Cardiac-derived extracellular vesicles carrying miR-4433b-3p accelerate cognitive decline and brain aging by suppressing TP53INP2-mediated neuronal autophagy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE329277 | GEO | 2026/09/16
REPOSITORIES: GEO
Similar Datasets
Project description:Extracellular vesicles (EVs) have several functions in the brain, serving as a mode of intercellular communication and as a pathway for disposal of cellular debris. While these functions serve to maintain healthy brain function, they may also contribute to diseases affecting the brain. EVs also change with aging of the brain, as levels of some EV subtypes increase at advanced ages in mice. These changes could be caused by aging-related changes such as inflammation, cellular senescence, or impairment of autophagy or mitochondrial function. Aging-related changes in brain EVs might also further aging-related changes, as levels of EVs in plasma may change with age and contribute to aging-related changes in inflammation and cellular metabolism. However, the effects of aging on brain EVs and the potential contribution of EVs to aging-related changes in the brain are not well understood. To address this question, we investigated the levels and protein contents of EVs isolated from brains of 4-, 12-, and 22-month–old C57Bl/6J mice. We detected no changes in EV levels, but observed age-dependent changes in EV proteins. EV fractions from aged (22-month–old) mice contained higher levels of extracellular matrix proteins than EV fractions from young (4-month–old) mice, with similar trends occurring in 12-month–old mice. Specifically, levels of hyaluronan and proteoglycan link proteins (Hapln) 1 and 2 were elevated in EV fractions from aged mice, as were levels of several chondroitin sulfate proteoglycans (CSPGs), which interact with Hapln1 and 2. Analysis of extracellular matrix in several brain regions of aged mice revealed increased immunolabeling for aggrecan, but an overall reduction in labeling with Wisteria floribunda agglutinin, which binds to chondroitin sulfate. These data are consistent with prior studies showing changes to the composition of extracellular matrix in aged brains, which might contribute to age-related cognitive decline. These findings reveal a novel association of EVs with changes in the extracellular matrix of the aging brain.
2025-05-07 | PXD052797 | Pride
Project description:Given the nefarious role that Extracellular vesicles (EVs) can play in disease pathogenesis, there is a growing interest in examining the contents of EVs in many disorders, including depression, HIV, and HIV-Associated Neurocognitive Disorder (HAND). EVs are particularly enriched with miRNA, and the nervous system expresses approximately 70% of all miRNA. miRNA typically regulate gene expression via degrading or suppressing mRNA translation, and these small non-coding RNAs, which are thought to be shuttled between cells via EVs, have been implicated in a host of diseases and conditions, including depression and cognitive decline. To our knowledge, however, this is the first study to examine brain-derived (bd) EV miRNA content in a preclinical model of HIV-associated CI and depression. We report 4 miRNAs, including miR-429-3p, miR-200c-3p, miR-183-5p, and miR-200b-3p, that are significantly upregulated in bdEVs of EcoHIV-infected mice and normalized by novel treatment.
2021-08-28 | GSE182743 | GEO
Project description:Resident cardiac macrophages, derived from primitive yolk sac precursors during embryogenesis, have increasingly been recognized for their distinct phenotype and functions in regulating homeostasis of the human heart. However, the profile of their extracellular vesicles (EVs) in cardiac signalling and regulation remains uncharted. Here, we employ differentiation of human pluripotent stem cell (hPSC)-derived primitive macrophages (Mac) for isolation of their secreted EVs and in-depth characterization of EV-miRNA cargo. Primitive macrophages secreted nanoscale EVs that expressed canonical EV markers, and miRNA sequencing highlighted a diverse and unique profile of miRNAs when compared to EVs sourced from other principal cardiac cell lineages and published data from monocyte-derived cells. In particular, we noted the abundance and enrichment of vascular-modulatory let-7 miRNAs and miR-126-3p. Functional screening of Mac-EVs in a 3D model of in vitro cardiac vasculogenesis confirmed enhanced early endothelial cell organization and branching. Establishing a reference for the human Mac-EV miRNome enables further hypothesis-driven mechanistic tests of Mac-EV miRNAs in mediating cardiac physiology and disease, opening the door to identification of therapeutic targets and modalities for cardiac repair.
2026-03-19 | GSE311002 | GEO
Project description:Advanced maternal age (AMA) patients experience decreased success from assisted reproductive technologies (ART), attributed to quantity and quality of oocytes, which is significantly influenced by the health of surrounding microenvironment. This microenvironment consists of extracellular vesicles in the follicular fluid. Follicular fluid extracellular vesicles (FF-EVs) are important communication mediators between ovarian somatic cells and the oocyte that could be playing a role in the changes of the follicle microenvironment as the ovary ages. To elucidate mechanisms that contribute to the age-related decline of oocyte quality, we characterized EVs and sequenced the small-RNA cargo from young (<32 y.o.) and AMA (>38 y.o.) patients' follicular fluid. We identified 23 differentially expressed microRNAs (DE miRNAs), specifically 12 downregulated and 11 upregulated, in young compared to aged FF-EVs (P value < 0.05, FDR < 0.10, Fold Change > 2). Target gene prediction and pathway analysis indicate up- and downregulated miRNAs target genes associated with oxidative stress response, such as the AGE-RAGE and HIF-1 signaling pathways. Specifically, NFKB1, STAT3, VEGFA, IGF1R, and PIK3R1 targeted by miR-9-5p, miR-223-3p, miR-205-5p, Mir-133a-3p, and miR-222-3p, respectively, and both BCL2 and IGF1 targeted by miR-1-3p. The results of our study reveal EVs and their associated miRNAs could provide a basis for a novel approach to mitigating the negative impacts of oxidative stress during ovarian aging.
2026-03-12 | GSE291875 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
2011-12-23 | E-GEOD-25009 | biostudies-arrayexpress
Project description:Previous work on murine models and humans demonstrated global as well as tissue-specific molecular ageing trajectories of RNAs. Extracellular vesicles (EVs) are membrane vesicles mediating the horizontal transfer of genetic information between different tissues. We sequenced small regulatory RNAs (sncRNAs) in two mouse plasma fractions at five time points across the lifespan from 2-18 months: (1) sncRNAs that are free-circulating (fc-RNA) and (2) sncRNAs bound outside or inside EVs (EV-RNA). Different sncRNA classes exhibit unique ageing patterns that vary between the fcRNA and EV-RNA fractions. While tRNAs showed the highest correlation with ageing in both fractions, rRNAs exhibited inverse correlation trajectories between the EV- and fc-fractions. For miRNAs, the EV-RNA fraction was exceptionally strongly associated with ageing, especially the miR-29 family in adipose tissues. Sequencing of sncRNAs and coding genes in fat tissue of an independent cohort of aged mice up to 27 months highlighted the pivotal role of miR-29a-3p and miR-29b-3p in ageing-related gene regulation that we validated in a third cohort by RT-qPCR.
2023-03-10 | GSE222857 | GEO
Project description:Aging is a major unmodifiable risk factor for cardiovascular disease (CVD). Replicative endothelial senescence (RES), characterized by permanent cell-cycle arrest and a senescence-associated secretory phenotype (SASP), is a hallmark of vascular aging and contributes to endothelial dysfunction. However, RES molecular mechanisms, particularly the role of extracellular vesicles (EVs), remain poorly understood. To elucidate these mechanisms, an integrated multi-omics approach (proteomics, transcriptomics, and miRNA profiling) was used to characterize senescent endothelial cells (ECs) and their secreted EVs compared with early-passage counterparts. Senescent ECs and EVs displayed canonical senescence signatures, exhibiting enrichment of cell cycle, DNA damage response, p53 and NF-κB signaling, and SASP components, which are strongly linked to CVD. Senescent EVs also showed a marked suppression of RNA metabolism, chromatin organization, and repair machinery, while carrying pro-inflammatory, adipogenic, and angiogenic mediators, reinforcing their role as vectors of secondary cellular senescence. Multi-omics integration revealed a coordinated regulatory network involving transcription factors (e.g., REST) and miRNAs. Angiogenic regulators miR-22-3p and miR-126-5p also emerged as RES mediators in both ECs and EVs, with miR-22-3p exhibiting compartment-specific regulation. Downregulation of key miRNAs (miR-335-3p, miR-590-3p, miR-29, and miR-17 families) promoted the derepression of downstream targets, driving endothelial phenotypic drift and dysfunction, primarily characterized by impaired PI3K–Akt signaling, maladaptive angiogenesis, and extracellular matrix remodeling. Our study provides a comprehensive map of RES-driven molecular alterations, identifying potential candidate biomarkers and therapeutic targets for age-related CVD. These findings also emphasize the role of EVs in propagating senescence and CVD risk, opening perspectives for EV-based interventions to counteract vascular aging.
2025-12-01 | GSE311039 | GEO
Project description:Aging is a major unmodifiable risk factor for cardiovascular disease (CVD). Replicative endothelial senescence (RES), characterized by permanent cell-cycle arrest and a senescence-associated secretory phenotype (SASP), is a hallmark of vascular aging and contributes to endothelial dysfunction. However, RES molecular mechanisms, particularly the role of extracellular vesicles (EVs), remain poorly understood. To elucidate these mechanisms, an integrated multi-omics approach (proteomics, transcriptomics, and miRNA profiling) was used to characterize senescent endothelial cells (ECs) and their secreted EVs compared with early-passage counterparts. Senescent ECs and EVs displayed canonical senescence signatures, exhibiting enrichment of cell cycle, DNA damage response, p53 and NF-κB signaling, and SASP components, which are strongly linked to CVD. Senescent EVs also showed a marked suppression of RNA metabolism, chromatin organization, and repair machinery, while carrying pro-inflammatory, adipogenic, and angiogenic mediators, reinforcing their role as vectors of secondary cellular senescence. Multi-omics integration revealed a coordinated regulatory network involving transcription factors (e.g., REST) and miRNAs. Angiogenic regulators miR-22-3p and miR-126-5p also emerged as RES mediators in both ECs and EVs, with miR-22-3p exhibiting compartment-specific regulation. Downregulation of key miRNAs (miR-335-3p, miR-590-3p, miR-29, and miR-17 families) promoted the derepression of downstream targets, driving endothelial phenotypic drift and dysfunction, primarily characterized by impaired PI3K–Akt signaling, maladaptive angiogenesis, and extracellular matrix remodeling. Our study provides a comprehensive map of RES-driven molecular alterations, identifying potential candidate biomarkers and therapeutic targets for age-related CVD. These findings also emphasize the role of EVs in propagating senescence and CVD risk, opening perspectives for EV-based interventions to counteract vascular aging.
2025-12-01 | GSE311038 | GEO
Project description:Human mesenchymal stem/stromal cells (hMSCs) hold significant potential for regenerative medicine due to their anti-inflammatory and pro-angiogenic secretome. In particular, 3D hMSC aggregates secrete EVs that have enhanced anti-inflammatory and immunomodulatory properties. However, safety and efficacy concerns associated with stem cell therapy have led to the discovery of cell-free approaches utilizing hMSC-derived extracellular vesicles (EVs). Despite their therapeutic promise, the clinical application of hMSC-EVs is limited by low production yield. This study investigates the scalable generation of hMSC-EVs from 3D aggregates in a novel Vertical-Wheel Bioreactor (VWBR) through shear stress-mediated biochemical cues, promoting cargo expression relevant to nerve regeneration and neuropathic treatment. Bone marrow-derived hMSCs were cultured as 3D aggregates in VWBRs and exposed to two different culture media—αMEM/FBS (serum-containing) and DMEM/F12/B27 (serum-free)—under three agitation speeds (25, 40, and 64 rpm). Metabolite and gene analyses were performed to assess EV biogenesis, focusing on ESCRT machinery markers. Results showed that hMSCs cultured in VWBR exhibited higher expression of EV biogenesis genes and glycolytic genes compared to static culture. αMEM/FBS (serum-containing) condition was more robust than DMEM/F12/B27 (serum-free) condition. EV yield (EV number per cell) increased by 3-10 fold (in serum-containing medium) in VWBR compared to static culture, with size of 120-180 nm and EV marker expression. microRNA-sequencing of the EVs shows the upregulation of miR-29a-3p, miR-451a, miR-224-5p, miR-16-5p, miR-133a-3p, and miR-143-3p, etc., reflecting a combination that enhances EV biogenesis, promotes metabolic reprogramming, and supports immunomodulatory behavior characteristics. Functional assays demonstrated that the generated EVs effectively modulated Schwann cell responses under neural inflammation, supporting their therapeutic potential. These findings highlight the role of VWBR-driven hydrodynamics in promoting EV production from 3D hMSC aggregates. This study advances the knowledge of dynamic aggregation and metabolic influence on 3D hMSC-EV production and fundamentally scale up the preconditioned techniques used to promote hMSC aggregation and the consequent EV secretion.
2026-01-21 | GSE316471 | GEO
Project description:Cardiovascular disease remains the leading cause of death worldwide, with coronary artery disease being the primary contributor. Our recent studies suggest that activation of leptin receptors (LepRs) in the brain can improve cardiac function following myocardial infarction. However, the mechanism by which this cardioprotective effect is transmitted from the brain to the heart remains unclear. We hypothesize that brain LepR activation stimulates brown adipose tissue (BAT) to secrete extracellular vesicles (EVs) enriched with cardioprotective factors. These EVs may safeguard the heart by modulating cardiac mitochondrial function and collagen deposition. Our findings indicate that BAT ablation or BAT sympathetic denervation diminishes the cardioprotective effects of brain LepR activation. We also observed an increased concentration of EVs within BAT of rats treated with ICV leptin compared to vehicle-treated controls, an effect abolished by BAT denervation. Furthermore, knockdown of Rab27a in BAT reduced the cardioprotective benefits of brain LepR activation. MicroRNA (miR)-29c-3p was identified as a cargo of leptin-stimulated BAT-derived EVs and appears to play a key role in mitigating cardiac fibrosis after IR injury in leptin-treated animals. Thus, activation of LepR in the brain protects the heart after IR injury via sympathetic mediated BAT-derived EVs enriched with miR-29c-3p.
2026-01-05 | GSE315349 | GEO