Abstract
BACKGROUND:
Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities.
METHODS:
In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia.
RESULTS:
The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain.
CONCLUSION:
Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.
Similar content being viewed by others
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Ciaramitaro P, Massimi L, Bertuccio A, Solari A, Farinotti M, Peretta P, et al. Diagnosis and treatment of Chiari malformation and syringomyelia in adults: international consensus document. Neurol Sci. 2022;43:1327–42.
Giner J, Pérez López C, Hernández B, Gómez de la Riva Á, Isla A, Roda JM. Update on the pathophysiology and management of syringomyelia unrelated to Chiari malformation. Neurología (Engl Ed). 2019;34:318–25.
Tsitouras V, Sgouros S. Syringomyelia and tethered cord in children. Childs Nerv Syst. 2013;29:1625–34.
Vandertop WP. Syringomyelia. Neuropediatrics. 2014;45:3–9.
Xu N, Xu T, Mirasol R, Holmberg L, Vincent PH, Li X, et al. Transplantation of human neural precursor cells reverses syrinx growth in a rat model of post-traumatic syringomyelia. Neurotherapeutics. 2021;18:1257–72.
Tingting Xu, Li X, Guo Y, Uhlin E, Holmberg L, Mitra S, et al. Multiple therapeutic effects of human neural stem cells derived from induced pluripotent stem cells in a rat model of post-traumatic syringomyelia. EBioMedicine. 2022;77:103882.
Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, et al. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci. 2019;20:2698.
Pereira IM, Marote A, Salgado AJ, Silva NA. Filling the gap: neural stem cells as a promising therapy for spinal cord injury. Pharmaceuticals (Basel). 2019;12:65.
Damianakis EI, Benetos IS, Evangelopoulos DS, Kotroni A, Vlamis J, Pneumaticos SG. Stem cell therapy for spinal cord injury: a review of recent clinical trials. Cureus. 2022;14: e24575.
Vaquero J, Zurita M, Rico MA, Aguayo C, Fernandez C, Rodriguez-Boto G, et al. Cell therapy with autologous mesenchymal stromal cells in post-traumatic syringomyelia. Cytotherapy. 2018;20:796–805.
Xie JL, Wang XR, Li MM, Tao ZH, Teng WW, Saijilafu. Mesenchymal stromal cell therapy in spinal cord injury: mechanisms and prospects. Front Cell Neurosci. 2022;16:862673.
Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Kumamaru H, Yao L, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 2016;22:479–87.
Rosenzweig ES, Brock JH, Lu P, Kumamaru H, Salegio EA, Kadoya K, et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med. 2018;24:484–90.
Ahn H, Lee SY, Jung WJ, Lee KH. Treatment of syringomyelia using uncultured umbilical cord mesenchymal stem cells: a case report and review of literature. World J Stem Cells. 2022;14:303–9.
Zhao Z, Wei Xu, Xie J, Wang Y, Li T, Zhang Y, et al. Bone marrow-derived mesenchymal stem cells (BM-MSCs) inhibit apoptosis of spinal cord cells in a kaolin-induced syringomyelia-associated scoliosis rabbit model. Int J Clin Exp Pathol. 2018;11:1890–9.
Ma L, Yao Q, Zhang C, Li M, Cheng L, Jian F. Chronic extradural compression of spinal cord leads to syringomyelia in rat model. Fluids Barriers CNS. 2020;17:50.
Yuan Y, Tang X, Bai YF, Wang S, An J, Wu Y, et al. Dopaminergic precursors differentiated from human blood-derived induced neural stem cells improve symptoms of a mouse Parkinson’s disease model. Theranostics. 2018;8:4679–94.
Li M, Wang Z, Zheng T, Huang T, Liu B, Han D, et al. characterization of human-induced neural stem cells and derivatives following transplantation into the central nervous system of a nonhuman primate and rats. Stem Cells Int. 2022;2022:1396735.
Meletis K, Barnabe-Heider F, Carlen M, Evergren E, Tomilin N, Shupliakov O, et al. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol. 2008;6: e182.
Carvalho-Paulo D, Bento Torres Neto J, Filho CS, de Oliveira TCG, de Sousa AA, Dos Reis RR, et al. Microglial morphology across distantly related species: phylogenetic, environmental and age influences on microglia reactivity and surveillance states. Front Immunol. 2021;12:683026.
Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39:3–18.
Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2016;53:1181–94.
Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, et al. Transplantation of M2-deviated microglia promotes recovery of motor function after spinal cord injury in mice. Mol Ther. 2020;28:254–65.
Bellver-Landete V, Bretheau F, Mailhot B, Vallieres N, Lessard M, Janelle ME, et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun. 2019;10:518.
Brennan FH, Li Y, Wang C, Ma A, Guo Q, Li Y, et al. Microglia coordinate cellular interactions during spinal cord repair in mice. Nat Commun. 2022;13:4096.
Kohno K, Shirasaka R, Yoshihara K, Mikuriya S, Tanaka K, Takanami K, et al. A spinal microglia population involved in remitting and relapsing neuropathic pain. Science. 2022;376:86–90.
Shenoy VS, Sampath R. Syringomyelia. Treasure Island: StatPearls; 2023.
Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–3.
Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci. 2020;10:112.
de Freria CM, Van Niekerk E, Blesch A, Lu P. Neural stem cells: promoting axonal regeneration and spinal cord connectivity. Cells. 2021;10:3296.
Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, et al. Neural stem/progenitor cell transplantation for spinal cord injury treatment; a systematic review and meta-analysis. Neuroscience. 2016;322:377–97.
Matyas JJ, Stewart AN, Goldsmith A, Nan Z, Skeel RL, Rossignol J, et al. Effects of bone-marrow-derived MSC transplantation on functional recovery in a rat model of spinal cord injury: comparisons of transplant locations and cell concentrations. Cell Transplant. 2017;26:1472–82.
Nelles DG, Hazrati LN. Ependymal cells and neurodegenerative disease: outcomes of compromised ependymal barrier function. Brain Commun. 2022;4:fcac288.
Saunders NR, Liddelow SA, Dziegielewska KM. Barrier mechanisms in the developing brain. Front Pharmacol. 2012;3:46.
Gilbert EAB, Lakshman N, Lau KSK, Morshead CM. Regulating endogenous neural stem cell activation to promote spinal cord injury repair. Cells. 2022;11:846.
Huang F, Gao T, Wang W, Wang L, Xie Y, Tai C, et al. Engineered basic fibroblast growth factor-overexpressing human umbilical cord-derived mesenchymal stem cells improve the proliferation and neuronal differentiation of endogenous neural stem cells and functional recovery of spinal cord injury by activating the PI3K-Akt-GSK-3beta signaling pathway. Stem Cell Res Ther. 2021;12:468.
Barnabe-Heider F, Goritz C, Sabelstrom H, Takebayashi H, Pfrieger FW, Meletis K, et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell. 2010;7:470–82.
Sabelström H, Stenudd M, Réu P, Dias DO, Elfineh M, Zdunek S, Damberg P, Göritz C, Frisén J. Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice. Science. 2013;342:637–40.
Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24:2143–55.
Gregoire CA, Goldenstein BL, Floriddia EM, Barnabe-Heider F, Fernandes KJ. Endogenous neural stem cell responses to stroke and spinal cord injury. Glia. 2015;63:1469–82.
Stenudd M, Sabelstrom H, Frisen J. Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol. 2015;72:235–7.
Brousse B, Mercier O, Magalon K, Daian F, Durbec P, Cayre M. Endogenous neural stem cells modulate microglia and protect against demyelination. Stem Cell Rep. 2021;16:1792–804.
Acknowledgements
This work was supported by the Beijing Municipal Natural Science Foundation [No. 583003]; Beijing Municipal Science and Technology Commission [Grant number: Z191199996619048 and L212007]; the National Natural Science Foundation of China [82171250 and 81973351]; Beijing Talents Foundation [2017000021223TD03]; Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan [CIT and TCD20180333]; Beijing Municipal Health Commission Fund [PXM2020_026283_000005]; Beijing One Hundred, Thousand, and Ten Thousand Talents Fund [2018A03]; and the Royal Society-Newton Advanced Fellowship [NA150482].
Author information
Authors and Affiliations
Contributions
The authors would like to thank XW and BQ for their contribution to the model-building and cell transplantation experiments. We also thank SC for the tissue sectioning and staining, TZ for preparing cells, and YG, LM, SL, QL, ZC, and FJ for their contribution to the design.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ethical statement
The animal studies were performed after receiving approval from the Institutional Animal Care and Use Committee (IACUC) of Xuanwu Hospital Capital Medical University (IACUC approval No. XW-20210723-1).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, M., Wang, X., Qi, B. et al. Treatment of Syringomyelia Characterized by Focal Dilatation of the Central Canal Using Mesenchymal Stem Cells and Neural Stem Cells. Tissue Eng Regen Med (2024). https://doi.org/10.1007/s13770-024-00637-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13770-024-00637-1