Human Neural Stem Cells Induce Central Nervous System Specific Regulatory T Cells From The Extreg Pool And Promote Repair In Models Of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS) and for which there is no cure. Current treatments focus on suppression of the immune system but fail to repair the resulting damage to the CNS. Neural stem cell (NSC) transplantation is a promising therapeutic strategy for treating neurodegenerative diseases through cell replacement and repair however it is unclear how these cells would mediate repair in MS. We report that human NSCs promote CNS specific T regulatory cells (Tregs) which activate endogenous repair pathways and promote remyelination in a murine model of MS. We observed remyelination, decreased inflammation and an increase in (CNS)-infiltrating CD4+CD25+FoxP3+ Tregs in EAE mice receiving an intra-spinal transplant of hNSCs. Recovery was not a result of cell replacement, as hNSCs underwent xenograft rejection, and was Treg dependent, as ablation of Tregs abrogated histopathological improvement. Treg expansion is antigen driven as hNSCs expanded CD25+FoxP3+ Tregs in-vitro when cultured with neural antigen restricted RAG2−/−2D2+ (R2D2) splenocytes but not RAG2−/−OT-II+ splenocytes. When co-cultured with B6 splenocytes, hNSCs drove the expansion of unique TCRs when compared to controls. Additionally, hNSC-Tregs also appear to derive from the exTreg pool suggesting both antigen specific expansion and antigen dependent maintenance of FOXP3 in CNS-specific Tregs. hNSC Tregs also have a unique expression profile and express transglutimase-2 which is implicated in oligodendrocyte dependent repair in the CNS.