Regulation of blood-brain barrier by astrocyte through mitochondrial transfer.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210187 | GEO | 2024/07/31
REPOSITORIES: GEO
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Project description:The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer be-tween donor and recipient cells, has recently been identified in a wide range of cell types. Intercel-lular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mito-chondria triggered similar transcriptome changes upon transplantation into the recipient astro-cytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant prolifera-tive effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling.
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Project description:Astrocytes are intimately linked with brain blood vessels, a relationship critical for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation.
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Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)
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Project description:Purpose: To identify the role of glycosylation of dentin matrix protein1 (DMP1), S89G-DMP1 point mutation mouse model was created with changing S89 to glycine(S89G). RNA sequencing were performed to compare the transcriptome differences between the neural stem cells or astrocytes separated form S89G-DMP1 and WT mice. Methods: mRNA profiles of astrocytes and neural stem cell separated from S89G-DMP1 and WT were generated by RNA sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat2(for astrocytes) or with HISAT2o (for neural stem cells). Results: Differential expression analyses with DESeq2 use raw read counts: 762 transcripts were downregulated and 991 transcripts were up-regulated in S89G-DMP1 astrocytes; 475 transcripts were downregulated and 343 transcripts were up-regulated in S89G-DMP1 neural stem cells. All the differential expressed genes were used for Heatmap analysis and KEGG or GO enrichment analyses. Conclusions: Our study represents the detailed transcriptome changes of astrocytes and neural stem cells with deglycosylated DMP1.
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