Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis
Abstract Background Transgender women (transfemales) often undergo gender-affirming hormone therapy (GAHT). However, the testicular impacts of feminising hormones present heterogeneity due to the complexity of testicular regulatory mechanisms. Method In this study, we analyzed approximately 49,385 s...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-025-01445-3 |
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| Summary: | Abstract Background Transgender women (transfemales) often undergo gender-affirming hormone therapy (GAHT). However, the testicular impacts of feminising hormones present heterogeneity due to the complexity of testicular regulatory mechanisms. Method In this study, we analyzed approximately 49,385 single-cell transcriptomes from transfemale human testicular tissue, comparing cellular composition with that of cisgender male individuals across a range of ages. Our approach included clustering of cell types, identification of marker genes, pseudotime analysis of germ cells, and comprehensive cell-cell interaction analyses. We employed immunohistochemistry, quantitative real-time PCR, and immunostaining to validate the key molecular signatures identified in the pathways of interest. Results GAHT led to a significant reduction in spermatogenic cells, accompanied by an unexpected increase in Sertoli cell numbers per seminiferous tubule, suggesting disrupted germ cell-Sertoli cell interactions. Molecular analyses revealed upregulation of genes such as Decorin (DCN), Myoglobin (MB), and Beta-2-Microglobulin (B2M) in Sertoli cells, with enrichment in pathways related to cell adhesion, cytokine response, and wnt signaling. Notably, β-catenin was significantly elevated and translocated into the nucleus of Sertoli cells determined by immunostaining analysis. Additionally, collagen fiber infiltration disrupted the testicular microenvironment, further impairing germline-Sertoli cell communication. Conclusion This study provides novel insights into the testicular alterations associated with GAHT in transfemales, particularly highlighting the role of germline-Sertoli cell interactions in testicular injury. Our findings contribute to a deeper understanding of the testicular response to feminizing hormones, offering a foundation for future therapeutic strategies. |
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| ISSN: | 2045-3701 |