Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model

Abstract

Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases.

Oligodendroglia: metabolic supporters of neurons

“…The Journal of Clinical Investigation (102). MCT1 was suggested to be mediating the enhanced remyelination, but as the authors used a nonspecific MCT1 inhibitor in this study, the true importance of MCT1 in remyelination remains enigmatic.…”

High-resolution in vivo identification of miRNA targets by Halo-Enhanced Ago2 Pulldown

“…(99) vs. All genes p = 1.7 × 10 -3 p = 5.0 × 10 -5 p = 8.5 × 10 -1 log2 (gliomas / cortices) CDF Among all miRNA families, the miR-219a-5p family had the highest number of targets in gliomas (300 out of 1,878 peaks contained 6mer, 7mer or 8mer seed matches to miR-219a-5p). miR-219-5p has been reported to regulate oligodendrocyte (OL) differentiation and myelination in mice via targeting important regulators of oligodendrocyte progenitor cell (OPC) maintenance (Dugas et al, 2010;Emery, 2010;Fan et al, 2017;Wang et al, 2017;Zhao et al, 2010). Interestingly, we observed a strong interaction between miR-219a-5p and Pdgfra (Figure 4f), a characteristic marker of OPCs and a key player in gliomagenesis.…”

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

“…Mice lacking miR‐219 demonstrate impaired remyelination after lysolecithin‐induced injury, and overexpression of miR‐219 in oligodendrocyte lineage cells is sufficient to promote remyelination (Wang, Moyano, et al, ). Overexpression of miR‐219 in cuprizone‐treated mice also delays demyelination (Liu et al, ), and transplantation of OPCs overexpressing miR‐219 promotes remyelination (Fan et al, ). Furthermore, intrathecal administration of miR‐219 mimics promotes remyelination in both the lysolecithin and experimental autoimmune encephalomyelitis (EAE) mouse models (Wang, Moyano, et al, ).…”