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Stem Leydig cells support macrophage immunological homeostasis through intercellular mitochondria transfer in a TRPM7-mediated manner in the testis

ABSTRACT: As a unique population of testicular mesenchymal stromal cells, stem Leydig cells (SLCs) have shown great promise in the treatment of male hypogonadism. The therapeutic functions of MSCs are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs have not been fully studied. Here, we found that transplanted SLCs restored testicular immunological homeostasis via damage signal-triggered transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated mitochondrial transfer to macrophages. Specifically, the results showed that SLCs transplantation restored male fertility and testosterone production in an ischemia‒reperfusion injury-induced acute inflammation model. This was achieved mainly via a mechanism involving the prevention of inflammatory cascades but not the differentiation to Leydig cells (LCs), the main testosterone-producing cells. Furthermore, we identified that ROS released from activated macrophages, which are the primary testicular immunocytes, induced nanotube-mediated mitochondrial transfer from SLCs to macrophages via TRPM7. Notably, TRPM7 knockdown by interfering RNA in transplanted SLCs compromised the therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. Collectively, SLC rescued testicular damage in testicular ischemia‒reperfusion mouse models, and the damage signal activated TRPM7 signaling and induced mitochondrial transfer from SLCs to macrophages, playing important roles in the repair of SLCs. These findings provide insight into the clinical translation of SLCs and suggest that strategies targeting mitochondrial transfer may be effective treatments for patients with male hypogonadism related to immune disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE254881 | GEO | 2024/02/01

REPOSITORIES: GEO

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Project description:Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cells function may have ultimate consequences. 3-methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue™ assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10µM) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 7540 proteins were identified in which the abundance of 87 proteins in unstimulated Leydig cells and 146 proteins in LH-stimulated Leydig cells were found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathion-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.

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Stem Leydig cells support macrophage immunological homeostasis through intercellular mitochondria transfer in a TRPM7-mediated manner in the testis

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