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Updated: Jan 13, 2026
Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
Published on: November 8, 2024
Profiling small extracellular vesicles microRNAs and their expressions in EVs-depleted plasma as biomarkers for
Bao-Yu Chen1, Jin-Jia Lin2, Huai-Hsuan Tseng3
1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract:
In schizophrenia (SZ), significant alterations in microRNAs (miRNAs) regulation and the underlying mechanisms of post-transcriptional modification have been observed. Extracellular vesicles (EVs) encapsulate miRNAs, protecting them from degradation and enabling long-range intercellular communication. While profiling sEV-derived miRNAs (sEV-miRNAs) is essential for understanding sEV-mediated signaling, examining sEV-associated miRNAs in EVs-depleted (dEV) plasma is equally important for evaluating their selectivity and potential roles in systemic physiological regulation. To investigate the hypothesis that specific miRNAs are selectively enriched in small EVs (sEVs), we compared sEV-miRNAs expression profiles between SZ patients and nonpsychotic controls (NC). We then conducted a side-by-side comparison of candidate sEV-associated miRNA expressions in dEV plasma. In the screening set (N = 24), five aberrantly expressed sEV-miRNAs (miR-23a, miR-103a, miR-182, miR-450b, and miR-4433b) were selected for further validation. In the validation set (N = 139), miR-23a, miR-103a, and miR-450b were highly expressed in SZ patients' sEVs, they were less expressed in dEV plasma. This could indicate miRNAs may play various roles in signal transduction based on their origin and distribution. An optimal marker panel (sEV-miR-103a, sEV-miR-450b, and dEV-miR-450b) was established to differentiate SZ patients from NC, yielding an area under the curve (AUC) of 0.988 and an accuracy of 0.935. In the 10-fold cross-validation model, AUC was 0.930, and accuracy was 0.887. Enrichment analysis showed that dysregulated sEV-associated miRNAs are involved in neurobiological and immune pathways in SZ. These findings support a link between SZ and altered posttranscriptional regulation mediated by specific sEV-miRNAs, highlighting their potential as therapeutic targets.
Insights
Specific microRNAs (miRNAs) found in extracellular vesicles (EVs) and depleted plasma can distinguish schizophrenia patients. These circulating miRNAs offer potential diagnostic biomarkers and therapeutic targets for schizophrenia.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Schizophrenia (SZ) involves altered microRNA (miRNA) regulation and post-transcriptional modifications.
- Extracellular vesicles (EVs), particularly small EVs (sEVs), transport miRNAs, facilitating intercellular communication.
- Investigating cell-free circulating miRNAs in EVs and EVs-depleted plasma is crucial for understanding systemic regulation and biomarker discovery.
Purpose of the Study:
- To determine if specific miRNAs are selectively enriched in small EVs (sEVs) in schizophrenia patients.
- To compare sEV-miRNA profiles and sEV-associated miRNAs in EVs-depleted plasma between SZ patients and nonpsychotic controls (NC).
- To identify a potential diagnostic biomarker panel for schizophrenia based on miRNA expression.
Main Methods:
- Compared sEV-miRNA expression profiles between 24 SZ patients and NC.
- Validated candidate miRNAs in sEVs and EVs-depleted plasma from 139 SZ patients and NC.
- Utilized receiver operating characteristic (ROC) analysis to establish a diagnostic marker panel.
- Performed enrichment analysis to identify biological pathways associated with dysregulated miRNAs.
Main Results:
- Five miRNAs (miR-23a, miR-103a, miR-182, miR-450b, miR-4433b) showed aberrant expression in screening.
- miR-23a, miR-103a, and miR-450b were upregulated in SZ sEVs and downregulated in SZ EVs-depleted plasma.
- An optimal marker panel (sEV-miR-103a, sEV-miR-450b, dEV-miR-450b) achieved high diagnostic accuracy (AUC=0.988, accuracy=0.935).
- Dysregulated miRNAs were linked to neurobiological and immune pathways relevant to SZ.
Conclusions:
- Altered expression of specific sEV-associated miRNAs is linked to schizophrenia.
- Circulating miRNAs in sEVs and EVs-depleted plasma show potential as diagnostic biomarkers for SZ.
- These findings highlight the role of altered post-transcriptional regulation in SZ pathogenesis and suggest therapeutic targets.
