Skip to main content

Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury

  • Chapter
  • First Online:
Cell Therapy for Brain Injury

Abstract

Various varieties of stem cells and methods of their administration are proposed as therapeutic modalities for neonatal hypoxic–ischemic (HI) brain injury. The widespread use of stem cells for this purpose and others, despite the lack of strong clinical evidence for their efficacy in most clinical situations, makes it incumbent to review the pathophysiology of the clinical condition of neonatal HI brain injury, the preclinical data dealing with animal HI injury, and the available clinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Volpe, J. Neurology of the newborn. 5th Ed. Philadelphia: Saunders/Elsevier Health Sciences; 2008. pp. 245–480.

    Google Scholar 

  2. Rosenkranz K, Kumbruch S, Lebermann K, et al. The chemokine SDF-1/CXCL12 contributes to the ‘homing’ of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain. J Neurosci Res. 2010;88:1223–33.

    CAS  PubMed  Google Scholar 

  3. Jiang L, Newman M, Saporta S, et al. MIP-1alpha and MCP-1 induce migration of human umbilical cord blood cells in models of stroke. Curr Neurovasc Res. 2008;5:118–24.

    Article  CAS  PubMed  Google Scholar 

  4. Lu X, Alshemali S, de Wynter EA, et al. Mesenchymal stem cells from CD34(-) human umbilical cord blood. Transfus Med. 2010;20:178–84

    Article  CAS  PubMed  Google Scholar 

  5. Tanaka N, Kamei N, Nakamae T, et al. CD133+ cells form human umbilical cord blood reduce cortical damage and promote axonal growth in neonatal rat organ co-cultures exposed to hypoxia. Int J Dev Neurosci. 2010;28:581–7.

    Article  PubMed  Google Scholar 

  6. Jiang T, Vaessen B, Lenvik T, et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol. 2002a;30:896–904.

    Article  CAS  PubMed  Google Scholar 

  7. Jiang Y, Jahagirdar B, Reinhardt RL, et al. Pluripotency of mesenchymal stem-cell-derived from adult marrow. Nature. 2002b;418:41–9.

    Article  CAS  PubMed  Google Scholar 

  8. Kazutoshi T, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  Google Scholar 

  9. Robbins RD, Prasain N, Maier BF, et al. Inducible pluripotent stem cells: not quite ready for prime time? Curr Opin Organ Transplant. 2010;15:61–7.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Greggio S, de Paula S, Azevedo PN, et al. Intra-arterial transplantation of human umbilical cord blood mononuclear cells in neonatal hypoxic-ischemic rats. Life Sci. 2014;96:33–9.

    Article  CAS  PubMed  Google Scholar 

  11. Huang HZ, Wen XH, Liu H, et al. Human umbilical cord blood mononuclear cell transplantation promotes long-term neurobehavioral functional development of newborn SD rats with hypoxic-ischemic brain injury. Zhonghua Er Ke Za Zhi. 2013;51:460–6.

    PubMed  Google Scholar 

  12. Wang XL, Zhao YS, Hu MY, et al. Umbilical cord blood cells regulate endogenous neural stem cell proliferation via hedgehog signaling in hypoxic ischemic neonatal rats. Brain Res. 2013b;1518:26–35.

    Article  CAS  PubMed  Google Scholar 

  13. Yamagata M, Yamamoto A, Kato E, et al. Human dental pulp-derived stem cells protect against hypoxic-ischemic brain injury in neonatal mice. Stroke. 2013;44:551–4.

    Article  PubMed  Google Scholar 

  14. de Paula S, Greggio S, Marinowic DR, et al. The dose-response effect of acute intravenous transplantation of human umbilical cord blood cells on brain damage and spatial memory deficits in neonatal hypoxia-ischemia. Neuroscience. 2012;210:431–41.

    Article  PubMed  Google Scholar 

  15. Park S, Koh SE, Maeng S, et al. Neural progenitors generated from the mesenchymal stem cells of first-trimester human placenta matured in the hypoxic-ischemic rat brain and mediated restoration of locomotor activity. Placenta. 2011;32:269–76.

    Article  CAS  PubMed  Google Scholar 

  16. Pimental-Coelho PM, Magalhaes ES, Lopes LM, et al. 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;19:351–8.

    Article  Google Scholar 

  17. Xia G, Hong X, Chen X, et al. Intracerebral transplantation of mesenchymal stem-cell-derived from human umbilical cord blood alleviated hypoxic ischemic brain injury in rat neonates. J Perinat Med. 2010;38:215–21.

    Article  PubMed  Google Scholar 

  18. Yasuhara T, Matsukawa N, Yu G, et al. Behavioral and histological characterization of intrahippocampal grafts of human bone mararrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury. Cell Transplant. 2006;15:231–8.

    Article  PubMed  Google Scholar 

  19. Yasuhara, T, Hara K, Maki M, Mays RW, et al. Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab. 2008;28:1804–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Qu SQ, Luan Z, Yin GC, et al. Transplantation of human fetal neural stem cells into cerebral ventricle of the neonatal rat following hypoxic-ischemic injury: survival, migration and differentiation. Zhongua Er Ke Za Zhi. 2005;43:576–9.

    Google Scholar 

  21. Meier CA, Middelanis J, Wasielewski B, et al. Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res. 2006;59:244–9.

    Article  PubMed  Google Scholar 

  22. de Paula S, Vitola AS, Greggio S, et al. Hemispheric brain injury and behavioral deficits induced by severe neonatal hypoxia-ischemia in rats are not attenuated by intravenous administration of human umbilical cord blood cells. Pediatr Res. 2009;65:631–5.

    Article  PubMed  Google Scholar 

  23. Riess P, Zhang C, Saatman KE, et al. Transplanted neural stem cells survive, differentiate, and improve neurological motor function after experimental traumatic brain injury. Neurosurgery. 2002;51:1043–52.

    PubMed  Google Scholar 

  24. Zhao LR, Duan WM, Reyes M, et al. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174:11–20.

    Article  PubMed  Google Scholar 

  25. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34( + ) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000;95:3289–96.

    CAS  PubMed  Google Scholar 

  26. Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation. 2003;107:1322–8.

    Article  CAS  PubMed  Google Scholar 

  27. Rajantie I, Ilmonen M, Alminaite A, et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood. 2004;104:2084–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Borlongan CV, Lind JG, Dillon-Carter O, et al. Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats. Brain Res. 2004;1010:108–16.

    Article  CAS  PubMed  Google Scholar 

  29. Vendrame M, Gemma C, de Mesquita D, et al. Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells Dev. 2005;14:595–604.

    Article  CAS  PubMed  Google Scholar 

  30. Vendrame M, Gemma C, Pennypacker KR, et al. Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol. 2006;199:191–200.

    Article  CAS  PubMed  Google Scholar 

  31. Walker PA, Shah SK, Jimenez F, et al. Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp Neurol. 2010;225:341–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Leonardo CC, Hall AA, Collier LA, et al. Human umbilical cord blood cell therapy blocks the morphological change and recruitment of CD11b-expressing, isolectin-binding proinflammatory cells after middle cerebral artery occlusion. J Neurosci Res. 2010;88:1213–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Rosenkranz K, Tenbruch M, May C, et al. Changes in interleukin-1 alpha serum levels after transplantation of umbilical cord blood cells in a model of perinatal hypoxic-ischemic brain damage. Ann Anat. 2013;195:122–7.

    Article  CAS  PubMed  Google Scholar 

  34. Bae SH, Kong TH, Lee HS, et al. Long-lasting paracrine effects of human cord blood cells on damaged neocortex in an animal model of cerebral palsy. Cell Transplant. 2012;21:2497–515.

    Article  PubMed  Google Scholar 

  35. Waisielewski B, Jensen A, Roth-Harer A, et al. Neuroglial activation and Cx43 expression are reduced upon transplantation of human umbilical cord blood cells after perinatal hypoxic-ischemic injury. Brain Res. 2012;1487:39–53.

    Article  Google Scholar 

  36. Rosenkranz K, Krumbach S, Tenbusch M, Marcus K, Marschner K, Dermietzel R, Meier C. Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell Tissue Res. 2012;348:429–38.

    Article  CAS  PubMed  Google Scholar 

  37. Li J, Zhu H, Liu Y, et al. Human mesenchymal stem cell transplantation protects against cerebral ischemic injury and upregulates interleukin-10 expression in Macaca fascicularis. Brain Res. 2010;1334:65–72.

    Article  CAS  PubMed  Google Scholar 

  38. Dayer AG, Jenny B, Sauvain MO, et al. Expression of FGF-2 in neural progenitor cells enhances their potential for cellular brain repair in the rodent cortex. Brain. 2007;130:2962–76.

    Article  PubMed  Google Scholar 

  39. Luan Z, Yin GC, Hu XH, et al. Treatment of an infant with severe neonatal hypoxic-ischemic encephalopathy sequelae with transplantation of human neural stem cells into cerebral ventricle. Zhonghua Er Ke Za Zhi. 2005;43:580–3.

    PubMed  Google Scholar 

  40. Cotten MG, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. 2014;164:973–979.e1. doi:10.1016/j.peds.2013.11.036.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Committee on Obstetrics Practice: Inappropriate use of the terms fetal distress and birth Asphyxia. Obstet Gynecol. 2005;106:1469–70.

    Google Scholar 

  42. Huang BY, Castillo M. Hypoxic-ischemic brain injury: imaging findings from birth to adulthood. Radiographics. 2008;28:417–39.

    Article  PubMed  Google Scholar 

  43. Rice JE, Vanucci RC, Brierly JB. The influence of immaturity on hypoxic-ischemic brain damage in the rat. Ann Neurol. 1981;9:131–41.

    Article  PubMed  Google Scholar 

  44. Johnston MV, Ferriero DM, Vannucci SJ, et al. Models of cerebral palsy; which ones are better. J Child Neurol. 2005;20:984–7.

    Article  PubMed  Google Scholar 

  45. Derrick M, Drobyshevsky A, Ji X, et al. A model of cerebral palsy from fetal hypoxia-ischemia. Stroke. 2007;38(2 Suppl):731–5.

    Article  PubMed  Google Scholar 

  46. Derrick M, Drobyshevsky A, Ji X, et al. Hypoxia-ischemic causes persistent movement deficits in a perinatal rabbit model of cerebral palsy: assessed by a new swim test. Int J Dev Neurosci. 2009;27:549–57.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Droboshevsky A, Derrick M, Luo K, et al. Near-term fetal hypoxia-ischemia in rabbits: MRI can predict muscle tone abnormalities and deep brain injury. Stroke. 2012;43:2757–63.

    Article  Google Scholar 

  48. Rousset CL, Kassem J, Aubert A, et al. Maternal exposure to lipopolysaccharide leads to transient motor dysfunction in neonatal rats. Dev Neurosci. 2013;35:172–81.

    Article  CAS  PubMed  Google Scholar 

  49. Kannan S, Saadani-Makki F, Balakrishnan B, et al. Magnitude of [(11)C]PK11195 binding is related to severity of motor deficits in a rabbit model of cerebral palsy induced by intrauterine endotoxin exposure. Dev Neurosci. 2011;33:231–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Stigger F, Felizzola AL, Kronbauer GA, et al. Effects of fetal exposure to lipolysaccharide, perinatal anoxia and sensorimotor restriction on motor skills and musculoskeletal tissue: implication for an animal model of cerebral palsy. Exp Neurol. 2011;228:183–91.

    Article  CAS  PubMed  Google Scholar 

  51. Min K, Song J, Kang JY, et al. Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells. 2013;31:581–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Chen G, Wang Y, Xu Z, et al. Neural stem-cell-lie cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. J Transl Med. 2013;11:21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Wang X, Cheng H, Hua R, et al. Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study. Cytotherapy. 2013;15:1549–62.

    Article  PubMed  Google Scholar 

  54. Li M, Yu A, Zhang F, Dai G, et al. Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells. J Transl Med. 2012;10:100.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Luan Z, Liu W, Qu S, Du K, et al. Effects of neural progenitor cell transplantation in children with severe cerebral palsy. Cell Transplant. 2012;21(Suppl 1):591–8.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James Carroll .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Carroll, J. (2015). Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury. In: Hess, D. (eds) Cell Therapy for Brain Injury. Springer, Cham. https://doi.org/10.1007/978-3-319-15063-5_16

Download citation

Publish with us

Policies and ethics