Intravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury
Graphical abstract
Introduction
There are approximately 5.3 million people living with the consequences of spinal cord injury (SCI) worldwide (Wyndaele and Wyndaele, 2006, van den Berg et al., 2010, Piltti et al., 2013). Local and segment-limited primary damage to the spinal cord is characterized by the rupture or contusion of axons and the subsequent development of hemorrhage, ischemia, and edema. The damaged area expands considerably during the first weeks due to secondary damage to neuronal and glial cells. The combination of primary and secondary damage results in necrosis with tissue loss and chronic paralysis with sensorimotor disturbances (Schwab et al., 2006).
A promising cell-based therapy in the treatment of SCI using mesenchymal stem cells (MSCs) is currently being investigated. However, most studies have focused on the acute phase of SCI (Tetzlaff et al., 2011). In an acute model of rodent SCI, direct transplantation of MSCs enhances functional recovery, promotes axonal regeneration, reduces lesion size and protects the corticospinal tract (CST) (Sasaki et al., 2009). Intravenous infusion of MSCs also improves functional outcome after acute (Quertainmont et al., 2012, Matsushita et al., 2015) and acute/subacute (Osaka et al., 2010) contusive SCI. However, there are a limited number of studies evaluating treatment efficacy during the chronic phase of SCI (Tetzlaff et al., 2011). It is an important clinical and research issue to develop approaches to provide therapeutic efficacy in chronic SCI.
In this study MSCs derived from bone marrow were intravenously delivered at 10 weeks after SCI to investigate whether systemic injections improve functional outcome after contusive chronic SCI. Evaluation of the behavioral outcome, histological changes, blood spinal cord barrier (BSCB) disruption, remyelination and sprouting of descending axon tracts were performed to study the structural and functional changes after MSC infusion in a model of chronic SCI in rats.
Section snippets
Experimental procedures
All experiments were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised 1996) and the institutional guidelines in Sapporo Medical University. The use of animals in this study was approved by the Animal Care and Use Committee of Sapporo Medical University. All methods and data were reported in accordance with guidelines provided by Animals in Research: Reporting in Vivo Experiments (ARRIVE) and
Behavioral analysis of locomotor function
Open field locomotor activity was assessed with the BBB scoring scale at 2 days before and weekly up to 20 weeks after SCI induction (Fig. 1). Before SCI induction, BBB scores had a value of 21. All animals demonstrated near-complete hind limb paraplegia immediately after SCI and then exhibited a gradual improvement that plateaued 6 weeks after injury. To examine whether infused MSCs improved functional outcome after chronic SCI, we randomized the rats and performed intravenous administration of
Discussion
In the present study, we demonstrated that intravenous administration of MSCs in the chronic phase of a severe contusive SCI model in the rat improved locomotor function. A precise definition of the chronic phase of SCI has not been established (Piltti et al., 2013). In our model, a severe contusive SCI was induced and spontaneous motor recovery was observed over several weeks. Spontaneous recovery peaked at about 6 week’s post-SCI and reached a persistent plateau. We chose 10 weeks after SCI as
Conclusion
In summary, intravenous infusion of MSCs resulted in improved locomotor function in chronic and severe SCI model in rats. There was a therapeutic effect of MSC administration even when administered 10 weeks after SCI induction. The therapeutic mechanisms include attenuation of BSCB disruption, sprouting and regeneration and remyelination of fiber tracts in the injured spinal cord. Thus, a cell-based MSC therapy may have therapeutic value in not only the acute phase following SCI, but also the
Acknowledgments
This work was supported in part by JSPS KAKENHI, Japan grant Numbers 26462213, 24890181, 25462227, 25462226, 16K10794, the AMED Translational Research Network Program (B51), the RR&D Service of U.S. Department of Veterans Affairs (B7335R, B9260L), the National Multiple Sclerosis Society (RG2135), and the Connecticut (CT) Stem Cell Research Program (12-SCB-Yale-05). We are thankful to the National BioResource Project – Rat (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing this strain of rat
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