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Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery.

ABSTRACT: Age-dependent alterations in microglia behavior have been implicated in neurodegeneration and CNS injuries. Here, we compared the transcriptional profiles of young versus aged microglia during stroke recovery. CD45^intermediateCD11b⁺ microglia were FACS-isolated from the brains of young (10-week-old) and aged (18-month-old) male mice with sham operation or 14 days after distal middle cerebral artery occlusion and subjected to RNA-sequencing analysis. Functional groups enriched in young microglia are indicative of upregulation in cell movement, cell interactions, inflammatory responses and angiogenesis, while aged microglia exhibited a reduction or no change in these features. We confirmed reduced chemoattractive capacities of aged microglia toward ischemic brain tissue in organotypic slide co-cultures, and delayed accumulation of aged microglia around dead neurons injected into the striatum in vivo. In addition, aging is associated with an overall failure to increase the expression of microglial genes involved in cell-cell interactions, such as CXCL10. Finally, impaired upregulation of pro-angiogenic genes in aged microglia was associated with a decline in neovascularization in aged mice compared to young mice after distal middle cerebral artery occlusion. This study provides a new resource to understand the mechanisms underlying microglial alterations in the aged brain milieu and sheds light on new strategies to improve microglial functions in aged stroke victims.

SUBMITTER: Jiang L

PROVIDER: S-EPMC7687033 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The polarization of microglia plays an important role in the outcome of ischemic stroke (IS). In the aged population, senescent microglia show a predominant pro-inflammatory phenotype, which leads to worse outcomes in aged ischemic stroke compared to young ischemic stroke. Recent research demonstrated that inducible pluripotent stem cell-derived small extracellular vesicles (iPSC-sEVs) possess the significant anti-ageing ability. We hypothesized that iPSC-sEVs could alleviate microglia senescence to regulate microglia polarization in aged ischemic stroke. In this study, we showed that treatment with iPSC-sEVs significantly alleviated microglia senescence as indicated by the decreased senescence-associated proteins including P16, P21, P53, and γ-H2AX as well as the activity of SA-β-gal, and inhibited pro-inflammatory activation of microglia both in vivo and in vitro. Furthermore, iPSC-sEVs shifted microglia from pro-inflammatory phenotype to anti-inflammatory phenotype, which reduced the apoptosis of neurons, and improved the outcome of aged stroke mice. Mechanism studies showed that iPSC-sEVs reversed the loss of Rictor and downstream p-AKT (s473) in senescent microglia, which was involved in the senescence and pro-inflammatory phenotype regulation of microglia. Inhibition of Rictor abolished the iPSC-sEVs-afforded phosphorylation of AKT and alleviation of inflammation of senescent microglia. Proteomics results indicated that iPSC-sEVs carried transforming growth factor-β1 (TGF-β1) to upregulate Rictor and p-AKT in senescent microglia, which could be hindered by blocking TGF-β1. Taken together, our work demonstrates iPSC-sEVs reverse the senescent characteristic of microglia in aged brains and therefore improve the outcome after stroke, at least, via delivering TGF-β1 to upregulate Rictor and p-AKT. Our data suggest that iPSC-sEVs might be a novelty therapeutic method for aged ischemic stroke and other diseases involving senescent microglia.

Project description:Over the last decade, microglia have been acknowledged to be key players in central nervous system (CNS) under both physiological and pathological conditions. They constantly survey the CNS environment and as immune cells, in pathological contexts, they provide the first host defense and orchestrate the immune response. It is well recognized that under pathological conditions microglia have both sequential and simultaneous, beneficial and detrimental effects. Cell-specific transcriptomics recently became popular in Neuroscience field allowing concurrent monitoring of the expression of numerous genes in a given cell population. Moreover, by comparing two or more conditions, these approaches permit to unbiasedly identify deregulated genes and pathways. A growing number of studies have thus investigated microglial transcriptome remodeling over the course of neuropathological conditions and highlighted the molecular diversity of microglial response to different diseases. In the present work, we restrict our review to microglia obtained directly from in vivo samples and not cell culture, and to studies using whole-genome strategies. We first critically review the different methods developed to decipher microglia transcriptome. In particular, we compare advantages and drawbacks of flow cytometry and laser microdissection to isolate pure microglia population as well as identification of deregulated microglial genes obtained via RNA sequencing (RNA-Seq) vs. microarrays approaches. Second, we summarize insights obtained from microglia transcriptomes in traumatic brain and spinal cord injuries, pain and more chronic neurological conditions including Amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD) and Multiple sclerosis (MS). Transcriptomic responses of microglia in other non-neurodegenerative CNS disorders such as gliomas and sepsis are also addressed. Third, we present a comparison of the most activated pathways in each neuropathological condition using Gene ontology (GO) classification and highlight the diversity of microglia response to insults focusing on their pro- and anti-inflammatory signatures. Finally, we discuss the potential of the latest technological advances, in particular, single cell RNA-Seq to unravel the individual microglial response diversity in neuropathological contexts.

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Transcriptomic and functional studies reveal undermined chemotactic and angiostimulatory properties of aged microglia during stroke recovery.

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