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A Cell Culture Model for Studying the Role of Neuron-Glia Interactions in Ischemia
Published on: November 14, 2020
Microglial Fkbp5 Impairs Post-Stroke Vascular Integrity and Regeneration by Promoting Yap1-Mediated Glycolysis and
Yanan Li1, Yanmei Qiu1, Yunlei Yang2,3,4,5
1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
The role of microglia in blood-brain barrier (BBB) leakage and neovascularization after ischemic stroke remains unclear. Here, a post-stroke perivascular niche of microglia characterized by low expression of M2 markers and elevated glycolysis, oxidative phosphorylation (OXPHOS), and phagocytic activity is identified, which is termed stroke-activated vascular-associated microglia (stroke-VAM). It is found that Fkbp5 acts as a central regulator driving BBB disruption and impaired neovascularization through stroke-VAM. Single-nucleus RNA sequencing (snRNA-seq) analysis of Cx3cr1Cre Fkbp5flox/flox (Fkbp5 cKO) mice in the ipsilateral hemisphere reveals enhanced interactions between stroke-VAM and endothelial cells, influencing signaling pathways that maintain BBB integrity and promote neovascularization. After ischemic injury, microglia in Fkbp5 cKO mice exhibits higher M2 marker expression and reduces glycolysis, OXPHOS, and phagocytosis, resulting in decreased BBB leakage and enhanced angiogenesis. Mechanistically, unbiased snRNA-seq analysis shows that the Hippo signaling pathway is altered in Fkbp5 cKO stroke-VAM. Fkbp5 inhibits Yap1 phosphorylation, facilitating its nuclear translocation. These findings provide new insights into how the perivascular microglial niche contributes to both the degradation and regeneration of cerebral vasculature, offering potential therapeutic avenues for acute ischemic stroke.
Insights
Researchers identified stroke-activated vascular-associated microglia (stroke-VAM) that regulate blood-brain barrier leakage and blood vessel regrowth after stroke. Inhibiting Fkbp5 in these microglia improves outcomes by reducing leakage and promoting new blood vessel growth.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- The role of microglia in blood-brain barrier (BBB) integrity and neovascularization post-ischemic stroke is not fully understood.
- Microglia near blood vessels form a unique niche with specific functional characteristics after stroke.
Purpose of the Study:
- To investigate the function of a specific microglial subset, stroke-activated vascular-associated microglia (stroke-VAM), in BBB leakage and neovascularization.
- To identify key regulators within stroke-VAM that influence cerebrovascular repair after ischemic injury.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) was performed on Fkbp5 conditional knockout (cKO) mice post-stroke.
- Analysis focused on microglia-endothelial cell interactions and signaling pathways, including the Hippo signaling pathway.
Main Results:
- Fkbp5 was identified as a key regulator of BBB disruption and impaired neovascularization via stroke-VAM.
- Fkbp5 inhibition in microglia (Fkbp5 cKO) led to decreased BBB leakage and enhanced angiogenesis.
- Fkbp5 was found to inhibit Yap1 phosphorylation, affecting its nuclear translocation and altering the Hippo signaling pathway in stroke-VAM.
Conclusions:
- Stroke-VAM plays a critical role in both the breakdown and regeneration of cerebral vasculature.
- Targeting Fkbp5 within the perivascular microglial niche presents a potential therapeutic strategy for acute ischemic stroke.
