Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells
Zhaohui Ruan1, Guosheng Cao2, Yisong Qian3
1Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Background And Purpose:
Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown.
Methods:
Wild-type (WT) and Lrg1 knockout (Lrg1-/-) mice were used to investigate the role of Lrg1 after cerebral ischemia‒reperfusion injury. The effects of Lrg1 knockout on brain infarct volume, blood‒brain barrier permeability, and neurological score (based on 2,3,5-triphenyl tetrazolium chloride, evans blue dye, hematoxylin, and eosin staining) were assessed. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and microvascular albumin leakage tests were utilized to investigate alterations in various cell components in brain tissue after Lrg1 knockout.
Results:
Lrg1 expression was increased in various cell types of brain tissue after cerebral ischemia‒reperfusion injury. Lrg1 knockout reduced cerebral edema and infarct size and improved neurological function after cerebral ischemia‒reperfusion injury. Single-cell RNA sequencing analysis of WT and Lrg1-/- mouse brain tissues after cerebral ischemia‒reperfusion injury revealed that Lrg1 knockout enhances blood‒brain barrier (BBB) by upregulating claudin 11, integrin β5, protocadherin 9, and annexin A2. Lrg1 knockout also promoted an anti-inflammatory and tissue-repairing phenotype in microglia and macrophages while reducing neuron and oligodendrocyte cell death.
Conclusions:
Our results has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.
Insights
Leucine-rich alpha-2 glycoprotein 1 (Lrg1) drives damage in cerebral ischemia-reperfusion injury. Removing Lrg1 protects the brain, reduces stroke severity, and enhances tissue repair, highlighting Lrg1 as a therapeutic target.
Area of Science:
- Neuroscience
- Pathology
- Molecular Biology
Background:
- Cerebral ischemia-reperfusion injury is a leading cause of stroke mortality.
- Current treatments are insufficient, necessitating novel therapeutic strategies.
- Leucine-rich alpha-2 glycoprotein 1 (Lrg1) is implicated in injury progression, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the role of Lrg1 in cerebral ischemia-reperfusion injury.
- To investigate Lrg1's impact on brain tissue and cellular components.
- To assess Lrg1 as a potential therapeutic target.
Main Methods:
- Utilized wild-type and Lrg1 knockout mouse models.
- Assessed infarct volume, blood-brain barrier permeability, and neurological function.
- Employed single-cell RNA sequencing, immunofluorescence, and albumin leakage tests.
Main Results:
- Lrg1 expression increased post-injury; Lrg1 knockout reduced infarct size and edema, improving neurological scores.
- Lrg1 knockout enhanced blood-brain barrier integrity by upregulating specific proteins.
- Lrg1 deficiency promoted anti-inflammatory and repair phenotypes in glial cells and reduced neuronal death.
Conclusions:
- Lrg1 significantly contributes to pathological processes in cerebral ischemia-reperfusion injury.
- Lrg1 modulates various cell types, influencing injury outcomes.
- Targeting Lrg1 presents a promising therapeutic strategy for stroke treatment.
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