The Effects of Umbilical Cord Blood and Cord Tissue Cell Therapies in Animal and Human Models of Cerebral Palsy

  • Jessica M. SunEmail author
  • Joanne Kurtzberg
Living reference work entry


Biologic and cell-based therapies are increasingly being developed for a multitude of diseases. They are being explored in the treatment of neurologic conditions, as traditional pharmacologic agents typically cannot fully address the pathologic complexity and resultant manifestations of injuries and diseases affecting the brain. Umbilical cord blood and cord tissue are attractive sources of cells for these therapies as they are readily available and easily obtained without risk to the donor infant or mother and because they can be routinely screened and banked. This chapter will describe the current state of investigations of umbilical cord blood and cord tissue-based therapies in the treatment of cerebral palsy due to an acquired brain injury and highlight some of the possibilities and challenges inherent in developing and assessing such therapies in this population.


Cerebral palsy Cell therapy Umbilical cord blood Mesenchymal stromal cells Brain connectivity 


  1. Ahn SY, Chang YS, Sung DK, Sung SI, Yoo HS, Lee JH, Oh WI, Park WS (2013) Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage. Stroke 44:497–504CrossRefGoogle Scholar
  2. Archambault J, Moreira A, McDaniel D, Winter L, Sun L, Hornsby P (2017) Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: A systematic review and meta-analysis of preclinical studies. PLoS One 12:e0189895CrossRefGoogle Scholar
  3. Aridas JD, McDonald CA, Paton MC, Yawno T, Sutherland AE, Nitsos I, Pham Y, Ditchfield M, Fahey MC, Wong F, Malhotra A, Castillo-Melendez M, Bhakoo K, Wallace EM, Jenkin G, Miller SL (2016) Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb. J Physiol 594:1421–1435CrossRefGoogle Scholar
  4. Arien-Zakay H, Lecht S, Bercu MM, Tabakman R, Kohen R, Galski H, Nagler A, Lazarovici P (2009) Neuroprotection by cord blood neural progenitors involves antioxidants, neurotrophic and angiogenic factors. Exp Neurol 216:83–94CrossRefGoogle Scholar
  5. Bliss T, Guzman R, Daadi M, Steinberg GK (2007) Cell transplantation therapy for stroke. Stroke 38:817–826CrossRefGoogle Scholar
  6. Borlongan CV, Hadman M, Sanberg CD, Sanberg PR (2004) Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 35:2385–2389CrossRefGoogle Scholar
  7. Carmichael ST (2003) Plasticity of cortical projections after stroke. Neuroscientist 9:64–75CrossRefGoogle Scholar
  8. Carr LJ, Harrison LM, Evans AL, Stephens JA (1993) Patterns of central motor reorganization in hemiplegic cerebral palsy. Brain 116. (Pt 5:1223–1247CrossRefGoogle Scholar
  9. Castillo-Melendez M, Yawno T, Jenkin G, Miller SL (2013) Stem cell therapy to protect and repair the developing brain: a review of mechanisms of action of cord blood and amnion epithelial derived cells. Front Neurosci 7:194CrossRefGoogle Scholar
  10. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682–2688CrossRefGoogle Scholar
  11. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, Chopp M (2003) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92:692–699CrossRefGoogle Scholar
  12. Chen J, Venkat P, Zacharek A, Chopp M (2014) Neurorestorative therapy for stroke. Front Hum Neurosci 8:382PubMedPubMedCentralGoogle Scholar
  13. Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, Smith PB, Goldstein RF, Fisher KA, Gustafson KE, Waters-Pick B, Swamy GK, Rattray B, Tan S, Kurtzberg J (2014) Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 164(5):973–979CrossRefGoogle Scholar
  14. Derrick M, Drobyshevsky A, Ji X, Tan S (2007) A model of cerebral palsy from fetal hypoxia-ischemia. Stroke 38:731–735CrossRefGoogle Scholar
  15. Donega V, Van Velthoven CT, Nijboer CH, Van Bel F, Kas MJ, Kavelaars A, Heijnen CJ (2013) Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One 8:e51253CrossRefGoogle Scholar
  16. Drobyshevsky A, Cotten CM, Shi Z, Luo K, Jiang R, Derrick M, Tracy ET, Gentry T, Goldberg RN, Kurtzberg J, Tan S (2015) Human umbilical cord blood cells ameliorate motor deficits in rabbits in a cerebral palsy model. Dev Neurosci 37:349–362CrossRefGoogle Scholar
  17. Englander ZA, Sun J, Laura C, Mikati MA, Kurtzberg J, Song AW (2015) Brain structural connectivity increases concurrent with functional improvement: evidence from diffusion tensor MRI in children with cerebral palsy during therapy. Neuroimage Clin 7:315–324CrossRefGoogle Scholar
  18. Guzzetta A, Bonanni P, Biagi L, Tosetti M, Montanaro D, Guerrini R, Cioni G (2007) Reorganisation of the somatosensory system after early brain damage. Clin Neurophysiol 118:1110–1121CrossRefGoogle Scholar
  19. Hanna SE, Bartlett DJ, Rivard LM, Russell DJ (2008) Reference curves for the gross motor function measure: percentiles for clinical description and tracking over time among children with cerebral palsy. Phys Ther 88:596–607CrossRefGoogle Scholar
  20. Huang L, Zhang C, Gu J, Wu W, Shen Z, Zhou X, Lu H (2018) A randomized, placebo-controlled trial of human umbilical cord blood mesenchymal stem cell infusion for children with cerebral palsy. Cell Transplant 27:325–334CrossRefGoogle Scholar
  21. Kang M, Min K, Jang J, Kim SC, Kang MS, Jang SJ, Lee JY, Kim SH, Kim MK, An SA, Kim M (2015) Involvement of immune responses in the efficacy of cord blood cell therapy for cerebral palsy. Stem Cells Dev 24:2259–2268CrossRefGoogle Scholar
  22. Kim ES, Ahn SY, Im GH, Sung DK, Park YR, Choi SH, Choi SJ, Chang YS, Oh W, Lee JH, Park WS (2012) Human umbilical cord blood-derived mesenchymal stem cell transplantation attenuates severe brain injury by permanent middle cerebral artery occlusion in newborn rats. Pediatr Res 72:277–284CrossRefGoogle Scholar
  23. Lei J, Firdaus W, Rosenzweig JM, Alrebh S, Bakhshwin A, Borbiev T, Fatemi A, Blakemore K, Johnston MV, Burd I (2015) Murine model: maternal administration of stem cells for prevention of prematurity. Am J Obstet Gynecol 212:639 e1–639. e10CrossRefGoogle Scholar
  24. Lin YC, Ko TL, Shih YH, Lin MY, Fu TW, Hsiao HS, Hsu JY, Fu YS (2011) Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke 42:2045–2053CrossRefGoogle Scholar
  25. Llado J, Haenggeli C, Maragakis NJ, Snyder EY, Rothstein JD (2004) Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol Cell Neurosci 27:322–331CrossRefGoogle Scholar
  26. 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 59:244–249CrossRefGoogle Scholar
  27. Min K, Song J, Kang JY, Ko J, Ryu JS, Kang MS, Jang SJ, Kim SH, Oh D, Kim MK, Kim SS, Kim M (2013) Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells 31:581–591CrossRefGoogle Scholar
  28. Mukai T, Mori Y, Shimazu T, Takahashi A, Tsunoda H, Yamaguchi S, Kiryu S, Tojo A, Nagamura-Inoue T (2017) Intravenous injection of umbilical cord-derived mesenchymal stromal cells attenuates reactive gliosis and hypomyelination in a neonatal intraventricular hemorrhage model. Neuroscience 355:175–187CrossRefGoogle Scholar
  29. Nan Z, Grande A, Sanberg CD, Sanberg PR, Low WC (2005) Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann N Y Acad Sci 1049:84–96CrossRefGoogle Scholar
  30. Park WS, Sung SI, Ahn SY, Sung DK, Im GH, Yoo HS, Choi SJ, Chang YS (2016) Optimal timing of mesenchymal stem cell therapy for neonatal intraventricular hemorrhage. Cell Transplant 25:1131–1144CrossRefGoogle Scholar
  31. Romanov YA, Tarakanov OP, Radaev SM, Dugina TN, Ryaskina SS, Darevskaya AN, Morozova YV, Khachatryan WA, Lebedev KE, Zotova NS, Burkova AS, Sukhikh GT, Smirnov VN (2015) Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. Cytotherapy 17(7):969–978CrossRefGoogle Scholar
  32. Rosenbaum PL, Walter SD, Hanna SE, Palisano RJ, Russell DJ, Raina P, Wood E, Bartlett DJ, Galuppi BE (2002) Prognosis for gross motor function in cerebral palsy: creation of motor development curves. JAMA 288:1357–1363CrossRefGoogle Scholar
  33. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (2007) Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6–13CrossRefGoogle Scholar
  34. Staudt M, Grodd W, Gerloff C, Erb M, Stitz J, Krageloh-Mann I (2002) Two types of ipsilateral reorganization in congenital hemiparesis: a TMS and fMRI study. Brain 125:2222–2237CrossRefGoogle Scholar
  35. 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 50:1980–1987CrossRefGoogle Scholar
  36. Sun J, Mikati M, Troy J, McLaughlin C, Jasien J, Case L, Worley G, Kurtzberg J (2017a) Sibling umbilical cord blood infusion is safe in children with cerebral palsy. Dev Med Child Neurol 59:115Google Scholar
  37. Sun JM, Song AW, Case LE, Mikati MA, Gustafson KE, Simmons R, Goldstein R, Petry J, McLaughlin C, Waters-Pick B, Chen LW, Wease S, Blackwell B, Worley G, Troy J, Kurtzberg J (2017b) Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized, placebo-controlled trial. Stem Cells Transl Med 6:2071–2078CrossRefGoogle Scholar
  38. Sutcliffe TL, Gaetz WC, Logan WJ, Cheyne DO, Fehlings DL (2007) Cortical reorganization after modified constraint-induced movement therapy in pediatric hemiplegic cerebral palsy. J Child Neurol 22:1281–1287CrossRefGoogle Scholar
  39. 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 114:330–338CrossRefGoogle Scholar
  40. Tanaka E, Ogawa Y, Mukai T, Sato Y, Hamazaki T, Nagamura-Inoue T, Harada-Shiba M, Shintaku H, Tsuji M (2018) Dose-dependent effect of intravenous administration of human umbilical cord-derived mesenchymal stem cells in neonatal stroke mice. Front Neurol 9:133CrossRefGoogle Scholar
  41. Van Velthoven CT, Kavelaars A, Van Bel F, Heijnen CJ (2010) Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun 24:387–393CrossRefGoogle Scholar
  42. Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T, Sanberg CD, Sanberg PR, Willing AE (2004) Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 35:2390–2395CrossRefGoogle Scholar
  43. 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 14:595–604CrossRefGoogle Scholar
  44. Wagenaar N, Nijboer CH, Van Bel F (2017) Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol 59:997–1003CrossRefGoogle Scholar
  45. Wang L, Ji H, Zhou J, Xie J, Zhong Z, Li M, Bai W, Li N, Zhang Z, Wang X, Zhu D, Liu Y, Wu M (2013a) Therapeutic potential of umbilical cord mesenchymal stromal cells transplantation for cerebral palsy: a case report. Case Rep Transplant 2013:146347PubMedPubMedCentralGoogle Scholar
  46. Wang X, Cheng H, Hua R, Yang J, Dai G, Zhang Z, Wang R, Qin C, An Y (2013b) Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study. Cytotherapy 15:1549–1562CrossRefGoogle Scholar
  47. Wang X, Hu H, Hua R, Yang J, Zheng P, Niu X, Cheng H, Dai G, Liu X, Zhang Z, An Y (2015) Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: pilot study on the correlation of efficacy and hereditary factors. Cytotherapy 17:224–231CrossRefGoogle Scholar
  48. Willing AE, Lixian J, Milliken M, Poulos S, Zigova T, Song S, Hart C, Sanchez-Ramos J, Sanberg PR (2003) Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. J Neurosci Res 73:296–307CrossRefGoogle Scholar
  49. Wood E, Rosenbaum P (2000) The gross motor function classification system for cerebral palsy: a study of reliability and stability over time. Dev Med Child Neurol 42:292–296CrossRefGoogle Scholar
  50. Yang B, Migliati E, Parsha K, Schaar K, Xi X, Aronowski J, Savitz SI (2013) Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke 44:3463–3472CrossRefGoogle Scholar
  51. You SH, Jang SH, Kim YH, Kwon YH, Barrow I, Hallett M (2005) Cortical reorganization induced by virtual reality therapy in a child with hemiparetic cerebral palsy. Dev Med Child Neurol 47:628–635CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Marcus Center for Cellular Cures, Robertson Clinical and Translational Cell Therapy ProgramDuke University Medical CenterDurhamUSA

Section editors and affiliations

  • Steven J. Bachrach
    • 1
    • 2
  1. 1.Department of Pediatrics (Emeritus)Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  2. 2.Sidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations