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Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

ABSTRACT: Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter (WM) impairment, but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods- Permanent distal middle cerebral artery occlusion was performed in wild-type, homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open field, and Morris water maze tests were used to assess neurobehavioral outcomes. Neuronal tissue loss, WM damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35 days after stroke. The functional integrity of WM was measured by electrophysiology. Primary microglia-oligodendrocyte cocultures were used for additional mechanistic studies. Results- T2DM exacerbated structural damage and impaired conduction of compound action potentials in WM 35 days after stroke. The deterioration in WM integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the proinflammatory modality. Coculture studies confirmed that microglia/macrophage polarization toward the proinflammatory phenotype under high glucose conditions suppressed oligodendrocyte precursor cell differentiation. Conclusions- Deterioration of WM integrity and impairments in oligodendrogenesis after stroke are associated with poor long-term functional outcomes in experimental diabetes mellitus. High glucose concentrations may shift microglia/macrophage polarization toward a proinflammatory phenotype, significantly impairing oligodendrocyte precursor cell differentiation and WM repair.

SUBMITTER: Ma S

PROVIDER: S-EPMC6205761 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

Ma Shubei S Wang Jianyi J Wang Yanling Y Dai Xuejiao X Xu Fei F Gao Xuguang X Johnson Joycelyne J Xu Na N Leak Rehana K RK Hu Xiaoming X Luo Yumin Y Chen Jun J

Stroke 20181001 10

Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter (WM) impairment, but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods- Permanent distal middle cerebral arter ...[more]

PMID: 30355111

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Project description:Rationale: White matter repair is critical for the cognitive and neurological functional recovery after ischemic stroke. M2 microglia are well-documented to enhance remyelination and their extracellular vesicles (EVs) mediate cellular function after brain injury. However, whether M2 microglia-derived EVs could promote white matter repair after cerebral ischemia and its underlying mechanism are largely unknown. Methods: EVs were isolated from IL-4 treated microglia (M2-EVs) and untreated microglia (M0-EVs). Adult ICR mice subjected to 90-minute transient middle cerebral artery occlusion received intravenous EVs treatment for seven consecutive days. Brain atrophy volume, neurobehavioral tests were examined within 28 days following ischemia. Immunohistochemistry, myelin transmission electron microscope and compound action potential measurement were performed to assess white matter structural remodeling, functional repair and oligodendrogenesis. The effects of M2-EVs on oligodendrocyte precursor cells (OPCs) were also examined in vitro. EVs' miRNA sequencing, specific miR-23a-5p knockdown in M2-EVs and luciferase reporter assay were used to explore the underlying mechanism. Results: M2-EVs reduced brain atrophy volume, promoted functional recovery, oligodendrogenesis and white matter repair in vivo, increased OPC proliferation, survival and differentiation in vitro. miR-23a-5p was enriched in M2-EVs and could promote OPC proliferation, survival and maturation, while knocking down miR-23a-5p in M2-EVs reversed the beneficial effects of M2-EVs both in vitro and in vivo. Luciferase reporter assay showed that miR-23a-5p directly targeted Olig3. Conclusion: Our results demonstrated that M2 microglia could communicate to OPCs through M2-EVs and promote white matter repair via miR-23a-5p possibly by directly targeting Olig3 after ischemic stroke, suggesting M2-EVs is a novel and promising therapeutic strategy for white matter repair in stroke and demyelinating disease.

Dataset Information

Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

Publications

Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

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