Advertisement

Neonatal Hypoxic-Ischemic Brain Damage: Human Umbilical Cord Blood Mononuclear Cells Transplantation

  • Pedro M. Pimentel-Coelho
  • Rosalia Mendez-Otero
Chapter
Part of the Tumors of the Central Nervous System book series (TCNS, volume 13)

Abstract

In the last decades, a great effort has been made to understand the physiopathology of neonatal hypoxic-ischemic encephalopathy (HIE), the main cause of long-term neurological impairments in term neonates. This effort was recently marked by a landmark advance in the treatment of HIE, represented by the significant neuroprotective effect of therapeutic hypothermia, in an example of successful translation of preclinical research findings to the bedside. However, at least 40% of the cooled infants will still die or have moderate/severe neurological disability, indicating that newer therapies are absolutely necessary. In this regard, umbilical cord blood mononuclear cells (UCBC), which are readily available for transplantation in the first hours after birth, have been shown to improve the neurological function when transplanted in several models of brain injury, including HIE. In this chapter we give a concise overview of recent studies evaluating the potential therapeutic role of UCBC transplantation in animal models of HIE. We also discuss the potential mechanisms underlying the action of these cells in the newborn brain and the current effort to translate these observations to patients in several ongoing clinical trials.

Keywords

Mesenchymal Stem Cell Cerebral Palsy Umbilical Cord Blood Therapeutic Hypothermia Cord Blood Bank 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Boltze J, Reich DM, Hau S, Reymann KG, Strassburger M, Lobsien D, Wagner DC, Kamprad M, Stahl T (2012) Assessment of neuroprotective effects of human umbilical cord blood mononuclear cell subpopulations in vitro and in vivo. Cell Transpl 21(4):723–737Google Scholar
  2. Broxmeyer HE (2011) Insights into the biology of cord blood stem/progenitor cells. Cell Prolif 44(Suppl 1):55–59PubMedCrossRefGoogle Scholar
  3. Dasari VR, Veeravalli KK, Saving KL, Gujrati M, Fassett D, Klopfenstein JD, Dinh DH, Rao JS (2008) Neuroprotection by cord blood stem cells against glutamate-induced apoptosis is mediated by Akt pathway. Neurobiol Dis 32:486–498PubMedCrossRefGoogle Scholar
  4. de Paula S, Vitola AS, Greggio S, de Paula D, Mello PB, Lubianca JM, Xavier LL, Fiori HH, Dacosta JC (2009) 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 65:631–635PubMedCrossRefGoogle Scholar
  5. Fan CG, Zhang QJ, Tang FW, Han ZB, Wang GS, Han ZC (2005) Human umbilical cord blood cells express neurotrophic factors. Neurosci Lett 380:322–325PubMedCrossRefGoogle Scholar
  6. Geissler M, Dinse HR, Neuhoff S, Kreikemeier K, Meier C (2011) Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex. PLoS One 6:e20194PubMedCentralPubMedCrossRefGoogle Scholar
  7. Gendelman HE, Appel SH (2011) Neuroprotective activities of regulatory T cells. Trends Mol Med 17:687–688PubMedCrossRefGoogle Scholar
  8. Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza I, Vassena R, Raya A, Boue S, Barrero MJ, Corbella BA, Torrabadella M, Veiga A, Izpisua Belmonte JC (2009) Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5:353–357PubMedCentralPubMedCrossRefGoogle Scholar
  9. Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, June CH, Blazar BR, Porter SB (2005) Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105:750–758PubMedCrossRefGoogle Scholar
  10. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE (2008) A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol 199:587–595PubMedCrossRefGoogle Scholar
  11. Greschat S, Schira J, Kury P, Rosenbaum C, de Souza Silva MA, Kogler G, Wernet P, Muller HW (2008) Unrestricted somatic stem cells from human umbilical cord blood can be differentiated into neurons with a dopaminergic phenotype. Stem Cells Dev 17:221–232PubMedCrossRefGoogle Scholar
  12. Higgins RD, Raju T, Edwards AD, Azzopardi DV, Bose CL, Clark RH, Ferriero DM, Guillet R, Gunn AJ, Hagberg H, Hirtz D, Inder TE, Jacobs SE, Jenkins D, Juul S, Laptook AR, Lucey JF, Maze M, Palmer C, Papile L, Pfister RH, Robertson NJ, Rutherford M, Shankaran S, Silverstein FS, Soll RF, Thoresen M, Walsh WF (2011) Hypothermia and other treatment options for neonatal encephalopathy: an executive summary of the Eunice Kennedy Shriver NICHD workshop. J Pediatr 159:851 e1–858 e1Google Scholar
  13. Johnston MV, Ferriero DM, Vannucci SJ, Hagberg H (2005) Models of cerebral palsy: which ones are best? J Child Neurol 20:984–987PubMedCrossRefGoogle Scholar
  14. Liu Y, Wang L, Kikuiri T, Akiyama K, Chen C, Xu X, Yang R, Chen W, Wang S, Shi S (2011) Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat Med 17:1594–1601PubMedCentralPubMedCrossRefGoogle Scholar
  15. London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S, Schwartz M (2011) Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J Exp Med 208:23–39PubMedCentralPubMedCrossRefGoogle Scholar
  16. Meier C, Middelanis J, Wasielewski B, Neuhoff S, Roth-Haerer A, Gantert M, Dinse HR, Dermietzel R, Jensen A (2006) Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res 59:244–249PubMedCrossRefGoogle Scholar
  17. Newman MB, Willing AE, Manresa JJ, Sanberg CD, Sanberg PR (2006) Cytokines produced by cultured human umbilical cord blood (HUCB) cells: implications for brain repair. Exp Neurol 199:201–208PubMedCrossRefGoogle Scholar
  18. Pimentel-Coelho PM, Magalhaes ES, Lopes LM, deAzevedo LC, Santiago MF, Mendez-Otero R (2010) 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 19:351–358PubMedCrossRefGoogle Scholar
  19. Ramos AL, Darabi R, Akbarloo N, Borges L, Catanese J, Dineen SP, Brekken RA, Perlingeiro RC (2010) Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood. Circ Res 107:1460–1469PubMedCentralPubMedCrossRefGoogle Scholar
  20. Reich DM, Hau S, Stahl T, Scholz M, Naumann W, Emmrich F, Boltze J, Kamprad M (2008) Neuronal hypoxia in vitro: investigation of therapeutic principles of HUCB-MNC and CD133+ stem cells. BMC Neurosci 9:91PubMedCentralPubMedCrossRefGoogle Scholar
  21. Rosenkranz K, Kumbruch S, Lebermann K, Marschner K, Jensen A, Dermietzel R, Meier C (2010) 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 88:1223–1233PubMedGoogle Scholar
  22. Rowe DD, Leonardo CC, Recio JA, Collier LA, Willing AE, Pennypacker KR (2012) Human umbilical cord blood cells protect oligodendrocytes from brain ischemia through Akt signal transduction. J Biol Chem 287(6):4177–4187Google Scholar
  23. Schira J, Gasis M, Estrada V, Hendricks M, Schmitz C, Trapp T, Kruse F, Kogler G, Wernet P, Hartung HP, Muller HW (2012) Significant clinical, neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Brain 135(Pt 2):431–446Google Scholar
  24. Sohlberg E, Saghafian-Hedengren S, Bremme K, Sverremark-Ekstrom E (2011) Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses. Immunology 133:41–50PubMedCentralPubMedCrossRefGoogle Scholar
  25. Sun J, Allison J, McLaughlin C, Sledge L, Waters-Pick B, Wease S, Kurtzberg J (2010) Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion 50:1980–1987PubMedCrossRefGoogle Scholar
  26. Taguchi A, Soma T, Tanaka H, Kanda T, Nishimura H, Yoshikawa H, Tsukamoto Y, Iso H, Fujimori Y, Stern DM, Naritomi H, Matsuyama T (2004) Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest 114:330–338PubMedCentralPubMedGoogle Scholar
  27. Tanaka N, Kamei N, Nakamae T, Yamamoto R, Ishikawa M, Fujiwara H, Miyoshi H, Asahara T, Ochi M, Kudo Y (2010) CD133+ cells from human umbilical cord blood reduce cortical damage and promote axonal growth in neonatal rat organ co-cultures exposed to hypoxia. Int J Dev Neurosci 28:581–587PubMedCrossRefGoogle Scholar
  28. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2010) Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci 30:9603–96011PubMedCrossRefGoogle Scholar
  29. Vendrame M, Gemma C, de Mesquita D, Collier L, Bickford PC, Sanberg CD, Sanberg PR, Pennypacker KR, Willing AE (2005) Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells Dev 14:595–604PubMedCrossRefGoogle Scholar
  30. Vendrame M, Gemma C, Pennypacker KR, Bickford PC, Davis Sanberg C, Sanberg PR, Willing AE (2006) Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol 199:191–200PubMedCrossRefGoogle Scholar
  31. Xia G, Hong X, Chen X, Lan F, Zhang G, Liao L (2010) Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates. J Perinat Med 38:215–221PubMedGoogle Scholar
  32. Yasuhara T, Hara K, Maki M, Xu L, Yu G, Ali MM, Masuda T, Yu SJ, Bae EK, Hayashi T, Matsukawa N, Kaneko Y, Kuzmin-Nichols N, Ellovitch S, Cruz EL, Klasko SK, Sanberg CD, Sanberg PR, Borlongan CV (2010) Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts. J Cell Mol Med 14:914–921PubMedCrossRefGoogle Scholar
  33. Ye Z, Zhan H, Mali P, Dowey S, Williams DM, Jang YY, Dang CV, Spivak JL, Moliterno AR, Cheng L (2009) Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114:5473–5480PubMedCentralPubMedCrossRefGoogle Scholar
  34. Yu G, Borlongan CV, Ou Y, Stahl CE, Yu S, Bae E, Kaneko Y, Yang T, Yuan C, Fang L (2010) In vitro non-viral lipofectamine delivery of the gene for glial cell line-derived neurotrophic factor to human umbilical cord blood CD34+ cells. Brain Res 1325:147–154PubMedCrossRefGoogle Scholar
  35. Zhang X, Hirai M, Cantero S, Ciubotariu R, Dobrila L, Hirsh A, Igura K, Satoh H, Yokomi I, Nishimura T, Yamaguchi S, Yoshimura K, Rubinstein P, Takahashi TA (2011) Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue. J Cell Biochem 112:1206–1218PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Pedro M. Pimentel-Coelho
    • 1
  • Rosalia Mendez-Otero
    • 1
  1. 1.Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil

Personalised recommendations