Skip to main content
SpringerLink
Log in

Allotransplantation of adult spinal cord tissues after complete transected spinal cord injury: Long-term survival and functional recovery in canines

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Spinal cord injury (SCI), especially complete transected SCI, leads to loss of cells and extracellular matrix and functional impairments. In a previous study, we transplanted adult spinal cord tissues (aSCTs) to replace lost tissues and facilitate recovery in a rat SCI model. However, rodents display considerable differences from human patients in the scale, anatomy and functions of spinal cord systems, and responses after injury. Thus, use of a large animal SCI model is required to examine the repair efficiency of potential therapeutic approaches. In this study, we transplanted allogenic aSCTs from adult dogs to the lesion area of canines after complete transection of the thoracic spinal cord, and investigated the long-term cell survival and functional recovery. To enhance repair efficiency, a growth factor cocktail was added during aSCT transplantation, providing a favorable microenvironment. The results showed that transplantation of aSCTs, in particular with the addition of growth factors, significantly improves locomotor function restoration and increases the number of neurofilament-, microtubule-associated protein 2-, 5-hydroxytryptamine-, choline acetyltransferase- and tyrosine hydroxylase-positive neurons in the lesion area at 6 months post-surgery. In addition, we demonstrated that donor neurons in aSCTs can survive for a long period after transplantation. This study showed for the first time that transplanting aSCTs combined with growth factor supplementation facilitates reconstruction of injured spinal cords, and consequently promotes long lasting motor function recovery in a large animal complete transected SCI model, and therefore could be considered as a possible therapeutic strategy in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Barber, R.P., Phelps, P.E., and Vaughn, J.E. (1991). Generation patterns of immunocytochemically identified cholinergic neurons at autonomic levels of the rat spinal cord. J Comp Neurol 311, 509–519.

    Article  CAS  Google Scholar 

  • Bonner, J.F., and Steward, O. (2015). Repair of spinal cord injury with neuronal relays: From fetal grafts to neural stem cells. Brain Res 1619, 115–123.

    Article  CAS  Google Scholar 

  • Bregman, B.S., McAtee, M., Dai, H.N., and Kuhn, P.L. (1997). Neurotrophic factors increase axonal growth after spinal cord injury and transplantation in the adult rat. Exp Neurol 148, 475–494.

    Article  CAS  Google Scholar 

  • Coumans, J.V., Lin, T.T.S., Dai, H.N., MacArthur, L., McAtee, M., Nash, C., and Bregman, B.S. (2001). Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci 21, 9334–9344.

    Article  CAS  Google Scholar 

  • Fan, C., Li, X., Zhao, Y., Xiao, Z., Xue, W., Sun, J., Li, X., Zhuang, Y., Chen, Y., and Dai, J. (2018). Cetuximab and Taxol co-modified collagen scaffolds show combination effects for the repair of acute spinal cord injury. Biomater Sci 6, 1723–1734.

    Article  CAS  Google Scholar 

  • Gulino, R., Litrico, L., and Leanza, G. (2010). Long-term survival and development of fetal ventral spinal grafts into the motoneuron-depleted rat spinal cord: Role of donor age. Brain Res 1323, 41–47.

    Article  CAS  Google Scholar 

  • Han, S., Wang, B., Jin, W., Xiao, Z., Chen, B., Xiao, H., Ding, W., Cao, J., Ma, F., Li, X., et al. (2014). The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. Spinal Cord 52, 867–873.

    Article  CAS  Google Scholar 

  • Han, S., Wang, B., Jin, W., Xiao, Z., Li, X., Ding, W., Kapur, M., Chen, B., Yuan, B., Zhu, T., et al. (2015). The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials 41, 89–96.

    Article  CAS  Google Scholar 

  • Han, S., Li, X., Xiao, Z., and Dai, J. (2018a). Complete canine spinal cord transection model: A large animal model for the translational research of spinal cord regeneration. Sci China Life Sci 61, 115–117.

    Article  Google Scholar 

  • Han, S., Xiao, Z., Li, X., Zhao, H., Wang, B., Qiu, Z., Li, Z., Mei, X., Xu, B., Fan, C., et al. (2018b). Human placenta-derived mesenchymal stem cells loaded on linear ordered collagen scaffold improves functional recovery after completely transected spinal cord injury in canine. Sci China Life Sci 61, 2–13.

    Article  CAS  Google Scholar 

  • Hellal, F., Hurtado, A., Ruschel, J., Flynn, K.C., Laskowski, C.J., Umlauf, M., Kapitein, L.C., Strikis, D., Lemmon, V., Bixby, J., et al. (2011). Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931.

    Article  CAS  Google Scholar 

  • Horner, P.J., Reier, P.J., and Stokes, B.T. (1996). Quantitative analysis of vascularization and cytochrome oxidase following fetal transplantation in the contused rat spinal cord. J Comp Neurol 364, 690–703.

    Article  CAS  Google Scholar 

  • Jakeman, L.B., and Reier, P.J. (2015). Fetal spinal cord transplantation after spinal cord injury: Around and back again. Neural Regener, 351–365.

  • Li, X., Liu, S., Zhao, Y., Li, J., Ding, W., Han, S., Chen, B., Xiao, Z., and Dai, J. (2016). Training neural stem cells on functional collagen scaffolds for severe spinal cord injury repair. Adv Funct Mater 26, 5835–5847.

    Article  CAS  Google Scholar 

  • Li, X., Zhao, Y., Cheng, S., Han, S., Shu, M., Chen, B., Chen, X., Tang, F., Wang, N., Tu, Y., et al. (2017). Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair. Biomaterials 137, 73–86.

    Article  CAS  Google Scholar 

  • Lin, H. (2019). Transplantation of adult spinal cord tissue: Transection spinal cord repair and potential clinical translation. Sci China Life Sci 62, 870–872.

    Article  Google Scholar 

  • Lynskey, J.V., Sandhu, F.A., Sandhu, F.A., Dai, H.N., Dai, H.N., McAtee, M., Slotkin, J.R., Slotkin, J.R., MacArthur, L., and Bregman, B.S. (2006). Delayed intervention with transplants and neurotrophic factors supports recovery of forelimb function after cervical spinal cord injury in adult rats. J Neurotrauma 23, 617–634.

    Article  Google Scholar 

  • Meletis, K., Barnabé-Heider, F., Carlén, M., Evergren, E., Tomilin, N., Shupliakov, O., and Frisén, J. (2008). Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol 6, e182.

    Article  Google Scholar 

  • Mothe, A.J., and Tator, C.H. (2005). Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience 131, 177–187.

    Article  CAS  Google Scholar 

  • Nout, Y.S., Rosenzweig, E.S., Brock, J.H., Strand, S.C., Moseanko, R., Hawbecker, S., Zdunowski, S., Nielson, J.L., Roy, R.R., Courtine, G., et al. (2012). Animal models of neurologic disorders: A nonhuman primate model of spinal cord injury. Neurotherapeutics 9, 380–392.

    Article  CAS  Google Scholar 

  • Nygren, L.G., Olson, L., and Seiger, Å. (1977). Monoaminergic reinnervation of the transected spinal cord by homologous fetal brain grafts. Brain Res 129, 227–235.

    Article  CAS  Google Scholar 

  • Olby, N., Harris, T., Burr, J., Muñana, K., Sharp, N., and Keene, B. (2004). Recovery of pelvic limb function in dogs following acute intervertebral disc herniations. J Neurotrauma 21, 49–59.

    Article  Google Scholar 

  • Pellegata, A.F., Tedeschi, A.M., and De Coppi, P. (2018). Whole organ tissue vascularization: Engineering the tree to develop the fruits. Front Bioeng Biotechnol 6, 56.

    Article  Google Scholar 

  • Ramer, L.M., Ramer, M.S., and Bradbury, E.J. (2014). Restoring function after spinal cord injury: Towards clinical translation of experimental strategies. Lancet Neurol 13, 1241–1256.

    Article  Google Scholar 

  • Reier, P.J., Perlow, M.J., and Guth, L. (1983). Development of embryonic spinal cord transplants in the rat. Dev Brain Res 10, 201–219.

    Article  Google Scholar 

  • Reier, P.J. (1985). Neural tissue grafts and repair of the injured spinal cord. Neuropathol Appl Neurobiol 11, 81–104.

    Article  CAS  Google Scholar 

  • Reier, P.J., Bregman, B.S., and Wujek, J.R. (1986). Intraspinal transplantation of embyronic spinal cord tissue in neonatal and adult rats. J Comp Neurol 247, 275–296.

    Article  CAS  Google Scholar 

  • Reier, P.J., Houle, J.D., Jakeman, L., Winialski, D., and Tessler, A. (1988). Transplantation of fetal spinal cord tissue into acute and chronic hemisection and contusion lesions of the adult rat spinal cord. Progress in Brain Research 78, 173–179.

    Article  CAS  Google Scholar 

  • Sheard, P., McCaig, C.D., and Harris, A.J. (1984). Critical periods in rat motoneuron development. Dev Biol 102, 21–31.

    Article  CAS  Google Scholar 

  • Shen, H., Chen, X., Li, X., Jia, K., Xiao, Z., and Dai, J. (2019). Transplantation of adult spinal cord grafts into spinal cord transected rats improves their locomotor function. Sci China Life Sci 62, 725–733.

    Article  Google Scholar 

  • Wu, G.H., Shi, H.J., Che, M.T., Huang, M.Y., Wei, Q.S., Feng, B., Ma, Y. H., Wang, L.J., Jiang, B., Wang, Y.Q., et al. (2018). Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue. Biomaterials 181, 15–34.

    Article  CAS  Google Scholar 

  • Yin, W., Li, X., Zhao, Y., Tan, J., Wu, S., Cao, Y., Li, J., Zhu, H., Liu, W., Tang, G., et al. (2018). Taxol-modified collagen scaffold implantation promotes functional recovery after long-distance spinal cord complete transection in canines. Biomater Sci 6, 1099–1108.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81891002 and 81971178), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16040700), the National Key Research and Development Program of China (2017YFA0104701, 2017YFA0104704, 2016YFC1101501 and 2016YFC1101502).

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China

    He Shen, Yan Zhuang & Jianwu Dai

  2. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China

    He Shen, Xi Chen, Bai Xu, Dezun Ma, Yannan Zhao, Bing Chen, Xianglin Hou, Jiayin Li, Ya Shi, Zhifeng Xiao & Jianwu Dai

  3. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China

    Shuyu Wu, Yudong Cao, Xianyong Fu, Jun Tan, Wen Yin, Juan Li & Xingjun Jiang

  4. Shigatse Branch, Xinqiao Hospital, Army Medical University (Third Military Medical University), Shigatse, 857000, China

    Xi Chen

  5. Department of Radiology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Li Meng

Authors
  1. He Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dezun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yannan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xianglin Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiayin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yudong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xianyong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wen Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Juan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Li Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ya Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Zhifeng Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Xingjun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jianwu Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhifeng Xiao, Xingjun Jiang or Jianwu Dai.

Ethics declarations

Compliance and ethics The author(s) declare that they have no conflict of interest. Animals were used with the approval of Animal Care and Use Committee of Institute of Genetics and Developmental Biology, the Chinese Academy of Sciences and Xiangya Hospital. Animal experiments were conducted in accordance with Guide for the Care and Use of Laboratory Animals from National Institutes of Health.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, H., Wu, S., Chen, X. et al. Allotransplantation of adult spinal cord tissues after complete transected spinal cord injury: Long-term survival and functional recovery in canines. Sci. China Life Sci. 63, 1879–1886 (2020). https://doi.org/10.1007/s11427-019-1623-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-019-1623-5

Keywords

Search

Navigation