Dataset Information

TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia.

ABSTRACT: Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα-epidermal growth factor receptor (EGFR)-was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGFα directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.

SUBMITTER: Dai X

PROVIDER: S-EPMC7026842 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia.

Dai Xuejiao X Chen Jie J Xu Fei F Zhao Jingyan J Cai Wei W Sun Zeyu Z Hitchens T Kevin TK Foley Lesley M LM Leak Rehana K RK Chen Jun J Hu Xiaoming X

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190305 3

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα-epidermal growth factor re ...[more]

PMID: 30834805

Similar Datasets

Project description:AimsCaloric restriction is a health-promoting lifestyle that has been reported to protect both white and gray matter in cases of ischemic stroke. This study will explore the underlying mechanism of restricted feeding (RF) and provide a theoretical basis for precise clinical treatment of stroke.MethodsIn this study, we pretreated C57BL/6J mice with 70% RF for a continuous 28-day period prior to 60 min of transient focal cerebral ischemia (tFCI). Histological staining, diffusion tensor imaging (DTI), and behavioral assessments were used to assess RF's neuroprotection following tFCI. Immunofluorescence staining, quantitative real-time PCR, and flow cytometry were conducted to evaluate brain inflammation post-tFCI. Western blot, immunofluorescence staining, tracers, and electric microscopy were used to assess the blood-brain barrier (BBB) integrity. Peripheral neutrophils were cleared by administrating an anti-Ly6G antibody.ResultsInitially, DTI, NeuN staining, and a batch of behavioral tests verified that RF significantly mitigated both gray/white matter injury and neurological deficits in the short- and long-term following tFCI. RF mice showed more anti-inflammatory microglia in their brains, along with reduced inflammatory cytokines, and chemokines. Interestingly, RF significantly reduced the neutrophils and macrophage infiltration. Subsequently, we observed that RF mice exhibited better BBB integrity following tFCI, with reduced neutrophil infiltration and matrix metalloprotein-9 release. Furthermore, the clearance of neutrophils with anti-Ly6G antibody in ad libitum feeding mice (LF-Ly6G) elicited comparable neuroprotective effects to those observed in RF, including improvements in neurological deficits, reductions in infarct volume, and mitigation of BBB damage.ConclusionsIn summary, our findings suggest that RF maintains the BBB integrity following ischemic stroke at least partially by reducing neutrophil infiltration, thereby alleviating both neurological and histological impairments.

Project description:BackgroundChronic cerebral hypoperfusion-induced demyelination causes progressive white matter injury, although the pathogenic pathways are unknown.MethodsThe Single Cell Portal and PanglaoDB databases were used to analyze single-cell RNA sequencing experiments to determine the pattern of EAAT3 expression in CNS cells. Immunofluorescence (IF) was used to detect EAAT3 expression in oligodendrocytes and oligodendrocyte progenitor cells (OPCs). EAAT3 levels in mouse brains were measured using a western blot at various phases of development, as well as in traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) mouse models. The mouse bilateral carotid artery stenosis (BCAS) model was used to create white matter injury. IF, Luxol Fast Blue staining, and electron microscopy were used to investigate the effect of remyelination. 5-Ethynyl-2-Deoxy Uridine staining, transwell chamber assays, and IF were used to examine the effects of OPCs' proliferation, migration, and differentiation in vivo and in vitro. The novel object recognition test, the Y-maze test, the rotarod test, and the grid walking test were used to examine the impact of behavioral modifications.ResultsA considerable amount of EAAT3 was expressed in OPCs and mature oligodendrocytes, according to single-cell RNA sequencing data. During multiple critical phases of mouse brain development, there were no substantial changes in EAAT3 levels in the hippocampus, cerebral cortex, or white matter. Furthermore, neither the TBI nor ICH models significantly affected the levels of EAAT3 in the aforementioned brain areas. The chronic white matter injury caused by BCAS, on the other hand, resulted in a strikingly high level of EAAT3 expression in the oligodendroglia and white matter. Correspondingly, blocking EAAT3 assisted in the recovery of cognitive and motor impairment as well as the restoration of cerebral blood flow following BCAS. Furthermore, EAAT3 suppression was connected to improved OPCs' survival and proliferation in vivo as well as faster OPCs' proliferation, migration, and differentiation in vitro. Furthermore, this study revealed that the mTOR pathway is implicated in EAAT3-mediated remyelination.ConclusionsOur findings provide the first evidence that abnormally high levels of oligodendroglial EAAT3 in chronic cerebral hypoperfusion impair OPCs' pro-remyelination actions, hence impeding white matter repair and functional recovery. EAAT3 inhibitors could be useful in the treatment of ischemia demyelination.

Dataset Information

TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia.

Publications

TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets