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Lithium has long been used to treat people with manic depression. Recently, Yick, et al. [1] from the University of Hong Kong reported that lithium reinforces the regeneration-promoting effects of chondroitinase ABC on rat rubrospinal neurons and strongly stimulates umbilical cord blood mononuclear cells (UCBMC) to proliferate and secrete neurotrophins in vitro and in vivo.
Lithium inhibits glycogen synthetase kinase III beta (GSK3β), which in turn inhibits nuclear factors that upregulate growth and survival genes in cells [2], including Wnt signalling[3], interleukins [4], and other cytokines [5]. Thus, lithium increases stem cell [6] and T-cell proliferation [7], enhances neuronal differentiation [8] but prevents differentiation of neural stem cells [9], increases factor levels in rat brains [10], prevents apoptosis of mouse neural stem cells [11], increases mouse neural progenitor proliferation [12], and enhances survival of human neural stem cells [13].
Umbilical cord blood(UCB) has long been used to treat hematopoietic disorders. It is readily available from banks and there is high probability of finding immune-compatible units. Being safe and available, there were over 8000 unrelated-donor cord blood transplants have been performed worldwide from 1993 to 2006.
Animal studies have shown that UCB cells are beneficial when transplanted shortly after spinal cord injury.
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Intravenous infusion of human UCB improves function in a mouse ALS model[14] and a rat SCI model[15]
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Intraspinal transplants of human CD34+ UCB cells improve recovery in different rat SCI models[15-16] and
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a dog SCI model[17]
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Intraspinal transplants of human CD34+ UCB cells plus BDNF improves recovery in injured rat spinal cords[18]
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Some investigators have reported differentiation of human UCB hUCB to oligodendrocytes and neurons as well as improved functional neurological recovery, strongly suggesting the feasibility and efficacy of the hUCB as a potential therapeutic intervention for SCI.
Recent study [19] found that lithium strongly stimulates umbilical cord blood mononuclear cells to profile and secrete neurotrophins in vitro and in vivo. This suggests that the combination therapy involving umbilical cord blood cell transplants plus lithium may have the better potential in restoring function for SCI than individual therapies.
References
1. Yick LW, So KF, Cheung PT and Wu WT (2004). Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J Neurotrauma. 21:932-43.
2. Phiel CJ and Klein PS (2001). Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 41:789-813.
3. Etheridge SL, Spencer GJ, Heath DJ and Genever PG (2004). Expression profiling and functional analysis of wnt signaling mechanisms in mesenchymal stem cells. Stem Cells. 22:849-60.
4. Merendino RA, Arena A, Gangemi S, Ruello A, Losi E, Bene A and D'Ambrosio FP (2000). In vitro interleukin-8 production by monocytes treated with lithium chloride from breast cancer patients. Tumori. 86:149-52.
5. Merendino RA, Mancuso G, Tomasello F, Gazzara D, Cusumano V, Chillemi S, Spadaro P and Mesiti M (1994). Effects of lithium carbonate on cytokine production in patients affected by breast cancer. J Biol Regul Homeost Agents. 8:88-91.
6. De Boer J, Wang HJ and Van Blitterswijk C (2004). Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng. 10:393-401.
7. Ohteki T, Parsons M, Zakarian A, Jones RG, Nguyen LT, Woodgett JR and Ohashi PS (2000). Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J Exp Med. 192:99-104.
8. Kim JS, Chang MY, Yu IT, Kim JH, Lee SH, Lee YS and Son H (2004). Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J Neurochem. 89:324-36.
9. Aubert J, Dunstan H, Chambers I and Smith A (2002). Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol. 20:1240-5.
10. Hellweg R, Lang UE, Nagel M and Baumgartner A (2002). Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry. 7:604-8.
11. Shimomura A, Nomura R and Senda T (2003). Lithium inhibits apoptosis of mouse neural progenitor cells. Neuroreport. 14:1779-82.
12. Hashimoto R, Senatorov V, Kanai H, Leeds P and Chuang DM (2003). Lithium stimulates progenitor proliferation in cultured brain neurons. Neuroscience. 117:55-61.
13. Willing AE, Zigova T, Milliken M, Poulos S, Saporta S, McGrogan M, Snable G and Sanberg PR (2002). Lithium exposure enhances survival of NT2N cells (hNT neurons) in the hemiparkinsonian rat. Eur J Neurosci. 16:2271-8.
14. Garbuzova-Davis S, et al. Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. Exp Neurol. 2002; 74:169-180
15. Papastefanaki F, et al. Grafts of Schwann cells engineered to express PSA-NCAM promote functional recovery after spinal cord injury. Brain. 130(Pt 8):2159-74, 2007
16. Sparta S, et al. Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. J Hematother Stem Cell Res 12:271-8, 2003
17. Dasari VR, et al. Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma. 24(2):391-410, 2007
18. Zhao ZM ,et al. Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant 13:113-122, 2004
19. 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 Aug;206(2):296-307
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