Translational Stroke Research

, Volume 4, Issue 2, pp 137–148 | Cite as

The Potential for Cell-Based Therapy in Perinatal Brain Injuries

  • Andre W. Phillips
  • Michael V. Johnston
  • Ali Fatemi
Original Article


Perinatal brain injuries are a leading cause of cerebral palsy worldwide. The potential of stem cell therapy to prevent or reduce these impairments has been widely discussed within the medical and scientific communities and an increasing amount of research is being conducted in this field. Animal studies support the idea that a number of stem cells types, including cord blood and mesenchymal stem cells have a neuroprotective effect in neonatal hypoxia–ischemia. Both these cell types are readily available in a clinical setting. The mechanisms of action appear to be diverse, including immunomodulation, activation of endogenous stem cells, release of growth factors, and anti-apoptotic effects. Here, we review the different types of stem cells and progenitor cells that are potential candidates for therapeutic strategies in perinatal brain injuries and summarize recent preclinical and clinical studies.


Stem cell Cerebral palsy Neonate Brain injury Hypoxia–ischemia 



The authors received funding from the National Institutes of Health (R01NS028208 to M.V.J., K08NS063956 to A.F., and P30HD024061 to A.W.P.).


  1. 1.
    Berger R, Garnier Y, Jensen A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002;9(6):319–28.PubMedCrossRefGoogle Scholar
  2. 2.
    Johnston MV, Hoon Jr AH. Cerebral palsy. Neuromol Med. 2006;8(4):435–50.CrossRefGoogle Scholar
  3. 3.
    Volpe JJ. Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res. 2001;50(5):553–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.PubMedGoogle Scholar
  5. 5.
    Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998;19(1):143–9.PubMedGoogle Scholar
  6. 6.
    Bartha AI, Foster-Barber A, Miller SP, Vigneron DB, Glidden DV, Barkovich AJ, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res. 2004;56(6):960–6. doi: 10.1203/01.PDR.0000144819.45689.BB.PubMedCrossRefGoogle Scholar
  7. 7.
    Falini A, Barkovich AJ, Calabrese G, Origgi D, Triulzi F, Scotti G. Progressive brain failure after diffuse hypoxic ischemic brain injury: a serial MR and proton MR spectroscopic study. AJNR Am J Neuroradiol. 1998;19(4):648–52.PubMedGoogle Scholar
  8. 8.
    Ramaswamy V, Miller SP, Barkovich AJ, Partridge JC, Ferriero DM. Perinatal stroke in term infants with neonatal encephalopathy. Neurology. 2004;62(11):2088–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Barkovich AJ, Sargent SK. Profound asphyxia in the premature infant: Imaging findings. AJNR Am J Neuroradiol. 1995;16(9):1837–46.PubMedGoogle Scholar
  10. 10.
    Johnston MV. Excitotoxicity in perinatal brain injury. Brain Pathol (Zurich, Switzerland). 2005;15(3):234–40.CrossRefGoogle Scholar
  11. 11.
    Northington FJ, Ferriero DM, Flock DL, Martin LJ. Delayed neurodegeneration in neonatal rat thalamus after hypoxia–ischemia is apoptosis. J Neurosci Off J Soc Neurosci. 2001;21(6):1931–8.Google Scholar
  12. 12.
    Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ. Early neurodegeneration after hypoxia–ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis. 2001;8(2):207–19. doi: 10.1006/nbdi.2000.0371.PubMedCrossRefGoogle Scholar
  13. 13.
    Northington FJ, Ferriero DM, Martin LJ. Neurodegeneration in the thalamus following neonatal hypoxia–ischemia is programmed cell death. Dev Neurosci. 2001;23(3):186–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Hoon Jr AH, Freese PO, Reinhardt EM, Wilson MA, Lawrie Jr WT, Harryman SE, et al. Age-dependent effects of trihexyphenidyl in extrapyramidal cerebral palsy. Pediatr Neurol. 2001;25(1):55–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Blumenthal I. Periventricular leucomalacia: a review. Eur J Pediatr. 2004;163(8):435–42. doi: 10.1007/s00431-004-1477-y.PubMedCrossRefGoogle Scholar
  16. 16.
    Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008;93(2):F153–61. doi: 10.1136/adc.2006.108837.PubMedCrossRefGoogle Scholar
  17. 17.
    Leviton A, Gilles F. Ventriculomegaly, delayed myelination, white matter hypoplasia, and “periventricular” leukomalacia: how are they related? Pediatr Neurol. 1996;15(2):127–36.PubMedCrossRefGoogle Scholar
  18. 18.
    Webber DJ, van Blitterswijk M, Chandran S. Neuroprotective effect of oligodendrocyte precursor cell transplantation in a long-term model of periventricular leukomalacia. Am J Pathol. 2009;175(6):2332–42. doi: 10.2353/ajpath.2009.090051.PubMedCrossRefGoogle Scholar
  19. 19.
    Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997;278(3):207–11.PubMedCrossRefGoogle Scholar
  20. 20.
    Leviton A, Gressens P. Neuronal damage accompanies perinatal white-matter damage. Trends Neurosci. 2007;30(9):473–8. doi: 10.1016/j.tins.2007.05.009.PubMedCrossRefGoogle Scholar
  21. 21.
    Bloch JR. Antenatal events causing neonatal brain injury in premature infants. J Obstet Gynecol Neonatal Nurs. 2005;34(3):358–66. doi: 10.1177/0884217505276255.PubMedCrossRefGoogle Scholar
  22. 22.
    Mitalipov S, Wolf D. Totipotency, pluripotency and nuclear reprogramming. Adv Biochem Eng Biotechnol. 2009;114:185–99. doi: 10.1007/10_2008_45.PubMedGoogle Scholar
  23. 23.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Leeb C, Jurga M, McGuckin C, Forraz N, Thallinger C, Moriggl R, et al. New perspectives in stem cell research: beyond embryonic stem cells. Cell Prolif. 2011;44 Suppl 1:9–14. doi: 10.1111/j.1365-2184.2010.00725.x.PubMedCrossRefGoogle Scholar
  25. 25.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science (New York, NY). 1998;282(5391):1145–7.CrossRefGoogle Scholar
  27. 27.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi: 10.1016/j.cell.2006.07.024.PubMedCrossRefGoogle Scholar
  28. 28.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. doi: 10.1016/j.cell.2007.11.019.PubMedCrossRefGoogle Scholar
  29. 29.
    Pluchino S, Zanotti L, Brini E, Ferrari S, Martino G. Regeneration and repair in multiple sclerosis: The role of cell transplantation. Neurosci Lett. 2009;456(3):101–6. doi: 10.1016/j.neulet.2008.03.097.PubMedCrossRefGoogle Scholar
  30. 30.
    Luskin MB, Pearlman AL, Sanes JR. Cell lineage in the cerebral cortex of the mouse studied in vivo and in vitro with a recombinant retrovirus. Neuron. 1988;1(8):635–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Turner DL, Cepko CL. A common progenitor for neurons and glia persists in rat retina late in development. Nature. 1987;328(6126):131–6. doi: 10.1038/328131a0.PubMedCrossRefGoogle Scholar
  32. 32.
    Goodwin HS, Bicknese AR, Chien SN, Bogucki BD, Quinn CO, Wall DA. Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat, and neural markers. Biol Blood Marrow Transplant. 2001;7(11):581–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Wurmser AE, Nakashima K, Summers RG, Toni N, D’Amour KA, Lie DC, et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature. 2004;430(6997):350–6. doi: 10.1038/nature02604.PubMedCrossRefGoogle Scholar
  34. 34.
    Condorelli G, Borello U, De Angelis L, Latronico M, Sirabella D, Coletta M, et al. Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: Implications for myocardium regeneration. Proc Natl Acad Sci U S A. 2001;98(19):10733–8. doi: 10.1073/pnas.191217898.PubMedCrossRefGoogle Scholar
  35. 35.
    Galli R, Borello U, Gritti A, Minasi MG, Bjornson C, Coletta M, et al. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci. 2000;3(10):986–91. doi: 10.1038/79924.PubMedCrossRefGoogle Scholar
  36. 36.
    Prockop DJ, Gregory CA, Spees JL. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A. 2003;100 Suppl 1:11917–23. doi: 10.1073/pnas.1834138100.PubMedCrossRefGoogle Scholar
  37. 37.
    Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, et al. Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci U S A. 2003;100(5):2397–402. doi: 10.1073/pnas.0437997100.PubMedCrossRefGoogle Scholar
  38. 38.
    Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002;416(6880):545–8. doi: 10.1038/nature729.PubMedCrossRefGoogle Scholar
  39. 39.
    Park KI, Teng YD, Snyder EY. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol. 2002;20(11):1111–7. doi: 10.1038/nbt751.PubMedCrossRefGoogle Scholar
  40. 40.
    Schwartz PH, Bryant PJ, Fuja TJ, Su H, O’Dowd DK, Klassen H. Isolation and characterization of neural progenitor cells from post-mortem human cortex. J Neurosci Res. 2003;74(6):838–51. doi: 10.1002/jnr.10854.PubMedCrossRefGoogle Scholar
  41. 41.
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54(3):403–14. doi: 10.1002/ana.10720.PubMedCrossRefGoogle Scholar
  42. 42.
    Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, McCarty JM, Rowley SD, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood. 2005;106(5):1867–74. doi: 10.1182/blood-2005-02-0468.PubMedCrossRefGoogle Scholar
  43. 43.
    McCulloch EA, Till JE. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res. 1960;13:115–25.PubMedCrossRefGoogle Scholar
  44. 44.
    da Silva ML, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(Pt 11):2204–13. doi: 10.1242/jcs.02932.Google Scholar
  45. 45.
    Paul G, Ozen I, Christophersen NS, Reinbothe T, Bengzon J, Visse E, et al. The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One. 2012;7(4):e35577. doi: 10.1371/journal.pone.0035577.PubMedCrossRefGoogle Scholar
  46. 46.
    Phillips AW, Falahati S, Desilva R, Shats I, Marx J, Arauz E, et al. Derivation of glial restricted precursors from E13 mice. J Vis Exp. 2012;64. doi: 10.3791/3462.
  47. 47.
    Rao MS, Mayer-Proschel M. Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. Dev Biol. 1997;188(1):48–63. doi: 10.1006/dbio.1997.8597.PubMedCrossRefGoogle Scholar
  48. 48.
    Walczak P, All AH, Rumpal N, Gorelik M, Kim H, Maybhate A, et al. Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination. Glia. 2011;59(3):499–510. doi: 10.1002/glia.21119.PubMedCrossRefGoogle Scholar
  49. 49.
    Goldman SA, Nedergaard M, Windrem MS. Glial progenitor cell-based treatment and modeling of neurological disease. Science (New York, NY). 2012;338(6106):491–5.CrossRefGoogle Scholar
  50. 50.
    Barnett SC, Hutchins AM, Noble M. Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev Biol. 1993;155(2):337–50. doi: 10.1006/dbio.1993.1033.PubMedCrossRefGoogle Scholar
  51. 51.
    Shyu WC, Liu DD, Lin SZ, Li WW, Su CY, Chang YC, et al. Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. J Clin Invest. 2008;118(7):2482–95. doi: 10.1172/JCI34363.PubMedCrossRefGoogle Scholar
  52. 52.
    Barnett SC, Chang L. Olfactory ensheathing cells and CNS repair: going solo or in need of a friend? Trends Neurosci. 2004;27(1):54–60. doi: 10.1016/j.tins.2003.10.011.PubMedCrossRefGoogle Scholar
  53. 53.
    Woodhall E, West AK, Chuah MI. Cultured olfactory ensheathing cells express nerve growth factor, brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor and their receptors. Brain Res Mol Brain Res. 2001;88(1–2):203–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Comi AM, Cho E, Mulholland JD, Hooper A, Li Q, Qu Y, et al. Neural stem cells reduce brain injury after unilateral carotid ligation. Pediatr Neurol. 2008;38(2):86–92. doi: 10.1016/j.pediatrneurol.2007.10.007.PubMedCrossRefGoogle Scholar
  55. 55.
    Tarasenko YI, Gao J, Nie L, Johnson KM, Grady JJ, Hulsebosch CE, et al. Human fetal neural stem cells grafted into contusion-injured rat spinal cords improve behavior. J Neurosci Res. 2007;85(1):47–57. doi: 10.1002/jnr.21098.PubMedCrossRefGoogle Scholar
  56. 56.
    Elsayed MH, Hogan TP, Shaw PL, Castro AJ. Use of fetal cortical grafts in hypoxic–ischemic brain injury in neonatal rats. Exp Neurol. 1996;137(1):127–41. doi: 10.1006/exnr.1996.0013.PubMedCrossRefGoogle Scholar
  57. 57.
    Bjorklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH. Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation. Acta Physiol Scand Suppl. 1983;522:1–7.PubMedGoogle Scholar
  58. 58.
    Bjorklund A, Gage FH, Schmidt RH, Stenevi U, Dunnett SB. Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippocampus reinnervated by septal suspension implants. Acta Physiol Scand Suppl. 1983;522:59–66.PubMedGoogle Scholar
  59. 59.
    Bjorklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH. Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. Acta Physiol Scand Suppl. 1983;522:9–18.PubMedGoogle Scholar
  60. 60.
    Gage FH, Bjorklund A, Stenevi U, Dunnett SB. Intracerebral grafting of neuronal cell suspensions. VIII. Survival and growth of implants of nigral and septal cell suspensions in intact brains of aged rats. Acta Physiol Scand Suppl. 1983;522:67–75.PubMedGoogle Scholar
  61. 61.
    Grabowski M, Brundin P, Johansson BB. Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: ingrowth of afferent fibers from the host brain. Exp Neurol. 1992;116(2):105–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Jansen EM, Solberg L, Underhill S, Wilson S, Cozzari C, Hartman BK, et al. Transplantation of fetal neocortex ameliorates sensorimotor and locomotor deficits following neonatal ischemic–hypoxic brain injury in rats. Exp Neurol. 1997;147(2):487–97. doi: 10.1006/exnr.1997.6596.PubMedCrossRefGoogle Scholar
  63. 63.
    Roach A, Takahashi N, Pravtcheva D, Ruddle F, Hood L. Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell. 1985;42(1):149–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Bird TD, Farrell DF, Sumi SM. Brain lipid composition of the shiverer mouse: (genetic defect in myelin development). J Neurochem. 1978;31(1):387–91.PubMedCrossRefGoogle Scholar
  65. 65.
    Lachapelle F, Gumpel M, Baulac M, Jacque C, Duc P, Baumann N. Transplantation of CNS fragments into the brain of shiverer mutant mice: extensive myelination by implanted oligodendrocytes. I Immunohistochemical Stud Dev Neurosci. 1983;6(6):325–34.CrossRefGoogle Scholar
  66. 66.
    Zhang SC, Ge B, Duncan ID. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc Natl Acad Sci U S A. 1999;96(7):4089–94.PubMedCrossRefGoogle Scholar
  67. 67.
    Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann 2nd G, et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nature Med. 2004;10(1):93–7. doi: 10.1038/nm974.PubMedCrossRefGoogle Scholar
  68. 68.
    Windrem MS, Schanz SJ, Guo M, Tian GF, Washco V, Stanwood N, et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell. 2008;2(6):553–65. doi: 10.1016/j.stem.2008.03.020.PubMedCrossRefGoogle Scholar
  69. 69.
    Zheng T, Rossignol C, Leibovici A, Anderson KJ, Steindler DA, Weiss MD. Transplantation of multipotent astrocytic stem cells into a rat model of neonatal hypoxic–ischemic encephalopathy. Brain Res. 2006;1112(1):99–105. doi: 10.1016/j.brainres.2006.07.014.PubMedCrossRefGoogle Scholar
  70. 70.
    Park KI, Hack MA, Ourednik J, Yandava B, Flax JD, Stieg PE, et al. Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: evidence from the effect of hypoxia–ischemia in the CNS on clonal “reporter” neural stem cells. Exp Neurol. 2006;199(1):156–78. doi: 10.1016/j.expneurol.2006.04.002.PubMedCrossRefGoogle Scholar
  71. 71.
    Park KI, Himes BT, Stieg PE, Tessler A, Fischer I, Snyder EY. Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: evidence from engraftment of neurotrophin-3-expressing stem cells in hypoxic–ischemic brain injury. Exp Neurol. 2006;199(1):179–90. doi: 10.1016/j.expneurol.2006.03.016.PubMedCrossRefGoogle Scholar
  72. 72.
    Pimentel-Coelho PM, Magalhaes ES, Lopes LM, de Azevedo LC, Santiago MF, Mendez-Otero R. Human cord blood transplantation in a neonatal rat model of hypoxic–ischemic brain damage: functional outcome related to neuroprotection in the striatum. Stem Cells Dev. 2010;19(3):351–8. doi: 10.1089/scd.2009.0049.PubMedCrossRefGoogle Scholar
  73. 73.
    Yasuhara T, Hara K, Maki M, Xu L, Yu G, Ali MM, et al. Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts. J Cell Mol Med. 2010;14(4):914–21. doi: 10.1111/j.1582-4934.2008.00671.x.PubMedCrossRefGoogle Scholar
  74. 74.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. doi: 10.1080/14653240600855905.PubMedCrossRefGoogle Scholar
  75. 75.
    Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, et al. Neural stem cell engraftment and myelination in the human brain. Sci Transl Med. 2012;4(155):155ra37.CrossRefGoogle Scholar
  76. 76.
    Meier C, Middelanis J, Wasielewski B, Neuhoff S, Roth-Haerer A, Gantert M, et al. Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res. 2006;59(2):244–9. doi: 10.1203/01.pdr.0000197309.08852.f5.PubMedCrossRefGoogle Scholar
  77. 77.
    Prasad VK, Kurtzberg J. Umbilical cord blood transplantation for non-malignant diseases. Bone Marrow Transplant. 2009;44(10):643–51. doi: 10.1038/bmt.2009.290.PubMedCrossRefGoogle Scholar
  78. 78.
    Yang WZ, Zhang Y, Wu F, Min WP, Minev B, Zhang M, et al. Safety evaluation of allogeneic umbilical cord blood mononuclear cell therapy for degenerative conditions. J Transl Med. 2010;8:75. doi: 10.1186/1479-5876-8-75.PubMedCrossRefGoogle Scholar
  79. 79.
    Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood. 2003;101(8):2999–3001. doi: 10.1182/blood-2002-06-1830.PubMedCrossRefGoogle Scholar
  80. 80.
    Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A. 1999;96(19):10711–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24(1):74–85. doi: 10.1634/stemcells.2004-0359.PubMedCrossRefGoogle Scholar
  82. 82.
    van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic–ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010;24(3):387–93. doi: 10.1016/j.bbi.2009.10.017.PubMedCrossRefGoogle Scholar
  83. 83.
    Fan CG, Zhang QJ, Tang FW, Han ZB, Wang GS, Han ZC. Human umbilical cord blood cells express neurotrophic factors. Neurosci Lett. 2005;380(3):322–5. doi: 10.1016/j.neulet.2005.01.070.PubMedCrossRefGoogle Scholar
  84. 84.
    Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63. doi: 10.1016/j.stem.2009.05.003.PubMedCrossRefGoogle Scholar
  85. 85.
    Phinney DG, Hill K, Michelson C, DuTreil M, Hughes C, Humphries S, et al. Biological activities encoded by the murine mesenchymal stem cell transcriptome provide a basis for their developmental potential and broad therapeutic efficacy. Stem Cells. 2006;24(1):186–98. doi: 10.1634/stemcells.2004-0236.PubMedCrossRefGoogle Scholar
  86. 86.
    Rosenkranz K, Meier C. Umbilical cord blood cell transplantation after brain ischemia—from recovery of function to cellular mechanisms. Ann Anat. 2011;193(4):371–9. doi: 10.1016/j.aanat.2011.03.005.PubMedCrossRefGoogle Scholar
  87. 87.
    Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, 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):18117–22. doi: 10.1073/pnas.0408258102.PubMedCrossRefGoogle Scholar
  88. 88.
    Lee IS, Jung K, Kim M, Park KI. Neural stem cells: properties and therapeutic potentials for hypoxic–ischemic brain injury in newborn infants. Pediatr Int. 2010;52(6):855–65. doi: 10.1111/j.1442-200X.2010.03266.x.PubMedCrossRefGoogle Scholar
  89. 89.
    Chen L, Huang H, Xi H, Xie Z, Liu R, Jiang Z, et al. Intracranial transplant of olfactory ensheathing cells in children and adolescents with cerebral palsy: a randomized controlled clinical trial. Cell Transplant. 2010;19(2):185–91. doi: 10.3727/096368910X492652.PubMedCrossRefGoogle Scholar
  90. 90.
    Shi X, Kang Y, Hu Q, Chen C, Yang L, Wang K, et al. A long-term observation of olfactory ensheathing cells transplantation to repair white matter and functional recovery in a focal ischemia model in rat. Brain Res. 2010;1317:257–67. doi: 10.1016/j.brainres.2009.12.061.PubMedCrossRefGoogle Scholar
  91. 91.
    Liu Y, Jiang X, Zhang X, Chen R, Sun T, Fok KL, et al. Dedifferentiation-reprogrammed mesenchymal stem cells with improved therapeutic potential. Stem Cells. 2011;29(12):2077–89. doi: 10.1002/stem.764.PubMedCrossRefGoogle Scholar
  92. 92.
    van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res. 2010;68(5):419–22. doi: 10.1203/PDR.0b013e3181f1c289.PubMedGoogle Scholar
  93. 93.
    Lee JA, Kim BI, Jo CH, Choi CW, Kim EK, Kim HS, et al. Mesenchymal stem-cell transplantation for hypoxic–ischemic brain injury in neonatal rat model. Pediatr Res. 2010;67(1):42–6. doi: 10.1203/PDR.0b013e3181bf594b.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Andre W. Phillips
    • 1
    • 2
  • Michael V. Johnston
    • 1
    • 2
    • 3
  • Ali Fatemi
    • 1
    • 2
    • 3
  1. 1.The Hugo W. Moser Research Institute at Kennedy Krieger InstituteJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of NeurologyJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of PediatricsJohns Hopkins UniversityBaltimoreUSA

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