAS  PubMed  Google Scholar 

  • Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110:1001–1020.

    CAS  PubMed  Google Scholar 

  • Purton LE, Scadden DT (2007) Limiting factors in murine hematopoietc stem cell assays. Cell Stem Cell 1:263–270.

    Article  CAS  PubMed  Google Scholar 

  • Rakic P (1985) Limits of neurogenesis in primates. Science 227:1054–1056.

    Article  CAS  PubMed  Google Scholar 

  • Ramalho-Santos M, Yoon S, Matsuzaki Y et al (2002) “Stemness” transcriptional profiling of embryonic and adult stem cells. Science 298:597–600.

    Article  CAS  PubMed  Google Scholar 

  • Ramon y Cajal S (1991) Degeneration and regeneration of the nervous system. Oxford University Press, New York

    Google Scholar 

  • Reynolds BA, Rietze RL (2005) Neural stem cells and neurospheres-reevaluating the relationship. Nat Methods 2:333–336.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710.

    Article  CAS  PubMed  Google Scholar 

  • Rochefort C, Gheusi G, Vincent JD et al (2002) Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improve odor memory. J Neurosci 22:2679–2689.

    CAS  PubMed  Google Scholar 

  • Roethlisberger FJ, Dickson WJ (1939) Management and the worker. Harvard University Press, Cambridge.

    Google Scholar 

  • Roy NS, Wang S, Jiang L et al (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271–277.

    Article  CAS  PubMed  Google Scholar 

  • Sanai N, Tramontin AD, Quinones-Hinojosa A et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744.

    Article  CAS  PubMed  Google Scholar 

  • Santa-Olalla J, Baizabal JM, Fregoso M et al (2003) The in vivo positional identity gene expression code is not preserved in neural stem cells grown in culture. Eur J Neurosci 18:1073–1084.

    Article  PubMed  Google Scholar 

  • Seaberg RM, van der Kooy D (2002) Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22:1784–1793.

    CAS  PubMed  Google Scholar 

  • Seri B, Garcia-Verdugo JM, McEwen BS et al (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160.

    CAS  PubMed  Google Scholar 

  • Seri B, Garcia-Verdugo JM, Collado-Morente L et al (2004) Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 478:359–378.

    Article  PubMed  Google Scholar 

  • Shors TJ (2008) From stem cells to grandmother cells: how neurogenesis relates to learning and memory. Cell Stem Cell 3:253–258.

    Article  CAS  PubMed  Google Scholar 

  • Shors TJ, Miesegaes G, Beylin A et al (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:372–376.

    Article  CAS  PubMed  Google Scholar 

  • Shors TJ, Townsend DA, Zhao M et al (2002) Neurogenesis may relate to some but not all types of hippocampul-dependent learning. Hippocampus 12:578–584.

    Article  PubMed  Google Scholar 

  • Siminovitch L, McCulloch EA, Till JE (1963) The distribution of colony-forming cells among spleen colonies. J Cell Physiol 62:327–336.

    Article  CAS  PubMed  Google Scholar 

  • Stanfield BB, Trice JE (1988) Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res 72:399–406.

    CAS  PubMed  Google Scholar 

  • Szele FG, Chesselet MF (1996) Cortical lesions induce an increase in cell number and PSA-NCAM expression in the subventricular zone of adult rats. J Comp Neurol 368:439–454.

    Article  CAS  PubMed  Google Scholar 

  • Tattersfield AS, Croon RJ, Liu YW et al (2004) Neurogenesis in the striatum of the quinolinic acid lesion model of Huntington’s disease. Neuroscience 127:319–332.

    Article  CAS  PubMed  Google Scholar 

  • Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222.

    Article  CAS  PubMed  Google Scholar 

  • van Praag H, Schinder AF, Christie BR et al (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034.

    Article  PubMed  Google Scholar 

  • Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436.

    Article  CAS  PubMed  Google Scholar 

  • Weiss S, Dunne C, Hewson J et al (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 16:7599–7609.

    CAS  PubMed  Google Scholar 

  • Wilson A, Laurenti E, Oser G et al (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118–1129.

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Levison SW (2006) Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone. Neuroscience 139:555–564.

    Article  CAS  PubMed  Google Scholar 

  • Zhang RL, Zhang ZG, Zhang L et al (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33–41.

    Article  CAS  PubMed  Google Scholar 

  • Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Loic P. Deleyrolle or Florian A. Siebzehnrubl .

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Deleyrolle, L.P., Reynolds, B.A., Siebzehnrubl, F.A. (2011). Surrogate Measures of Adult Stem Cell Self-Renewal: The Neural Stem Cell Paradigm. In: Phinney, D. (eds) Adult Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-61779-002-7_7

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