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Proteomics data of extracellular vesicles, which are specifically derived from Leydig cells or testicular macrophage cells respectively within the mouse testis, offer detailed and comprehensive insights into the unique biochemical compositions and potential roles of these vesicles in the testicular microenvironment.

ABSTRACT: Testosterone synthesis in male mammals occurs predominantly in testicular Leydig cells (LCs), a process that is energetically demanding and results in cellular component damage. Despite this, LCs are long-lived and rarely renew, suggesting the presence of specialized mechanisms to maintain LCs homeostasis under these constraints. Emerging evidence highlights intercellular material transfer as a critical process in various physiological contexts, yet its role in LCs homeostasis and function is largely unexplored. Here, we uncover testosterone production has a causal link to bidirectional materials transfers between LCs and testicular macrophages (tMacs). LCs release extracellular vesicles (EVs) containing defective mitochondria, which are eliminated by CD206hi tMacs in a TREM2-dependent process. Conditional deletion of Trem2 in tMacs disrupts this mitochondrial transfer, leading to impaired testosterone synthesis. Conversely, MHCIIhi tMacs enhance testosterone production by transferring EVs containing functional mitochondria to LCs. This EVs-mediated communication depends on ITGB1-VCAM1 interaction, and conditional deletion of Vcam1 in LCs hinders this mitochondrial transfer, compromising testosterone production. Together, our findings reveal an unrecognized bidirectional mitochondrial transfer loop between LCs and tMacs that safeguards LCs homeostasis and testosterone production. This study offers novel insights into the mechanism of testosterone regulation and suggests potential therapeutic targets for male primary hypogonadism.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: Suyuan Zhang

LAB HEAD: Andy P. Xiang

PROVIDER: PXD059780 | Pride | 2026-01-24

REPOSITORIES: Pride

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			Action	DRS
	MS230184.raw	Raw
	ms230184-chimerys.xlsx	Xlsx

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.

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