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Towards Clinical Application of Stem Cells in Neurodegenerative Disorders

  • Olle Lindvall
  • Zaal Kokaia
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Stem cells have the capacity to generate neurons and glia cells which are lost in neurodegenerative diseases such as Parkinson’s disease and stroke. The adult brain’s own neural stem cells are potential novel therapeutic targets because they produce neurons and glia in response to injury and could become affected by the degenerative process. Besides cell replacement, stem cell-based approaches can also improve function by modulating inflammation, preventing neurons from dying, and increasing angiogenesis. These exciting laboratory findings should now be responsibly translated to the clinic. However, the development of stem cell-based therapies for human neurodegenerative diseases will require major research efforts so that the mechanisms regulating the proliferation, migration, differentiation, survival and function of stem cells are much better understood and can be effectively controlled. Strategies to prevent tumor formation must be developed. Finally, the functional efficacy of stem cells or their derivatives, their mechanisms of action, and absence of significant adverse effects should be demonstrated in animal models with pathology and symptomatology resembling the human disease.

Keywords

Parkinson’s disease Alzheimer’s disease Stroke Neurogenesis Transplantation 

Notes

Acknowledgments

Our own work was supported by the Swedish Research Council, Juvenile Diabetes Research Foundation, and EU projects LSHB-2006-037526 (StemStroke), and 222943 (Neurostemcell).

References

  1. 1.
    Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell 2008; 3:591–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Lindvall O, Hyun I. Medical innovation versus stem cell tourism. Science 2009; 324:1664–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008; 14:504–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, et al. Lewy bodies in grafted ­neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008; 14:501–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Lindvall O, Björklund A. Cell therapy in Parkinson’s disease. NeuroRx. 2004; 1:382–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Piccini P, Brooks DJ, Björklund A, Gunn RN, Grasby PM, Rimoldi O, et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci. 1999; 2:1137–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson’s disease. Trends Pharmacol Sci. 2009; 30:260–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al. Disease-specific induced pluripotent stem cells. Cell 2008; 134:877–86.PubMedCrossRefGoogle Scholar
  9. 9.
    Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009; 136:964–77.PubMedCrossRefGoogle Scholar
  10. 10.
    Tabar V, Tomishima M, Panagiotakos G, Wakayama S, Menon J, Chan B, et al. Therapeutic cloning in individual Parkinsonian mice. Nat Med. 2008; 14:379–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006; 12:1259–68.PubMedCrossRefGoogle Scholar
  12. 12.
    Carlsson T, Carta M, Munoz A, Mattsson B, Winkler C, Kirik D, et al. Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in Parkinsonian rats is determined by the extent of dopamine neuron degeneration. Brain 2008; 132:319–35.PubMedCrossRefGoogle Scholar
  13. 13.
    Manabe T, Tatsumi K, Inoue M, Makinodan M, Yamauchi T, Makinodan E, et al. L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells. Cell Death Differ. 2007; 14:1080–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132:645–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Biscaro B, Lindvall O, Hock C, Ekdahl C, Nitsch R. Aβ immunotherapy protects morphology and survival of adult-born neurons in doubly transgenic APP/PS1 mice. J Neurosci. 2009; 29:14108–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis. 2006; 24:1–14.PubMedCrossRefGoogle Scholar
  17. 17.
    Gan L, Qiao S, Lan X, Chi L, Luo C, Lien L, et al. Neurogenic responses to amyloid-beta plaques in the brain of Alzheimer’s disease-like transgenic (pPDGFAPPSw, Ind) mice. Neurobiol Dis. 2008; 29:71–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 2004; 101:343–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Kempermann G. Adult Neurogenesis: Stem Cells and Neuronal Development in the Adult Brain. New York: Oxford University Press; 2005.Google Scholar
  20. 20.
    Li B, Yamamori H, Tatebayashi Y, Shafit-Zagardo B, Tanimukai H, Chen S, et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol. 2008; 67:78–84.PubMedCrossRefGoogle Scholar
  21. 21.
    Becker M, Lavie V, Solomon B. Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2007; 104:1691–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005; 11:551–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009; 15:331–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Daadi MM, Maag AL, Steinberg GK. Adherent self-renewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model. PLoS One 2008; 3:e1644.PubMedCrossRefGoogle Scholar
  25. 25.
    Daadi MM, Li Z, Arac A, Grueter BA, Sofilos M, Malenka RC, et al. Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther. 2009; 17:1282–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Darsalia V, Kallur T, Kokaia Z. Survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum. Eur J Neurosci. 2007; 26:605–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Lindvall O, Kokaia Z. Neurogenesis following stroke affecting the adult brain. In: Gage F, Kempermann G, Song H, editors. Adult Neurogenesis. New York: Cold Spring Harbor Laboratory Press; 2008. pp. 549–70.Google Scholar
  28. 28.
    Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009; 8:491–500.PubMedCrossRefGoogle Scholar
  29. 29.
    Darsalia V, Heldmann U, Lindvall O, Kokaia Z. Stroke-induced neurogenesis in aged brain. Stroke 2005; 36:1790–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Jin K, Wang X, Xie L, Mao XO, Zhu W, Wang Y, et al. Evidence for stroke-induced neurogenesis in the human brain. Proc Natl Acad Sci USA 2006; 103:13198–202.PubMedCrossRefGoogle Scholar
  31. 31.
    Macas J, Nern C, Plate KH, Momma S. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci. 2006; 26:13114–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Minger SL, Ekonomou A, Carta EM, Chinoy A, Perry RH, Ballard CG. Endogenous neurogenesis in the human brain following cerebral infarction. Regen Med. 2007; 2:69–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002; 8:963–70.PubMedCrossRefGoogle Scholar
  34. 34.
    Onda T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab. 2008; 28:329–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, et al. Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 2006; 129(Pt 10):2734–45.PubMedCrossRefGoogle Scholar
  36. 36.
    Bacigaluppi M, Pluchino S, Jametti LP, Kilic E, Kilic U, Salani G, et al. Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms. Brain 2009; 132(Pt 8):2239–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J, et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 2005; 103:38–45.PubMedCrossRefGoogle Scholar
  38. 38.
    Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005; 57:874–82.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Olle Lindvall
    • 1
  • Zaal Kokaia
  1. 1.Laboratory of Neurogenesis and Cell Therapy, Wallenberg Neuroscience Center, Lund Stem Cell CenterUniversity HospitalLundSweden

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