Human placenta-derived mesenchymal stem cells loaded on linear ordered collagen scaffold improves functional recovery after completely transected spinal cord injury in canine
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Traumatic spinal cord injury (SCI) is a major challenge in the clinic. In this study, we sought to examine the synergistic effects of linear ordered collagen scaffold (LOCS) and human placenta-derived mesenchymal stem cells (hPMSCs) when transplanted into completely transected beagle dogs. After 36 weeks observation, we found that LOCS+hPMSCs implants promoted better hindlimb locomotor recovery than was observed in the non-treatment (control) group and LOCS group. Histological analysis showed that the regenerated tissue after treatment was well integrated with the host tissue, and dramatically reduced the volume of cystic and chondroitin sulfate proteoglycans (CSPGs) expression. Furthermore, the LOCS+hPMSCs group also showed more neuron-specific βIII-tubulin (Tuj-1)- and NeuN-positive neurons in the lesion area, as well as axonal regeneration, remyelination and synapse formation in the lesion site. Additionally, dogs in the LOCS+hPMSCs group experienced enhanced sprouting of both ascending (CGRP-positive) sensory fibers and descending (5-HT- and TH-positive) motor fibers at the lesion area. All these data together suggested that the combined treatment had beneficial effects on neuronal regeneration and functional improvement in a canine complete transection model. Therefore, LOCS+hPMSCs implantation holds a great promise for bridging the nerve defect and may be clinically useful in the near future.
Keywordsspinal cord injury hPMSCs LOCS canine regeneration
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This work was supported by the “Strategic Priority Research Program of the Chinese Academy of Sciences” (XDA01030000), the key Research Program of the Chinese Academy of Sciences (ZDRW-ZS-2016-2), the National Natural Science Foundation of China (81572131, 81571213), the Natural Science Foundation of Jiangsu Province (BL2012004, BK20151210), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the key Research and Development Program of Ministry of Science and Technology (2016YFC1101500).
- Assunção-Silva, R.C., Gomes, E.D., Sousa, N., Silva, N.A., and Salgado, A.J. (2015). Hydrogels and cell based therapies in spinal cord injury regeneration. Stem Cells Int doi: 10.1155/2015/948040.Google Scholar
- Bartholomew, A., Sturgeon, C., Siatskas, M., Ferrer, K., McIntosh, K., Patil, S., Hardy, W., Devine, S., Ucker, D., Deans, R., Moseley, A., and Hoffman, R. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30, 42–48.CrossRefPubMedGoogle Scholar
- Cao, J., Sun, C., Zhao, H., Xiao, Z., Chen, B., Gao, J., Zheng, T., Wu, W., Wu, S., Wang, J., and Dai, J. (2011). The use of laminin modified linear ordered collagen scaffolds loaded with laminin-binding ciliary neurotrophic factor for sciatic nerve regeneration in rats. Biomaterials 32, 3939–3948.CrossRefPubMedGoogle Scholar
- Cao, Q., Xu, X.M., Devries, W.H., Enzmann, G.U., Ping, P., Tsoulfas, P., Wood, P.M., Bunge, M.B., and Whittemore, S.R. (2005). Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25, 6947–6957.CrossRefPubMedPubMedCentralGoogle Scholar
- Courtine, G., Gerasimenko, Y., van den Brand, R., Yew, A., Musienko, P., Zhong, H., Song, B., Ao, Y., Ichiyama, R.M., Lavrov, I., Roy, R.R., Sofroniew, M.V., and Edgerton, V.R. (2009). Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat Neurosci 12, 1333–1342.CrossRefPubMedPubMedCentralGoogle Scholar
- Ding, Y., Yan, Q., Ruan, J.W., Zhang, Y.Q., Li, W.J., Zhang, Y.J., Li, Y., Dong, H., and Zeng, Y.S. (2009). Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats. BMC Neurosci 10, 35.CrossRefPubMedPubMedCentralGoogle Scholar
- Du, B.L., Zeng, X., Ma, Y.H., Lai, B.Q., Wang, J.M., Ling, E.A., Wu, J.L., and Zeng, Y.S. (2015). Graft of the gelatin sponge scaffold containing genetically-modified neural stem cells promotes cell differentiation, axon regeneration, and functional recovery in rat with spinal cord transection. J Biomed Mater Res A 103, 1533–1545.CrossRefPubMedGoogle Scholar
- Han, Q., Jin, W., Xiao, Z., Ni, H., Wang, J., Kong, J., Wu, J., Liang, W., Chen, L., Zhao, Y., Chen, B., and Dai, J. (2010). The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an EGFR neutralizing antibody. Biomaterials 31, 9212–9220.CrossRefPubMedGoogle Scholar
- Han, S., Wang, B., Jin, W., Xiao, Z., Li, X., Ding, W., Kapur, M., Chen, B., Yuan, B., Zhu, T., Wang, H., Wang, J., Dong, Q., Liang, W., and Dai, J. (2015). The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials 41, 89–96.CrossRefPubMedGoogle Scholar
- Hiruma, H., Saito, A., Ichikawa, T., Kiriyama, Y., Hoka, S., Kusakabe, T., Kobayashi, H., and Kawakami, T. (2000). Effects of substance P and calcitonin gene-related peptide on axonal transport in isolated and cultured adult mouse dorsal root ganglion neurons. Brain Res 883, 184–191.CrossRefPubMedGoogle Scholar
- Hsieh, J.Y., Wang, H.W., Chang, S.J., Liao, K.H., Lee, I.H., Lin, W.S., Wu, C.H., Lin, W.Y., and Cheng, S.M. (2013). Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS ONE 8, e72604.CrossRefPubMedPubMedCentralGoogle Scholar
- Jiang, Y., Jahagirdar, B.N., Reinhardt, R.L., Schwartz, R.E., Keene, C.D., Ortiz-Gonzalez, X.R., Reyes, M., Lenvik, T., Lund, T., Blackstad, M., Du, J., Aldrich, S., Lisberg, A., Low, W.C., Largaespada, D.A., and Verfaillie, C.M. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49.CrossRefPubMedGoogle Scholar
- Lukovic, D., Moreno-Manzano, V., Lopez-Mocholi, E., Rodriguez-Jiménez, F.J., Jendelova, P., Sykova, E., Oria, M., Stojkovic, M., and Erceg, S. (2015). Complete rat spinal cord transection as a faithful model of spinal cord injury for translational cell transplantation. Sci Rep 5, 9640.CrossRefPubMedPubMedCentralGoogle Scholar
- Sharp, K.G., Dickson, A.R., Marchenko, S.A., Yee, K.M., Emery, P.N., Laidmåe, I., Uibo, R., Sawyer, E.S., Steward, O., and Flanagan, L.A. (2012). Salmon fibrin treatment of spinal cord injury promotes functional recovery and density of serotonergic innervation. Exp Neurol 235, 345–356.CrossRefPubMedPubMedCentralGoogle Scholar
- Shi, Q., Gao, W., Han, X.L., Zhu, X.S., Sun, J., Xie, F., Hou, X.L., Yang, H.L., Dai, J.W., and Chen, L. (2014). Collagen scaffolds modified with collagen-binding bFGF promotes the neural regeneration in a rat hemisected spinal cord injury model. Sci China Life Sci 57, 232–240.CrossRefPubMedGoogle Scholar
- Thompson, C.K., Jayaraman, A., Kinnaird, C., and Hornby, T.G. (2011). Methods to quantify pharmacologically induced alterations in motor function in human incomplete SCI. J Vis Exp doi: 10.3791/2148.Google Scholar
- Xiao, Z., Tang, F., Tang, J., Yang, H., Zhao, Y., Chen, B., Han, S., Wang, N., Li, X., Cheng, S., Han, G., Zhao, C., Yang, X., Chen, Y., Shi, Q., Hou, S., Zhang, S., and Dai, J. (2016). One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci 59, 647–655.CrossRefPubMedGoogle Scholar