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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-025-01445-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235262533533696 |
|---|---|
| author | Jun Yu Longfei Hu Huixia Li Xiaofeng Li Chaoye Ma Ting Jiang Yongxin Liu Xue Wang Xia Li Liandong Zuo Haocheng Lin Wenming Xu Yiwen Zhou Yang Liu Hao Chen |
| author_facet | Jun Yu Longfei Hu Huixia Li Xiaofeng Li Chaoye Ma Ting Jiang Yongxin Liu Xue Wang Xia Li Liandong Zuo Haocheng Lin Wenming Xu Yiwen Zhou Yang Liu Hao Chen |
| author_sort | Jun Yu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e91089216c7a4135aae6253f5db2a731 |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-e91089216c7a4135aae6253f5db2a7312025-08-20T04:02:50ZengBMCCell & Bioscience2045-37012025-07-0115111610.1186/s13578-025-01445-3Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testisJun Yu0Longfei Hu1Huixia Li2Xiaofeng Li3Chaoye Ma4Ting Jiang5Yongxin Liu6Xue Wang7Xia Li8Liandong Zuo9Haocheng Lin10Wenming Xu11Yiwen Zhou12Yang Liu13Hao Chen14Institute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversitySingleron BiotechnologiesInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityDepartment of Laboratory Medicine, Peking University Shenzhen HospitalInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityGMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityDepartment of Urology, Peking University Third Hospital, Peking UniversityJoint Lab of Reproductive Medicine of SCU-CUHK, Lab of Reproductive Genetics and Epigenetics, Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, West China Second University Hospital, Sichuan UniversityDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineInstitute of Reproductive Medicine, Medical School, Institute of Special Environmental Medicine, Nantong UniversityAbstract 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.https://doi.org/10.1186/s13578-025-01445-3Single-cell RNA sequencingCell communicationTesticular impairment |
| spellingShingle | Jun Yu Longfei Hu Huixia Li Xiaofeng Li Chaoye Ma Ting Jiang Yongxin Liu Xue Wang Xia Li Liandong Zuo Haocheng Lin Wenming Xu Yiwen Zhou Yang Liu Hao Chen Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis Cell & Bioscience Single-cell RNA sequencing Cell communication Testicular impairment |
| title | Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis |
| title_full | Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis |
| title_fullStr | Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis |
| title_full_unstemmed | Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis |
| title_short | Single-cell RNA sequencing uncovers abnormal Sertoli-cell elevation and testicular niche impairment in the transfemales’s testis |
| title_sort | single cell rna sequencing uncovers abnormal sertoli cell elevation and testicular niche impairment in the transfemales s testis |
| topic | Single-cell RNA sequencing Cell communication Testicular impairment |
| url | https://doi.org/10.1186/s13578-025-01445-3 |
| work_keys_str_mv | AT junyu singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT longfeihu singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT huixiali singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT xiaofengli singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT chaoyema singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT tingjiang singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT yongxinliu singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT xuewang singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT xiali singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT liandongzuo singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT haochenglin singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT wenmingxu singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT yiwenzhou singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT yangliu singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis AT haochen singlecellrnasequencinguncoversabnormalsertolicellelevationandtesticularnicheimpairmentinthetransfemalesstestis |