Main Article Content
Introduction: Despite decades of extensive research, spinal cord injury (SCI) remains a complex health burden mainly affecting active patients and may cause a catastrophic permanent paralysis of the limbs (tetraplegia) and might even result in death. The current treatments are not sufficient to repair such damage. The development and discovery of the treatments that are capable of inducing the regeneration of axonal functions are hindered by the injured spinal cord’s limited neuroplasticity. Mesenchymal stem cells (MSCs) are ideal transplantable cells which have been shown to modulate the injury cascade of SCI mostly through paracrine effects.
Objective: This systematic review and meta-analysis aimed to investigate the association between the MSCs treatment and neuroregenerative effects in the SCI model-rodents by assessing the locomotor development based on Basso-Beattie-Bresnahan (BBB)/Basso Mice Scale (BMS) locomotor rating scale.
Materials and Methods: This meta-analysis was reported based on criteria from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A literature search was conducted with multiple electronic databases, such as PubMed, ScienceDirect, Scopus, Google Scholar. Mean Difference (MD) and Standard Deviation (SD) with the confidence interval (CI) of 95% were used to determine the association between MSCs therapy and the increase in the BBB scale after SCI. Fixed and Random Effect Model was used based on heterogeneity level and p value<0.05 was considered statistically significant. Risk of biases were assessed for each study using Cochrane Risk of Bias (RoB) tool developed by the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE).
Results: Twenty studies were included in the qualitative synthesis, and eleven studies were included in the quantitative meta-analysis. The current study showed that MSCs therapy for SCI was very beneficial (pooled MD=4.71, 95% CI (3.86-5.55), p=0.006, I2=59%).
Conclusion: This systematic review and meta-analysis provide valuable evidence suggesting MSCs as a potential treatment for SCI.
Keywords: Spinal cord injury, MSCs, regenerative medicine, systematic review, meta-analysis
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
© Journal of Asian Medical Students’ Association (JAMSA). Released under a Creative Commons license.
Haider T, Höftberger R, Rüger B, Mildner M, Blumer R, Mitterbauer A et al. The secretome of
apoptotic human peripheral blood mononuclear cells attenuates secondary damage following
spinal cord injury in rats. Experimental Neurology. 2015;267:230-242.
Willis CM, Nicaise AM, Peruzzotti-Jametti L, Pluchino S The neural stem cell secretome and
its role in brain repair. Brain Res. 2020. 1729:146615.
Pajer K, Bellák T, Nógrádi A. The mutual interaction between the host spinal cord and grafted
undifferentiated stem cells fosters the production of a lesion-induced secretome. Neural
Regeneration Research. 2020;15(10):1844.
Liu J, Yang X, Jiang L, Wang C, Yang M. Neural plasticity after spinal cord injury. Neural
regeneration research. 2012;7:386-391.
Wang H, Song G, Chuang H, Chiu C, Abdelmaksoud A, Ye Y et al. Portrait of glial scar in
neurological diseases. International Journal of Immunopathology and Pharmacology.
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;322:377-397.
Khan S, Mafi P, Mafi R, Khan W. A Systematic Review of Mesenchymal Stem Cells in Spinal
Cord Injury, Intervertebral Disc Repair and Spinal Fusion. Current Stem Cell Research &
Qin C, Guo Y, Yang D, Yang M, Du L, Li J. Induced Pluripotent Stem Cell Transplantation
Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cellular Physiology and Biochemistry.
Xu P, Yang X. The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal
Cord Injury Patients: A Meta-Analysis and Systematic Review. Cell Transplantation.
Veneruso V, Rossi F, Villella A, Bena A, Forloni G, Veglianese P. Stem cell paracrine effect
and delivery strategies for spinal cord injury regeneration. Journal of Controlled Release.
Sharif-Alhoseini M, Khormali M, Rezaei M, Safdarian M, Hajighadery A, Khalatbari M et al.
Animal models of spinal cord injury: a systematic review. Spinal Cord. 2017;55(8):714-721.
BASSO D, BEATTIE M, BRESNAHAN J. A Sensitive and Reliable Locomotor Rating Scale
for Open Field Testing in Rats. Journal of Neurotrauma. 1995;12(1):1-21.
Barros Filho T, Molina A. Analysis of the sensitivity and reproducibility of the Basso, Beattie,
Bresnahan (BBB) scale in wistar rats. Clinics. 2008;63(1):103-108.
Basso D, Fisher L, Anderson A, Jakeman L, Mctigue D, Popovich P. Basso Mouse Scale for
Locomotion Detects Differences in Recovery after Spinal Cord Injury in Five Common Mouse
Strains. Journal of Neurotrauma. 2006;23(5):635-659.
Borges P, Cristante A, Barros-Filho T, Natalino R, Santos G, Marcon R. Standardization of a
spinal cord lesion model and neurologic evaluation using mice. Clinics. 2018;73:1-6.
Oliveri R, Bello S, Biering-Sørensen F. Mesenchymal stem cells improve locomotor recovery
in traumatic spinal cord injury: Systematic review with meta-analyses of rat models.
Neurobiology of Disease. 2014;62:338-353.
Gollie J, Guccione A. Overground Locomotor Training in Spinal Cord Injury: A PerformanceBased Framework. Topics in Spinal Cord Injury Rehabilitation. 2017;23(3):226-233.
Basso D. Behavioral Testing After Spinal Cord Injury: Congruities, Complexities, and
Controversies. Journal of Neurotrauma. 2004;21(4):395-404.
Hooijmans C, Rovers M, de Vries R, Leenaars M, Ritskes-Hoitinga M, Langendam M.
SYRCLE’s risk of bias tool for animal studies. BMC Medical Research Methodology.
Ramalho BDS, De Almeida FM, Sales CM, De Lima S, Martinez AMB. Injection of bone
marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative
to spinal cord injury treatment in mice. Neural Regen Res. 2018;13(6):1046–53.
Tian T, Yu Z, Zhang N, Chang Y, Zhang Y, Zhang L, et al. Modified acellular nerve-delivering
PMSCs improve functional recovery in rats after complete spinal cord transection. Biomater
Sci. 2017;5(12):2480–92. 22. Tsai M-J, Liou D-Y, Lin Y-R, Weng C-F, Huang M-C, Huang W-C, et al. Attenuating Spinal
Cord Injury by Conditioned Medium from Bone Marrow Mesenchymal Stem Cells. J Clin Med.
Zeng X, Qiu XC, Ma YH, Duan JJ, Chen YF, Gu HY, et al. Integration of donor mesenchymal
stem cell-derived neuron-like cells into host neural network after rat spinal cord transection.
Biomaterials [Internet]. 2015;53:184–201. Available from:
Yang EZ, Zhang GW, Xu JG, Chen S, Wang H, Cao LL, et al. Multichannel polymer scaffold
seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal
regeneration and functional recovery after rat spinal cord injury. Acta Pharmacol Sin [Internet].
;38(5):623–37. Available from: http://dx.doi.org/10.1038/aps.2017.11
Feng L, Gan H, Zhao W, Liu Y. Effect of transplantation of olfactory ensheathing cell
conditioned medium induced bone marrow stromal cells on rats with spinal cord injury. Mol
Med Rep. 2017;16(2):1661–8.
Cizkova D, Cubinkova V, Smolek T, Murgoci AN, Danko J, Vdoviakova K, et al. Localized
intrathecal delivery of mesenchymal stromal cells conditioned medium improves functional
recovery in a rat model of spinal cord injury. Int J Mol Sci. 2018;19(3):1–13.
Lindsay SL, Toft A, Griffin J, M. M. Emraja A, Barnett SC, Riddell JS. Human olfactory
mesenchymal stromal cell transplants promote remyelination and earlier improvement in gait
co-ordination after spinal cord injury. Glia. 2017;65(4):639–56.
Lu Y, Zhou Y, Zhang R, Wen L, Wu K, Li Y, et al. Bone Mesenchymal Stem Cell-Derived
Extracellular Vesicles Promote Recovery Following Spinal Cord Injury via Improvement of
the Integrity of the Blood-Spinal Cord Barrier. Front Neurosci. 2019;13.
Munter JP d., Beugels J, Munter S, Jansen L, Cillero-Pastor B, Moskvin O, et al. Standardized
human bone marrow-derived stem cells infusion improves survival and recovery in a rat model
of spinal cord injury. J Neurol Sci [Internet]. 2019;402:16–29.
Amemori T, Jendelová P, Růžičková K, Arboleda D, Syková E. Co-transplantation of olfactory
ensheathing glia and mesenchymal stromal cells does not have synergistic effects after spinal
cord injury in the rat. Cytotherapy. 2010;12(2):212-225.
Galhom RA, Hussein Abd El Raouf HH, Mohammed Ali MH. Role of bone marrow derived
mesenchymal stromal cells and Schwann-like cells transplantation on spinal cord injury in adult
male albino rats. Biomed Pharmacother[Internet].2018;108(September):1365–75. Available
Krupa P, Vackova I, Ruzicka J, Zaviskova K, Dubisova J, Koci Z, et al. The effect of human
mesenchymal stem cells derived from Wharton’s Jelly in spinal cord injury treatment is dosedependent and can be facilitated by repeated application. Int J Mol Sci. 2018;19(5).33. Matsushita T, Lankford KL, Arroyo EJ, Sasaki M, Neyazi M, Radtke C, et al. Diffuse and
persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly
recovers following intravenous infusion of bone marrow mesenchymal stem cells. Exp Neurol
Stewart A, Kendziorski G, Deak Z, Brown D, Fini M, Copely K et al. Co-transplantation of
mesenchymal and neural stem cells and overexpressing stromal-derived factor-1 for treating
spinal cord injury. Brain Research. 2017;1672:91-105.
Muniswami DM, Kanthakumar P, Kanakasabapathy I, Tharion G. Motor recovery after
transplantation of bone marrow mesenchymal stem cells in rat models of spinal cord injury.
Ann Neurosci. 2018;25(3):126–40.
Ning GZ, Song WY, Xu H, Zhu R Sen, Wu QL, Wu Y, et al. Bone marrow mesenchymal stem
cells stimulated with low-intensity pulsed ultrasound: Better choice of transplantation treatment
for spinal cord injury: Treatment for SCI by LIPUS-BMSCs transplantation. CNS Neurosci
Okuda A, Horii-Hayashi N, Sasagawa T, Shimizu T, Shigematsu H, Iwata E, et al. Bone
marrow stromal cell sheets may promote axonal regeneration and functional recovery with
suppression of glial scar formation after spinal cord transection injury in rats. J Neurosurg
Seo DK, Kim JH, Min J, Yoon HH, Shin ES, Kim SW, et al. Enhanced axonal regeneration by
transplanted Wnt3a-secreting human mesenchymal stem cells in a rat model of spinal cord
injury. Acta Neurochir (Wien). 2017;159(5):947–57.
Song JL, Zheng W, Chen W, Qian Y, Ouyang YM, Fan CY. Lentivirus-mediated microRNA124 gene-modified bone marrow mesenchymal stem cell transplantation promotes the repair of
spinal cord injury in rats. Exp Mol Med [Internet]. 2017;49(5):e332-