Human umbilical cord-derived mesenchymal stromal cells promote sensory recovery in a spinal cord injury rat model


While paralysis is widely appreciated to impact the quality-of-life after spinal cord injuries (SCIs), neuropathic chronic pain may also occur in many cases. In this study, we investigated whether human umbilical cord-derived mesenchymal stromal cells (hUCMSCs) possess the therapeutic potential to reduce neuropathic pain following SCI in rats. Spinal cord hemitransection, which was used as a rat SCI pain model, induced tactile hypersensitivity in the hind paw and hyperexcitability of wild dynamic range neurons in response to natural cutaneous stimuli. Following hemitransection, we transplanted hUCMSCs into the spinal cord. Attenuation of neuronal hyperexcitability was observed in the hUCMSC-treated group compared with that observed in the vehicle-treated group. Immunohistochemistry showed that the transplanted hUCMSCs retained the expression of gammaamino butyric acid (GABA). The results suggest that transplanted hUCMSCs ameliorate GABAergic inhibition in the spinal cord. In summary, the production of GABA plays a critical role in the plasticity of neuropathic pain after implantation of hUCMSCs.

Share and Cite:

Takikawa, S. , Yamamoto, A. , Sakai, K. , Shohara, R. , Iwase, A. , Kikkawa, F. and Ueda, M. (2013) Human umbilical cord-derived mesenchymal stromal cells promote sensory recovery in a spinal cord injury rat model. Stem Cell Discovery, 3, 155-163. doi: 10.4236/scd.2013.33020.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Baker, D.E., Harrison, N.J., Maltby, E., Smith, K., Moore, H.D., et al. (2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nature Biotechnology, 25, 207-215. doi:10.1038/nbt1285
[2] Erceg, S., Ronaghi, M., Oria, M., Rosello, M.G., Arago, M.A., et al. (2010) Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells, 28, 1541-1549. doi:10.1002/stem.489
[3] Ronaghi, M., Erceg, S., Moreno-Manzano, V. and Stojkovic, M. (2010) Challenges of stem cell therapy for spinal cord injury: Human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells? Stem Cells, 28, 93-99.
[4] Sasaki, M., Radtke, C., Tan, A.M., Zhao, P., Hamada, H., et al. (2009) BDNF-hypersecreting human mesenchymal stem cells promote functional recovery, axonal sprouting, and protection of corticospinal neurons after spinal cord injury. The Journal of Neuroscience, 29, 14932-14941. doi:10.1523/JNEUROSCI.2769-09.2009
[5] Sakai, K., Yamamoto, A., Matsubara, K., Nakamura, S., Naruse, M., et al. (2012) Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. Journal of Clinical Investigation, 122, 80-90.
[6] Mitchell, K.E., Weiss, M.L,, Mitchell, B.M., Martin, P., Davis, D., et al. (2003) Matrix cells from Wharton’s jelly form neurons and glia. Stem Cells, 21, 50-60. doi:10.1634/stemcells.21-1-50
[7] Hu, S.L., Luo, H.S., Li, J.T., Xia, Y.Z., Li, L., et al. (2010) Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Critical Care Medicine, 38, 2181-2189. doi:10.1097/CCM.0b013e3181f17c0e
[8] Shohara, R., Yamamoto, A., Takikawa, S., Iwase, A., Hibi, H., et al. (2012) Mesenchymal stromal cells of human umbilical cord Wharton’s jelly accelerate wound healing by paracrine mechanisms. Cytotherapy, 14, 1171-1181. doi:10.3109/14653249.2012.706705
[9] Yezierski, R.P. (1996) Pain following spinal cord injury: The clinical problem and experimental studies. Pain, 68, 185-194. doi:10.1016/S0304-3959(96)03178-8
[10] Kim, D.S., Jung, S.J., Nam, T.S., Jeon, Y.H., Lee, D.R., et al. (2010) Transplantation of GABAergic neurons from ESCs attenuates tactile hypersensitivity following spinal cord injury. Stem Cells, 28, 2099-2108. doi:10.1002/stem.526
[11] Stubley, L.A., Martinez, M.A., Karmally, S., Lopez, T., Cejas, P., et al. (2001) Only early intervention with gamma-aminobutyric acid cell therapy is able to reverse neuropathic pain after partial nerve injury. Journal of Neurotrauma, 18, 471-477. doi:10.1089/089771501750171092
[12] Fode, C., Ma, Q., Casarosa, S., Ang, S.L., Anderson, D.J., et al. (2000) A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes & Development, 14, 67-80.
[13] Miyoshi, G., Bessho, Y., Yamada, S. and Kageyama, R. (2004) Identification of a novel basic helix-loop-helix gene, Heslike, and its role in GABAergic neurogenesis. The Journal of Neuroscience, 24, 3672-3682. doi:10.1523/JNEUROSCI.5327-03.2004
[14] Glasgow, S.M., Henke, R.M., Macdonald, R.J., Wright, C.V. and Johnson, J.E. (2005) Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development, 132, 5461-5469. doi:10.1242/dev.02167
[15] Karahuseyinoglu, S., Cinar, O., Kilic, E., Kara, F., Akay, G.G., et al. (2007) Biology of stem cells in human umbilical cord stroma: In situ and in vitro surveys. Stem Cells, 25, 319-331. doi:10.1634/stemcells.2006-0286
[16] Sarugaser, R., Lickorish, D., Baksh, D., Hosseini, M.M. and Davies, J.E. (2005) Human umbilical cord perivascular (HUCPV) cells: A source of mesenchymal progenitors. Stem Cells, 23, 220-229. doi:10.1634/stemcells.2004-0166
[17] Weiss, S., Dunne, C., Hewson, J., Wohl, C., Wheatley, M., et al. (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. The Journal of Neuroscience, 16, 7599-7609.
[18] Pastrana, E., Silva-Vargas, V. and Doetsch, F. (2011) Eyes wide open: A critical review of sphere-formation as an assay for stem cells. Cell Stem Cell, 8, 486-498. doi:10.1016/j.stem.2011.04.007
[19] Pitcher, G.M., Ritchie, J. and Henry, J.L. (1999) Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. Journal of Neuroscience Methods, 87, 185-193. doi:10.1016/S0165-0270(99)00004-7
[20] Zhang, L., Zhang, H.T., Hong, S.Q., Ma, X., Jiang, X.D., et al. (2009) Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochemical Research, 34, 2030-2039. doi:10.1007/s11064-009-9992-x
[21] Eaton, M.J., Plunkett, J.A., Martinez, M.A., Lopez, T., Karmally, S., et al. (1999) Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic neuropathic pain. Cell Transplant, 8, 87-101.
[22] Mukhida, K., Mendez, I., McLeod, M., Kobayashi, N., Haughn, C., et al. (2007) Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. Stem Cells, 25, 2874-2885. doi:10.1634/stemcells.2007-0326
[23] Coull, J.A., Boudreau, D., Bachand, K., Prescott, S.A., Nault, F., et al. (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature, 424, 938-942. doi:10.1038/nature01868
[24] Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., et al. (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature, 438, 1017-1021. doi:10.1038/nature04223
[25] Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., et al. (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 424, 778-783. doi:10.1038/nature01786
[26] Lyden, P.D. and Lonzo, L. (1994) Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist. Stroke, 25, 189-196. doi:10.1161/01.STR.25.1.189
[27] Dai, W., Hale, S.L., Martin, B.J., Kuang, J.Q., Dow, J.S., et al. (2005) Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: Short- and long-term effects. Circulation, 112, 214-223. doi:10.1161/CIRCULATIONAHA.104.527937
[28] Kinnaird, T., Stabile, E., Burnett, M.S., Shou, M., Lee, C.W., et al. (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 109, 1543-1549. doi:10.1161/01.CIR.0000124062.31102.57
[29] Cejas, P.J., Martinez, M., Karmally, S., McKillop, M., McKillop, J., et al. (2000) Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction. Pain, 86, 195-210. doi:10.1016/S0304-3959(00)00245-1
[30] Eaton, M.J., Plunkett, J.A., Karmally, S., Martinez, M.A. and Montanez, K. (1998) Changes in GAD- and GABA-immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. Journal of Chemical Neuroanatomy, 16, 57-72. doi:10.1016/S0891-0618(98)00062-3
[31] Llado, J., Haenggeli, C., Maragakis, N.J., Snyder, E.Y. and Rothstein, J.D. (2004) Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Molecular and Cellular Neuroscience, 27, 322-331. doi:10.1016/j.mcn.2004.07.010
[32] Rafuse, V.F., Soundararajan, P., Leopold, C., Robertson, H.A. (2005) Neuroprotective properties of cultured neural progenitor cells are associated with the production of sonic hedgehog. Neuroscience, 131, 899-916. doi:10.1016/j.neuroscience.2004.11.048

Copyright © 2021 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.