Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord.
The transplantation of neural stem/progenitor cells (NPCs) is a promising therapeutic strategy for spinal cord injury (SCI). However, to date NPC transplantation has exhibited only limited success in the treatment of chronic SCI. Here, we show that chondroitin sulfate proteoglycans (CSPGs) in the glial scar around the site of chronic SCI negatively influence the long-term survival and integration of transplanted NPCs and their therapeutic potential for promoting functional repair and plasticity. We targeted CSPGs in the chronically injured spinal cord by sustained infusion of chondroitinase ABC (ChABC). One week later, the same rats were treated with transplants of NPCs and transient infusion of growth factors, EGF, bFGF, and PDGF-AA. We demonstrate that perturbing CSPGs dramatically optimizes NPC transplantation in chronic SCI. Engrafted NPCs successfully integrate and extensively migrate within the host spinal cord and principally differentiate into oligodendrocytes. Furthermore, this combined strategy promoted the axonal integrity and plasticity of the corticospinal tract and enhanced the plasticity of descending serotonergic pathways. These neuroanatomical changes were also associated with significantly improved neurobehavioral recovery after chronic SCI. Importantly, this strategy did not enhance the aberrant synaptic connectivity of pain afferents, nor did it exacerbate posttraumatic neuropathic pain. For the first time, we demonstrate key biological and functional benefits for the combined use of ChABC, growth factors, and NPCs to repair the chronically injured spinal cord. These findings could potentially bring us closer to the application of NPCs for patients suffering from chronic SCI or other conditions characterized by the formation of a glial scar.
Division of Genetics and Development, Toronto Western Research Institute and Krembil Neuroscience Center, University Health Network, Toronto, Ontario M5T 2S8, Canada. karimis@cc.umanitoba.ca
Soheila
S
Karimi-Abdolrezaee
Eftekhar
E
Eftekharpour
Jian
J
Wang
Desiree
D
Schut
Michael G
MG
Fehlings
D053687:Adult Stem Cells / Q000637:transplantation*; D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D002810:Chondroitinases and Chondroitin Lyases / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D009474:Neurons / Q000637:transplantation*; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*
D036341:Intercellular Signaling Peptides and Proteins; D002810:Chondroitinases and Chondroitin Lyases