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Epicardial-derived cells secrete extracellular vesicles that modulate gene expression in the cardiac response to ischemia-reperfusion injury [EV miRNAseq]

ABSTRACT: The epicardium is an essential regulator of cardiac development, homeostasis, and injury. While advanced 3D human cardiac tissue models now facilitate physiologically relevant exploration of epicardial–myocardial interactions, the composition and impacts of epicardial cell-secreted extracellular vesicles (EVs) in regulating cardiac physiology remain incompletely understood. Here we harnessed an “Epicardial Biowire” platform integrating human epicardial cells with functional myocardium, applying transcriptomics to reveal enriched vesicle transport in engineered tissues containing epicardial cells. Profiling epicardial-EVs identified key miRNAs in their cargo and indicated considerable conservation of miRNA cargo through stimulated epithelial‐to‐mesenchymal transition. Supplementation of epicardial-EVs to engineered tissues undergoing simulated ischemia–reperfusion injury influenced gene expression associated with reduction of extracellular matrix remodeling, fibroblast modulation, and suppression of cell-ECM interactions. Correlation of EV‐miRNAs with mRNA targets highlighted implications of miR‐30d‐5p, miR‐9‐5p, miR‐16‐5p, and the let‐7 family, supporting a potential role for epicardial-EVs and their miRNA cargo in moderating deleterious fibrotic activation and matrix remodelling during myocardial injury in vitro. Collectively, these findings expand our understanding of epicardial-EV composition and function, highlighting epicardial signalling as a promising avenue to direct cardiac repair and inspiring the design of future EV‐based therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300517 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Objectives: Secretion of extracellular vesicles (EV) and associated micro-RNAs (miR) is altered during cellular stress and may serve as biomarkers of organ injury. We hypothesized that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. Design: Predictive accuracy biomarker study performed in the cohort of the REVAKI-2 trial Setting: Single center ICU between September 2015 and September 2018 Interventions: Intravenous sildenafil citrate 12.5 mg kg-1 over 150 min or dextrose 5% at the commencement of surgery. Measurements and main results: Urine samples were collected before and 24 hours after the procedure from 93 cardiac surgery patients. Urine EV concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced to detect differentially expressed miR. Verification was performed with advanced TaqMan assays in samples from all patients. Urine EV concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for aquaporin-2 and β1-integrin also increasing. Pre surgery podocalyxin-positive EV were significantly lower, and β1-integrin EV werehigher in patients with AKI. The levels of the former correlated with the severity of theinjury. miR-125a-5p was expressed at higher levels in urine from patients with AKI stage 2/3. Levels of miR-10a-5p decreased after surgery in AKI patients; its levels correlated with the severity of the injury. Preoperative levels of podocalyxin EVs and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 80.9%) AKI prediction. Conclusions: Lower levels of podocalyxin-positive EV at baseline predict the severity of post-surgery AKI. Urine EV concentrations and miR expression offer excellent predictive accuracy when combined with commonly measured biomarkers.

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.

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Epicardial-derived cells secrete extracellular vesicles that modulate gene expression in the cardiac response to ischemia-reperfusion injury [EV miRNAseq]

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