White-Matter Repair as a Novel Therapeutic Target for Early Adversity

Early adversity (EA) impairs myelin development in a manner that persists later in life across diverse mammalian species including humans, non-human primates, and rodents. These observations, coupled with the highly conserved nature of myelin development suggest that animal models can provide important insights into the molecular mechanisms by which EA impairs myelin development later in life and the impact of these changes on network connectivity, cognition, and behavior. However, this area of translational research has received relatively little attention and no comprehensive review is currently available to address these issues. This is particularly important given some recent mechanistic studies in rodents and the availability of new agents to increase myelination. The goals of this review are to highlight the need for additional pre-clinical work in this area and to provide specific examples that demonstrate the potential of this work to generate novel therapeutic interventions that are highly needed.

Abstract TMP30: M2 Microglia Derived Exosomes Promote White Matter Repair and Long-Term Functional Recovery After Focal Cerebral Ischemia in Mice

Objectives: White matter injury aggravates neurological and cognitive impairment in experimental ischemic stroke. M2 microglia promote oligodendrocyte precursor cells survival and differentiation, and further enhance white matter repair. However, the molecular mechanism is unclear. Here, we explored the effect and mechanism of M2 microglia-derived exosomes on white matter repair after focal cerebral ischemia in mice. Methods: Microglia BV2 cells were polarized to M2 phenotype by IL-4 stimulation. Exosomes were isolated from M2 microglia (M2-Exo) and unstimulated microglia as a control (M0-Exo). M2-Exo and M0-Exo (100 μg) were intravenously injected after 90-minute middle cerebral artery occlusion in mice (n=72). Brain atrophy volume and neuro behavioral outcomes were examined in 28 days following focal cerebral ischemia. Oligodendrocyte precursor cells survival, differentiation and white matter integrity were evaluated. Exosomal miRNA and target gene were further examined to explore molecular mechanism. Results: M2-Exo treatment promoted sensorimotor and memory function recovery ( p <0.05), and further reduced brain atrophy compared to the M0-Exo control group ( p <0.001). Immunostaining showed that M2-Exo increased the number of BrdU + /Pdgfr-α + and BrdU + /adenomatous polyposis coli + cells, enhanced myelin basic protein fluorescence-intensity compared to the control ( p <0.05). M2-Exo increased oligodendrocyte precursor cell survival under OGD in vi tro , ( p <0.05) and differentiation ( p <0.05). Exosomal miRNA sequencing and PCR identified that miR-23a-5p was enriched in M2-Exo. Conclusion: Our results showed that M2-Exo treatment enhanced oligodendrocyte precursor cell survival and differentiation, further promoted white matter repair and long-term functional recovery, suggesting that M2-Exo is a novel therapeutic strategy for the white matter repair after ischemic brain injury.

Abstract TP112: Delayed Oligodendrocyte Maturation Corresponds to Myelin and Motor Recovery After Neonatal Stroke

Introduction: Neonatal stroke is a common cause of lifelong neurologic disability. White matter repair after neonatal stroke has been understudied. Objective: Characterize acute myelin injury within striatal white matter and determine if endogenous remyelination occurs chronically. Methods: Postnatal day 10 (p10) mice underwent MCAO for 60 minutes, followed by reperfusion, and animals were sacrificed on post-op day (POD) 3, 14 or 28. Immunohistochemistry (IHC) was used to assess oligodendrocyte maturation, and white matter integrity. Gait was assessed on POD 14 or 30. Results: On POD3 there is a significant decrease in neuronal density in the ipsilateral striatum compared to contralateral. There is also a significant reduction in mature oligodendrocytes density. At this timepoint, axons are preserved (measured as %SMI34 + pixels), but there is significant myelin loss (measured as %MBP + pixels) in the ipsilateral striatum (fig 1A-D). On POD 14 there is persistently decreased myelin density in ipsilateral striatum compared to contralateral, and the proportion of oligodendrocytes with a mature phenotype (Olig2 + CC1 + /Olig2 + ) is significantly lower. Both myelin density and maturational index of oligodendrocytes recover by POD 28. At fourteen days after MCAO there is a significant reduction in gait length on the left side, which recovers by 28 days (fig1 E-G). Conclusions: 60 minute MCAO in neonatal mice produces striatal injury with oligodendrocyte and myelin loss but preservation of axons, providing a substrate for repair. Myelin deficit persists at 14 days, and there is an oligodendrocyte maturational delay at this same time. Myelination and oligodendrocyte maturation recover between 14 and 28 days, corresponding to recovery of motor function. Future studies will focus on whether interventions that accelerate oligodendrocyte maturation and re-myelination can improve early functional outcome.

Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts

White matter repair through transplantation of allogeneic glial progenitors is now feasible in immune-deficient animals, but the immunological barrier precludes its clinical translation. Li et al. develop a strategy based on co-stimulation blockade that induces immunological hyporesponsiveness and supports long-term functionality of allotransplanted myelinating oligodendrocytes.