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Cord Blood and Lithium Therapy of Spinal Cord Injury (SCI)
Umbilical cord blood (UCB) contains many stem cells per volume, more than adult bone marrow. In the past 20 years, UCB transplants have saved thousands of people suffering from disorders of the blood and immune system. Since 2005, UCB transplants are known to cure Krabbe's disease [1], a neurological disease that prevents myelination, and a variety of metabolic disorders [2]. Many researchers have reported that UCB may be beneficial for acquired neurological conditions such as stroke [3-4] and cerebral palsy [5-6].
Cord blood is stored in two types of banks: public or private (family). The former hold cord blood donated for the purposes of transplantation to other people, and are strictly regulated by the U.S. Food and Drug Administration (FDA). The latter are cord blood stored by families for private use by the donor. In general, the quality of privately banked cord blood is significantly lower in family banks [6]. On the other hand, autologous (self) cord blood units should have the best immunological match. Patients who did not store their own cord blood can utilize HLA-matched units from public banks.
UCB transplants improved recovery in rat [7-11] and dog [12-15] SCI models. UCB cells may help injured spinal cords through a variety of mechanisms [16-21], including stimulating myelination, suppressing inflammation, and preventing cell death. Studies have shown that various populations of stem cells in the UCB are all effective. These include unfractionated mono-nuclear cells in UCB [22-26], CD34+ cells [8, 27-29], multipotent cells cultured from UCB [10], mesenchymal stem cells [30-33], CD133+ pluripotent stem cells [34], and cultured neuron-like UCB cells [35], as well as UCB cells genetically modified to make neurons [36, 37] and to secrete growth factors [38, 39].
Lithium stimulates spinal cord regeneration [41-42] and stem cell proliferation in rats after SCI [43-44]. Lithium is the reference therapy for manic depression, taken by over 30 million people around the world. Lithium stimulates bone marrow and neural stem cells [44] to proliferate and to produce growth factors [45]. In humans, lithium significantly increases the brain's gray matter volume [46]. We therefore proposed that the UCB stem cells and lithium have synergistic effects on SCI recovery.
The China Spinal Cord Injury Network (ChinaSCINet) formed in 2006 to test promising SCI therapies. The network has 24 leading SCI centers in China, Hong Kong, and Taiwan. The clinical trials in the network are testing injections of UCB stem cells into the spinal cord and oral lithium treatment, individually and in combination, in patients with chronic (>1yr) and subacute (2day - 2week) SCI (Table 1). The UCB given to patients come from donors that match at least 4 out of 6 recipient HLA. These UCB are donated by the cord blood bank StemCyte.
Table 1. ChinaSCINet trials
Name | SCI | No. | Treatment Groups | Comments |
CN101 | >1yr | 20 | 6w oral lithium carbonate (Li, titrated to 0.8-1.0 mM in serum) | Phase 1 open label, adverse events |
CN102A | >1yr | 40 | Placebo vs. 6w of Li (0.8-1.2 mM serum levels) | Phase 2 randomized double blind |
CN102B | >1yr | 40 | A-C: 4, 8, or 16 μl x4 (100,000 cells/ μl) UCB transplants; D. 16 μliter cells with MP; E. 16 μliter cells with MP + Li | Phase 2 escalating dose, randomized, open label, ASIA motor/sensory scores |
CN102C | 2day- 2wk | 40 | A: Surgery; B: 6w of Li; C: 4x 16 μliters UCB; D: UCB +Li | Phase 2 randomized double blind, ongoing |
CN103 | >1yr | 400 | UCB vs UCB + 6w oral Li (stratified ASIA A, B, C) | Phase 3 randomized double blind, 2013 |
Legend: Oral lithium carbonate is increased every 3 days until serum Li >0.6 and <1.0 mM. Escalating doses of UCBMC (4, 8, or 16 μl of 100,000 cells/ μl) are injected into dorsal root entry zones above and below the injury site. MP is 30 mg/kg methylprednisolone given intravenously. |
ChinaSCINet is conducting five clinical trials to establish the safety and feasibility of UCB and lithium treatments of SCI. CN101 showed that lithium is safe for patients with chronic SCI [47]. CN102A revealed no difference in neurological improvement between chronic SCI patients who received lithium or a placebo, but lithium reduced neuropathic pain [48]; a follow-up phase 3 trial is planned. CN102B has to date transplanted 28 patients (8 in Hong Kong, 20 in Kunming) and CN102C has randomized 30 subjects. CN103 is a phase 3 trial aimed at ascertaining whether UCB with or without lithium improves recovery.
In summary, the goal of ChinaSCINet is to conduct clinical trials of promising therapies for SCI. So far, UCB transplants appear to be safe and some subjects are regaining sensory and motor function. We plan to initiate phase 3 trials in 2013 in China, USA, Norway, and India. ChinaSCINet will continue to study promising therapies and compare them against the best therapy found in CN103.
References
- Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med. 2005;352(20):2069-81. [PMID: 15901860]
- Prasad VK, Mendizabal A, Parikh SH, Szabolcs P, Driscoll TA, Page K, Lakshminarayanan S, Allison J, Wood S, Semmel D, Escolar ML, Martin PL, Carter S, Kurtzberg J. Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood. 2008;112(7):2979-89. [PMID: 18587012]
- Boltze J, Kowalski I, Geiger K, Reich D, Gunther A, Buhrle C, Egger D, Kamprad M, Emmrich F. Experimental treatment of stroke in spontaneously hypertensive rats by CD34and CD34 cord blood cells. Ger Med Sci. 2005;3:Doc09. [PMID: 19675726]
- Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T, Sanberg CD, Sanberg PR, Willing AE. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 2004;35(10):2390-5. [PMID: 15322304]
- Harris DT. Cord blood stem cells: a review of potential neurological applications. Stem Cell Rev. 2008;4(4):269-74. [PMID: 18679834]
- Sun J, Allison J, McLaughlin C, Sledge B, Waters-Pick B, Wease S, Kurtzberg J. Difference in quality between privately and publicly banked umbilicl cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurological disorders. Transfusion 2010; 50 (9): 1980-1987. [PMID: 20546200]
- Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD, Sanberg PR. Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. J Hematother Stem Cell Res. 2003;12(3):271-8. [PMID: 12857368]
- Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ, Han ZC. Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant. 2004;13(2):113-22. [PMID: 15129757]
- Kuh SU, Cho YE, Yoon DH, Kim KN, Ha Y. Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien). 2005;147(9):985-92. [PMID: 16010451]
- Chua SJ, Bielecki R, Yamanaka N, Fehlings MG, Rogers IM, Casper RF. The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine. 2010;35(16):1520-6. [PMID: 20581748]
- Kaner T, Karadag T, Cirak B, Erken HA, Karabulut A, Kiroglu Y, Akkaya S, Acar F, Coskun E, Genc O, Colakoglu N. The effects of human umbilical cord blood transplantation in rats with experimentally induced spinal cord injury. Journal of neurosurgery Spine. 2010;13(4):543-51. [PMID: 20887153]
- Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS, Kweon OK. Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs. J Vet Sci. 2007;8(3):275-82. [PMID: 17679775]
- Lee JH, Chang HS, Kang EH, Chung DJ, Choi CB, Hwang SH, Han H, Kim HY. Percutaneous transplantation of human umbilical cord blood-derived multipotent stem cells in a canine model of spinal cord injury. J Neurosurg Spine. 2009;11(6):749-57. [PMID: 19951029]
- Seo MS, Jeong YH, Park JR, Park SB, Rho KH, Kim HS, Yu KR, Lee SH, Jung JW, Lee YS, Kang KS. Isolation and characterization of canine umbilical cord blood-derived mesenchymal stem cells. J Vet Sci. 2009;10(3):181-7. [PMID: 19687617]
- Park SS, Byeon YE, Ryu HH, Kang BJ, Kim Y, Kim WH, Kang KS, Han HJ, Kweon OK. Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: Involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin. Cell transplantation. 2011. [PMID: 21375803]
- Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS, Dinh DH. Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma. 2007;24(2):391-410. [PMID: 17376002]
- Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS, Dinh DH. Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury. Neurochem Res. 2008;33(1):134-49. [PMID: 17703359]
- Dasari VR, Veeravalli KK, Saving KL, Gujrati M, Fassett D, Klopfenstein JD, Dinh DH, Rao JS. Neuroprotection by cord blood stem cells against glutamate-induced apoptosis is mediated by Akt pathway. Neurobiol Dis. 2008;32(3):486-98. [PMID: 18930139]
- Dasari VR, Veeravalli KK, Tsung AJ, Gondi CS, Gujrati M, Dinh DH, Rao JS. Neuronal apoptosis is inhibited by cord blood stem cells after spinal cord injury. J Neurotrauma. 2009;26(11):2057-69. [PMID: 19469692]
- Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, Rao JS. Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neurobiol Dis. 2009;36(1):200-12. [PMID: 19631747]
- Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, Rao JS. Stem cells downregulate the elevated levels of tissue plasminogen activator in rats after spinal cord injury. Neurochem Res. 2009;34(7):1183-94. [PMID: 19152029]
- Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD, Sanberg PR. Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res. 2003;12(3):255-70. [PMID: 12857367]
- Roussos I, Rodriguez M, Villan D, Ariza A, Rodriguez L, Garcia J. Development of a rat model of spinal cord injury and cellular transplantation. Transplant Proc. 2005;37(9):4127-30. [PMID: 16386643]
- Bigini P, Veglianese P, Andriolo G, Cova L, Grignaschi G, Caron I, Daleno C, Barbera S, Ottolina A, Calzarossa C, Lazzari L, Mennini T, Bendotti C, Silani V. Intracerebroventricular administration of human umbilical cord blood cells delays disease progression in two murine models of motor neuron degeneration. Rejuvenation Res. 2011;14(6):623-39. [PMID: 21978082]
- Garbuzova-Davis S, Rodrigues MC, Mirtyl S, Turner S, Mitha S, Sodhi J, Suthakaran S, Eve DJ, Sanberg CD, Kuzmin-Nichols N, Sanberg PR. Multiple intravenous administrations of human umbilical cord blood cells benefit in a mouse model of ALS. PLoS ONE. 2012;7(2):e31254. [PMID: 22319620]
- Rodrigues LP, Iglesias D, Nicola FC, Steffens D, Valentim L, Witczak A, Zanatta G, Achaval M, Pranke P, Netto CA. Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al]. 2012;45(1):49-57. [PMID: 22183246]
- Kao CH, Chen SH, Chio CC, Lin MT. Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock. 2008;29(1):49-55. [PMID: 17666954]
- Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H, Yamazaki M. The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. J Neurosurg Spine. 2006;5(5):424-33. [PMID: 17120892]
- Chen SH, Huang KF, Lin MT, Chang FM. Human umbilical cord blood cells or estrogen may be beneficial in treating heatstroke. Taiwan J Obstet Gynecol. 2007;46(1):15-25. [PMID: 17389184]
- Momin EN, Mohyeldin A, Zaidi HA, Vela G, Quinones-Hinojosa A. Mesenchymal stem cells: new approaches for the treatment of neurological diseases. Current stem cell research & therapy. 2010;5(4):326-44. [PMID: 20528757]
- Malgieri A, Kantzari E, Patrizi MP, Gambardella S. Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art. Int J Clin Exp Med. 2010;3(4):248-69. [PMID: 21072260]
- Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS, Hwang SH, Han H, Choe BY, Kim HY. Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury. Journal of the neurological sciences. 2011;300(1-2):86-96. [PMID: 21071039]
- Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y, Oh W, Chang JW, Jeun SS. Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther. 2011;2(5):38. [PMID: 21939558]
- Tanaka N, Kamei N, Nakamae T, Yamamoto R, Ishikawa M, Fujiwara H, Miyoshi H, Asahara T, Ochi M, Kudo Y. CD133+ cells from human umbilical cord blood reduce cortical damage and promote axonal growth in neonatal rat organ co-cultures exposed to hypoxia. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2010;28(7):581-7. [PMID: 20673797]
- Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI, Kim YJ. Neurally induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreport. 2008;19(13):1259-63. [PMID: 18695504]
- Song S, Sanchez-Ramos J. Preparation of neural progenitors from bone marrow and umbilical cord blood. Methods Mol Biol. 2008;438:123-34. [PMID: 18369754]
- Zwart I, Hill AJ, Girdlestone J, Manca MF, Navarrete R, Navarrete C, Jen LS. Analysis of neural potential of human umbilical cord blood-derived multipotent mesenchymal stem cells in response to a range of neurogenic stimuli. J Neurosci Res. 2008;86(9):1902-15. [PMID: 18338797]
- Rizvanov AA, Kiyasov AP, Gaziziov IM, Yilmaz TS, Kaligin MS, Andreeva DI, Shafigullina AK, Guseva DS, Kiselev SL, Matin K, Palotas A, Islamov RR. Human umbilical cord blood cells transfected with VEGF and L(1)CAM do not differentiate into neurons but transform into vascular endothelial cells and secrete neuro-trophic factors to support neuro-genesis-a novel approach in stem cell therapy. Neurochem Int. 2008;53(6-8):389-94. [PMID: 18948156]
- Rizvanov AA, Guseva DS, Salafutdinov, II, Kudryashova NV, Bashirov FV, Kiyasov AP, Yalvac ME, Gazizov IM, Kaligin MS, Sahin F, Mukhamedyarov MA, Palotas A, Islamov RR. Genetically modified human umbilical cord blood cells expressing vascular endothelial growth factor and fibroblast growth factor 2 differentiate into glial cells after transplantation into amyotrophic lateral sclerosis transgenic mice. Experimental biology and medicine. 2011;236(1):91-8. [PMID: 21163822]
- Su H, Zhang W, Guo J, Guo A, Yuan Q, Wu W. Lithium enhances the neuronal differentiation of neural progenitor cells in vitro and after transplantation into the avulsed ventral horn of adult rats through the secretion of brain-derived neurotrophic factor. Journal of Neurochemistry. 2009;108(6):1385-98. [PMID: 19183259]
- Su H, Chu TH, Wu W. Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord. Exp Neurol. 2007;206(2):296-307. [PMID: 17599835]
- Yick LW, So KF, Cheung PT, Wu WT. Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. Journal of Neurotrauma. 2004;21(7):932-43. [PMID: 15307905]
- Dill J, Wang H, Zhou F, Li S. Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. J Neurosci. 2008;28(36):8914-28. [PMID: 18768685]
- Young W. Review of lithium effects on brain and blood. Cell transplantation. 2009;18(9):951-75. [PMID: 19523343]
- Zhu Z, Kremer P, Tadmori I, Ren Y, Sun D, He X, Young W. Lithium Suppresses Astrogliogenesis by Neural Stem and Progenitor Cells by Inhibiting STAT3 Pathway Independently of Glycogen Synthase Kinase 3 Beta. PLoS ONE. 2011;6(9):e23341. [PMID: 21931595]
- Kempton MJ, Geddes JR, Ettinger U, Williams SC, Grasby PM. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry. 2008;65(9):1017-32. [PMID: 18762588]
- Wong YW, Tam S, So KF, Chen JY, Cheng WS, Luk KD, Tang SW, Young W. A three-month, open-label, single-arm trial evaluating the safety and pharmacokinetics of oral lithium in patients with chronic spinal cord injury. Spinal Cord. 2011;49(1):94-8. [PMID: 20531359]
- Yang ML, Li JJ, So KF, Chen JY, Cheng WS, Wu J, Wang ZM, Gao F, Young W. Efficacy and safety of lithium carbonate treatment of chronic spinal cord injuries: a double-blind, randomized, placebo-controlled clinical trial. Spinal Cord. 2011. [PMID: 22105463]