As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte–OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1–A2 astrocytes and OPC–OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl2. At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1‐like astrocytes; however, the number of A2‐like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte‐conditioned medium (ACM) was added. However, injured‐ACM was unable to improve OPC maturation. Incubation with CoCl2 changed astrocytes from A2‐like to A1‐like, and mitochondrial migration was also reduced. A Trkβ agonist was able to maintain astrocytes from A1‐like to A2‐like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1‐like astrocytes protects against white matter injury. Trkβ agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases.Main pointsProlonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.
Stroke is the leading cause of disability, and stroke survivors suffer from long-term sequelae even after receiving recombinant tissue plasminogen activator therapy and endovascular intracranial thrombectomy. Increasing evidence suggests that exosomes, nano-sized extracellular membrane vesicles, enhance neurogenesis, angiogenesis, and axonal outgrowth, all the while suppressing inflammatory reactions, thereby enhancing functional recovery after stroke. A systematic literature review to study the association of stroke recovery with exosome therapy was carried out, analyzing species, stroke model, source of exosomes, behavioral analyses, and outcome data, as well as molecular mechanisms. Thirteen studies were included in the present systematic review. In the majority of studies, exosomes derived from mesenchymal stromal cells or stem cells were administered intravenously within 24 h after transient middle cerebral artery occlusion, showing a significant improvement of neurological severity and motor functions. Specific microRNAs and molecules were identified by mechanistic investigations, and their amplification was shown to further enhance therapeutic effects, including neurogenesis, angiogenesis, axonal outgrowth, and synaptogenesis. Overall, this review addresses the current advances in exosome therapy for stroke recovery in preclinical studies, which can hopefully be preparatory steps for the future development of clinical trials involving stroke survivors to improve functional outcomes.
Cerebral artery fenestration is a rare variant of the vascular architecture, but its existence is well documented. The common site of fenestration is the vertebra-basilar artery and it may be found incidentally with subarachnoid hemorrhage. However, fenestration-related cerebral infarction is rare. We analyzed the clinical characteristics, stroke etiology, and image findings of fenestration-related cerebral infarction of the vertebrobasilar artery. We reviewed our hospital records and previously published reports to find cases of fenestration-related cerebral infarction. We excluded those with unknown clinical features or radiological findings. We retrieved 4 cases of fenestration-related infarction from our hospital, in which vascular change, headache, vertigo/dizziness, and dissection in stroke etiology were detected. In eight previously reported cases of fenestration-related infarction, similar vascular changes were noted, but they were mainly diagnosed as embolic stroke of undetermined source. However, based on the criteria for dissection in this study, dissection as the stroke etiology was suspected in the previously reported cases. Many hypotheses have been proposed for the development of dissection, thrombus, and aneurysms in fenestration. Although an embryological and morphological study is needed, clinicians must consider basilar artery fenestration-related infarction as a differential diagnosis and intensive non-invasive image study is recommended.
Aims White matter lesions (WMLs) are involved in the pathological processes leading to cognitive decline and dementia. We examined the mechanisms underlying the exacerbation of ischemia‐induced cognitive impairment and WMLs by diet‐induced obesity, including lipopolysaccharide (LPS)‐triggered neuroinflammation via toll‐like receptor (TLR) 4. Methods Wild‐type (WT) and TLR4‐knockout (KO) C57BL/6 mice were fed a high‐fat diet (HFD) or low‐fat diet (LFD), and subjected to bilateral carotid artery stenosis (BCAS). Diet groups were compared for changes in gut microbiota, intestinal permeability, systemic inflammation, neuroinflammation, WML severity, and cognitive dysfunction. Results In WT mice, HFD induced obesity and increased cognitive impairment and WML severity compared with LFD‐fed mice following BCAS. HFD caused gut dysbiosis and increased intestinal permeability, and plasma LPS and pro‐inflammatory cytokine concentrations. Furthermore, HFD‐fed mice had higher LPS levels and higher neuroinflammatory status, including increased TLR4 expression, in WMLs. In TLR4‐KO mice, HFD also caused obesity and gut dysbiosis but did not increase cognitive impairment or WML severity after BCAS. No difference was found between HFD‐ and LFD‐fed KO mice for LPS levels or inflammatory status in either plasma or WMLs. Conclusion Inflammation triggered by LPS–TLR4 signaling may mediate obesity‐associated exacerbation of cognitive impairment and WMLs from brain ischemia.
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