Mechanisms of oligodendrocyte regeneration from ventricular-subventricular zone-derived progenitor cells in white matter diseases

White matter dysfunction is an important part of many CNS disorders including multiple sclerosis (MS) and vascular dementia. Within injured areas, myelin loss and oligodendrocyte death may trigger endogenous attempts at regeneration. However, during disease progression, remyelination failure may eventually occur due to impaired survival/proliferation, migration/recruitment, and differentiation of oligodendrocyte precursor cells (OPCs). The ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) are the main sources of neural stem/progenitor cells (NSPCs), which can give rise to neurons as well as OPCs. Under normal conditions in the adult brain, the V-SVZ progenitors generate a large number of neurons with a small number of oligodendrocyte lineage cells. However, after demyelination, the fate of V-SVZ-derived progenitor cells shifts from neurons to OPCs, and these newly generated OPCs migrate to the demyelinating lesions to ease white matter damage. In this mini-review, we will summarize the recent studies on extrinsic (e.g., vasculature, extracellular matrix (ECM), cerebrospinal fluid (CSF)) and intrinsic (e.g., transcription factors, epigenetic modifiers) factors, which mediate oligodendrocyte generation from the V-SVZ progenitor cells. A deeper understanding of the mechanisms that regulate the fate of V-SVZ progenitor cells may lead to new therapeutic approaches for ameliorating white matter dysfunction and damage in CNS disorders

Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia–reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke

Oligodendrocyte Precursor Cells Support Blood-Brain Barrier Integrity via TGF-β Signaling

Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity

CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation

There are numerous barriers to white matter repair after CNS injury and the underlying mechanisms remain to be fully understood. In this study, we propose the hypothesis that inflammatory macrophages in damaged white matter attack oligodendrocyte precursor cells (OPCs) via TLR4 signaling thus interfering with this endogenous progenitor recovery mechanism. Primary cell culture experiments demonstrate that peritoneal macrophages can attack and digest OPCs via TLR4 signaling, and this phagocytosis of OPCs can be inhibited by using CD200-Fc to downregulate TLR4. In an in vivo model of white matter ischemia induced by endothelin-1, treatment with D200-Fc suppressed TLR4 expression in peripherally circulating macrophages, thus restraining macrophage phagocytosis of OPCs and leading to improved myelination. Taken together, these findings suggest that deleterious macrophage effects may occur after white matter ischemia, whereby macrophages attack OPCs and interfere with endogenous recovery responses. Targeting this pathway with CD200 may offer a novel therapeutic approach to amplify endogenous OPC-mediated repair of white matter damage in mammalian brain

Characteristics of Clinical Symptoms, Cerebral Images and Stroke Etiology in Vertebro-Basilar Artery Fenestration-Related Infarction

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

Analysis for Stroke Etiology in Duplicated/Accessory MCA-Related Cerebral Infarction: Two Case Report and Brief Literature Review

Duplication and accessory of the middle cerebral artery (MCA) constitute a rare congenital variation. MCA anomalies are found at a lesser frequency than the vascular anomalies of the other major intracranial arteries. Duplicated/accessory MCA was usually noted incidentally with subarachnoid hemorrhage, due to resulted aneurysmal formation. However, duplicated/accessory MCA-related cerebral infarction is rarer. We report two cases of cerebral infarction due to dissection at the entry of the duplicate/accessory MCA. Both cases were similar in dissected site and clinical course, without headache or injury. In 20 previously reported cases and our two cases of duplicated/accessory MCA-related infarction, mean age (55.8 ± 21.2 years) was slightly younger for cerebral infarction, and stroke etiology was mainly embolism. The main etiologies of stroke were embolism and dissection. Considering embolism etiology, proximal site of arterial diameter changing lesion was a common site for embolism, as duplicated/accessory MCA was usually smaller than normal M1 segment. In cerebral dissection cases, the dissected site was similar to our cases. Numerous mechanisms of dissection were considered, but they mainly included dysfunction of the media and endothelium or shearing stress at the entry of duplication. As the detailed mechanisms of cerebral dissection remain unknown, clinicians should include a differential diagnosis for MCA dissection