PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke

Nakamura, Akari; Sakai, Seiichiro; Taketomi, Yoshitaka; Tsuyama, Jun; Miki, Yoshimi; Hara, Yuichiro; Arai, Nobutaka; Kawaji, Hideya; Murakami, Makoto; Shichita, Takashi

doi:10.1016/j.neuron.2023.06.024

Cited by 13 publications

(17 citation statements)

References 67 publications

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“…Based on single‐cell sequencing data, personalized treatment strategies can be provided for patients and improve treatment effects. Taken together, single‐cell sequencing technology plays a key role in solving AIS research and can deeply reveal the molecular mechanism of stroke, treatment targets, and the development of personalized treatment strategies 50,145,178,187,188 . Although single‐cell sequencing technology is now widely used, it is undeniable that single‐cell sequencing technology currently has certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Deng,

Hu,

Zhou

et al. 2023

CNS Neurosci Ther

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BackgroundAcute ischemic stroke (AIS) is a common cerebrovascular event associated with high incidence, disability, and poor prognosis. Studies have shown that various cell types, including microglia, astrocytes, oligodendrocytes, neurons, and neutrophils, play complex roles in the early stages of AIS and significantly affect its prognosis. Thus, a comprehensive understanding of the mechanisms of action of these cells will be beneficial for improving stroke prognosis. With the rapid development of single‐cell sequencing technology, researchers have explored the pathophysiological mechanisms underlying AIS at the single‐cell level.MethodWe systematically summarize the latest research on single‐cell sequencing in AIS.ResultIn this review, we summarize the phenotypes and functions of microglia, astrocytes, oligodendrocytes, neurons, neutrophils, monocytes, and lymphocytes, as well as their respective subtypes, at different time points following AIS. In particular, we focused on the crosstalk between microglia and astrocytes, oligodendrocytes, and neurons. Our findings reveal diverse and sometimes opposing roles within the same cell type, with the possibility of interconversion between different subclusters.ConclusionThis review offers a pioneering exploration of the functions of various glial cells and cell subclusters after AIS, shedding light on their regulatory mechanisms that facilitate the transformation of detrimental cell subclusters towards those that are beneficial for improving the prognosis of AIS. This approach has the potential to advance the discovery of new specific targets and the development of drugs, thus representing a significant breakthrough in addressing the challenges in AIS treatment.

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Section: Discussionmentioning

confidence: 99%

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Deng,

Hu,

Zhou

et al. 2023

CNS Neurosci Ther

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“…Supplementary tables present information on the changes in cerebral blood flow during ischemia, the number of excluded mice, physiological data, and the survival rate. To evaluate the neurological deficits, we conducted the corner and cylinder tests (details of the experimental methods have been provided elsewhere; 3 ). For the cylinder test, the neurological score was calculated as follows: (number of non-impaired forelimb contacts – number of impaired forelimb contacts)/(number of non-impaired forelimb contacts + number of impaired forelimb contacts).…”

Section: Methodsmentioning

confidence: 99%

“…An ATAC-seq library was prepared according to the protocol described elsewhere 3 . For the fragmentation and tagmentation of genomic DNA, 50,000 nuclei isolated from CD45 int CD11b int cells were treated with Tn5 transposase (Illumina, Nextera DNA Library Preparation Kit).…”

Section: Methodsmentioning

confidence: 99%

“…BV2 cells or CD45 int CD11b int cells (100,000–200,000 cells from the sham-operated or ischemic hemisphere) were pelleted for 3 min at 600× g at room temperature and used to prepare the CUT&Tag library using a bench top CUT& Tag V.2 protocol with slight modifications. The detailed experimental procedure was described previously 3 . Anti-YY1 (Abcam, ab109237) and anti-ZNF384 (Sigma, HPA004051) antibodies were used for primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…Stroke induces acute harmful inflammation and brain swelling, which worsens a patient’s prognosis; therefore, much effort is focused on acute treatments and prevention of stroke. When stroke patients overcome the acute phase, brain inflammation resolves around 1 week after stroke onset, and spontaneous brain recovery mechanisms improve the neurological deficits 3 . Rehabilitation is a common method to enhance recovery mechanisms and improve functional prognosis after brain injury; however, therapeutic drugs that enhance these recovery processes have not been developed.…”

Section: Introductionmentioning

confidence: 99%

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Sustaining microglial reparative function enhances stroke recovery

Tsuyama,

Sakai,

Kurabayashi

et al. 2024

Preprint

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Neurological symptoms after brain injury can remain as lifelong detrimental sequelae since most spontaneous brain recovery disappears within a few months after brain injury. Microglia play an essential role in recovery processes after brain injury; however, cellular and molecular mechanisms that diminish spontaneous brain functional recovery remain unknown. We discovered by cellular fate analysis that reparative myeloid cells remained in the post-stroke brain even after losing their reparative function. ZFP384 was identified as a pivotal transcriptional regulator that diminished recovery phase-associated gene expression in reparative myeloid cells, turning them into ruined cells which lost reparative functions. ZFP384 diminished the YY1-mediated chromatin interaction necessary for expressing recovery phase-associated genes. Antisense oligonucleotide against Zfp384 sustained the broad range of neural repair effects of myeloid cells and enhanced stroke recovery, even in the chronic phase of ischemic stroke recovery. Thus, therapeutics preventing the myeloid reparative immunity from reaching a ruined state sustains brain functional recovery.

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Adaptive Metabolic Responses Facilitate Blood‐Brain Barrier Repair in Ischemic Stroke via BHB‐Mediated Epigenetic Modification of ZO‐1 Expression

Li,

Liu,

et al. 2024

Advanced Science

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Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta‐hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood‐brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO‐ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO‐1 by enhancing local β‐hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO‐ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

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PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke

Cited by 13 publications

References 67 publications

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Perspective from single‐cell sequencing: Is inflammation in acute ischemic stroke beneficial or detrimental?

Sustaining microglial reparative function enhances stroke recovery

Adaptive Metabolic Responses Facilitate Blood‐Brain Barrier Repair in Ischemic Stroke via BHB‐Mediated Epigenetic Modification of ZO‐1 Expression

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