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Improving Memory with Stem Cell Transplantation

  • Chapter
Regulatory Networks in Stem Cells

Abstract

Stem cell transplantation is heralded as an exciting and novel approach to treat a wide variety of human brain disorders for which only palliative therapies currently exist. The clinical application of stem cells for the treatment of neurological disorders such as Alzheimer disease, the most common cause of age-related dementia, remains untested. A growing body of work, however, suggests that stem cell transplantation may provide important therapeutic benefits: ameliorating cognition, memory, and locomotor function, albeit via indirect mechanisms. Although neuronal replacement strategies remain a major focus of stem cell research, recent studies indicate that stem cells may provide therapeutic utility not necessarily by replacing dead or dysfunctional cells but by enhancing the survival, health, and activity of existing endogenous neurons. In this chapter, we review the limited regenerative capacity of the brain and the potential role of adult neural stem cells in memory. We also discuss recent advances showing that neural stem cell transplantation provides therapeutic utility for neurological disease in large part via indirect mechanisms. Although neuronal replacement may provide some benefit, indirect mechanisms such as neurotrophic support, immune modulation, and enzyme replacement likely play a far more prominent role in stem cell–mediated functional recovery. Taken together, these studies suggest that at least in the short-term, harnessing or enhancing these alternate mechanisms may provide a more achievable method to treat human disease.

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References

  1. Ramon y, Cajal S. Degeneration and regeneration of the nervous system. London: Oxford University Press; 1928.

    Google Scholar 

  2. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124(3):3–35.

    Article  Google Scholar 

  3. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4(11):11–7.

    Article  Google Scholar 

  4. Bhardwaj RD, Curtis MA, Spalding KL, et al. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci U S A. 2006;103(33):33–8.

    Article  Google Scholar 

  5. Rousselot P, Lois C, Alvarez-Buylla A. Embryonic (PSA) N-CAM reveals chains of migrating neuroblasts between the lateral ventricle and the olfactory bulb of adult mice. J Comp Neurol. 1995;351(1):1–61.

    Article  Google Scholar 

  6. Magavi SS, Macklis JD. Manipulation of neural precursors in situ: induction of neurogenesis in the neocortex of adult mice. Neuropsychopharmacology. 2001;25(6):6–35.

    Article  Google Scholar 

  7. Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435(4):4–17.

    Article  Google Scholar 

  8. Fuchs E, Gould E. Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci. 2000;12(7):7–4.

    Article  Google Scholar 

  9. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410(6826):6826–6.

    Article  Google Scholar 

  10. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development. 2003;130(2):2–9.

    Article  Google Scholar 

  11. Hastings NB, Gould E. Rapid extension of axons into the CA3 region by adult-generated granule cells. J Comp Neurol. 1999;413(1):1–54.

    Article  Google Scholar 

  12. Markakis EA, Gage FH. Adult-generated neurons in the dentate gyrus send axonal projections to field CA3 and are surrounded by synaptic vesicles. J Comp Neurol. 1999;406(4):4–60.

    Article  Google Scholar 

  13. Stanfield BB, Trice JE. Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Exp Brain Res. 1988;72(2):2–406.

    Article  Google Scholar 

  14. Ge S, Yang CH, Hsu KS, Ming GL, Song H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron. 2007;54(4):4–66.

    Article  Google Scholar 

  15. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999;96(23):23–31.

    Google Scholar 

  16. Lagace DC, Whitman MC, Noonan MA, et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J Neurosci. 2007;27(46):46–9.

    Article  Google Scholar 

  17. Neves G, Cooke SF, Bliss TV. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev. 2008;9(1):1–75.

    Google Scholar 

  18. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 1999;2(3):3–5.

    Article  Google Scholar 

  19. Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci. 2006;9(6):6–7.

    Article  Google Scholar 

  20. Kee N, Teixeira CM, Wang AH, Frankland PW. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci. 2007;10(3): 3–62.

    Article  Google Scholar 

  21. Ramirez-Amaya V, Marrone DF, Gage FH, Worley PF, Barnes CA. Integration of new neurons into functional neural networks. J Neurosci. 2006;26(47):47–41.

    Article  Google Scholar 

  22. Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci. 2007;27(12):12–9.

    Article  Google Scholar 

  23. Floyd CL, Lyeth BG. Astroglia: important mediators of traumatic brain injury. Prog Brain Res. 2007;161:61–79.

    Article  PubMed  CAS  Google Scholar 

  24. Yamasaki TR, Blurton-Jones M, Morrissette DA, Kitazawa M, Oddo S, LaFerla FM. Neural stem cells improve memory in an inducible mouse model of neuronal loss. J Neurosci. 2007;27(44):44–33.

    Article  Google Scholar 

  25. Kandel ER, Schwartz JH, Jessell TM. Principles of neural science. 4th ed. New York: McGraw-Hill Health Professions Division; 2000.

    Google Scholar 

  26. Qu T, Brannen CL, Kim HM, Sugaya K. Human neural stem cells improve cognitive function of aged brain. Neuroreport. 2001;12(6):6–32.

    Article  Google Scholar 

  27. Fernandez CI, Alberti E, Mendoza Y, et al. Motor and cognitive recovery induced by bone marrow stem cells grafted to striatum and hippocampus of impaired aged rats: functional and therapeutic considerations. Ann N Y Acad Sci. 2004;1019:48–52.

    Article  PubMed  Google Scholar 

  28. Rasmussen T, Schliemann T, Sorensen JC, Zimmer J, West MJ. Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging. 1996;17(1):1–7.

    Article  Google Scholar 

  29. Hoane MR, Becerra GD, Shank JE, et al. Transplantation of neuronal and glial precursors dramatically improves sensorimotor function but not cognitive function in the traumatically injured brain. J Neurotrauma. 2004;21(2):2–74.

    Article  Google Scholar 

  30. Gao J, Prough DS, McAdoo DJ, et al. Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury. Exp Neurol. 2006;201(2):2–92.

    Article  Google Scholar 

  31. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R. Mattson MP, Akbari Y, and LaFerla FM. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003;39:409–421.

    Article  PubMed  CAS  Google Scholar 

  32. Parish CL, Castelo-Branco G, Rawal N, et al. Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice. J Clin Invest. 2008;118(1):1–60.

    Article  Google Scholar 

  33. Lee JP, Jeyakumar M, Gonzalez R, et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med. 2007;13(4):4–47.

    Article  Google Scholar 

  34. Domeniconi M, Filbin MT. Overcoming inhibitors in myelin to promote axonal regeneration. J Neurol Sci. 2005;233(1–2):43–7.

    Article  PubMed  CAS  Google Scholar 

  35. Buchli AD, Schwab ME. Inhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system. Ann Med. 2005;37(8): 8–67.

    Article  Google Scholar 

  36. Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition. J Neurosci. 2003;23(28):28–88.

    Google Scholar 

  37. Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci. 2004;24(28):28–9.

    Article  Google Scholar 

  38. Taylor L, Jones L, Tuszynski MH, Blesch A. Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord. J Neurosci. 2006;26(38):38–21.

    Article  Google Scholar 

  39. Tuszynski MH, Gage FH. Maintaining the neuronal phenotype after injury in the adult CNS. Neurotrophic factors, axonal growth substrates, and gene therapy. Mol Neurobiol. 1995;10(2–3): 151–67.

    Article  PubMed  CAS  Google Scholar 

  40. Gauthier LR, Charrin BC, Borrell-Pages M, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004;118(1):1–38.

    Article  Google Scholar 

  41. Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol. 1999;57(4):4–84.

    Article  Google Scholar 

  42. Salehi A, Delcroix JD, Belichenko PV, et al. Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006;51(1):1–42.

    Article  Google Scholar 

  43. Bentz K, Molcanyi M, Riess P, et al. Embryonic stem cells produce neurotrophins in response to cerebral tissue extract: cell line-dependent differences. J Neurosc Res. 2007;85(5): 5–64.

    Google Scholar 

  44. Kamei N, Tanaka N, Oishi Y, et al. BDNF, NT-3, and NGF released from transplanted neural progenitor cells promote corticospinal axon growth in organotypic cocultures. Spine. 2007;32(12): 12–8.

    Article  Google Scholar 

  45. Pan HC, Cheng FC, Chen CJ, et al. Post-injury regeneration in rat sciatic nerve facilitated by neurotrophic factors secreted by amniotic fluid mesenchymal stem cells. J Clin Neurosci. 2007;14(11):11–98.

    Article  Google Scholar 

  46. Pisati F, Bossolasco P, Meregalli M, et al. Induction of neurotrophin expression via human adult mesenchymal stem cells: implication for cell therapy in neurodegenerative diseases. Cell Transplant. 2007;16(1):1–55.

    Google Scholar 

  47. Wei P, Liu J, Zhou HL, et al. Effects of engrafted neural stem cells derived from GFP transgenic mice in Parkinson’s diseases rats. Neurosci Lett. 2007;419(1):1–54.

    Article  Google Scholar 

  48. Redmond DE, Jr., Bjugstad KB, Teng YD, et al. Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A. 2007;104(29):29–80.

    Article  Google Scholar 

  49. Li J, Imitola J, Snyder EY, Sidman RL. Neural stem cells rescue nervous purkinje neurons by restoring molecular homeostasis of tissue plasminogen activator and downstream targets. J Neurosci. 2006;26(30):30–48.

    Article  Google Scholar 

  50. Ebert AD, Beres AJ, Barber AE, Svendsen CN. Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson’s disease. Exp Neurol. 2008;209(1):1–23.

    Article  Google Scholar 

  51. Suzuki M, McHugh J, Tork C, et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE. 2007;2(1):e689.

    Article  PubMed  Google Scholar 

  52. Wang XJ, Liu WG, Zhang YH, Lu GQ, Chen SD. Effect of transplantation of c17.2 cells transfected with interleukin-10 gene on intracerebral immune response in rat model of Parkinson’s disease. Neurosci Lett. 2007;423(2):2–9.

    Article  Google Scholar 

  53. Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol. 2007;61(3): 3–27.

    Article  Google Scholar 

  54. Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev. 2007;8(3):3–32.

    Google Scholar 

  55. Mueller FJ, McKercher SR, Imitola J, et al. At the interface of the immune system and the nervous system: how neuroinflammation modulates the fate of neural progenitors in vivo. Ernst Schering Res Found Workshop. 2005;(53):83–114.

    Google Scholar 

  56. Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101(52):52–22.

    Article  Google Scholar 

  57. Jeyakumar M, Butters TD, Dwek RA, Platt FM. Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis. Neuropathol Appl Neurobiol. 2002;28(5):5–57.

    Article  Google Scholar 

  58. Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci U S A. 1990;87(5):5–6.

    Article  Google Scholar 

  59. Sidman RL, Li J, Stewart GR, et al. Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice. Brain Res. 2007;1140:195–204.

    Article  PubMed  CAS  Google Scholar 

  60. Selkoe DJ. Clearing the brain’s amyloid cobwebs. Neuron. 2001;32(2):2–80.

    Article  Google Scholar 

  61. Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, Selkoe DJ. Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease. PLoS Med. 2007;4(8):e262.

    Article  PubMed  Google Scholar 

  62. Marr RA, Rockenstein E, Mukherjee A, et al. Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci. 2003;23(6):6–6.

    Google Scholar 

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Correspondence to Frank M. LaFerla .

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC

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Blurton-Jones, M., Yamasaki, T.R., LaFerla, F.M. (2009). Improving Memory with Stem Cell Transplantation. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_43

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