Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users
Abstract The injectable contraceptive, depot medroxyprogesterone acetate (DMPA), is associated with compromised cervical mucosal barriers. High-resolution spatial transcriptomics is applied here to reveal the spatial localization of these altered molecular markers. Ectocervical tissue samples from K...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-024-83775-9 |
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| author | Vilde Kaldhusdal Mathias Franzen Boger Annelie Tjernlund Adam D. Burgener Frideborg Bradley Julie Lajoie Kenneth Omollo Joshua Kimani Keith Fowke Paulo Czarnewski Kristina Broliden |
| author_facet | Vilde Kaldhusdal Mathias Franzen Boger Annelie Tjernlund Adam D. Burgener Frideborg Bradley Julie Lajoie Kenneth Omollo Joshua Kimani Keith Fowke Paulo Czarnewski Kristina Broliden |
| author_sort | Vilde Kaldhusdal |
| collection | DOAJ |
| description | Abstract The injectable contraceptive, depot medroxyprogesterone acetate (DMPA), is associated with compromised cervical mucosal barriers. High-resolution spatial transcriptomics is applied here to reveal the spatial localization of these altered molecular markers. Ectocervical tissue samples from Kenyan sex workers using DMPA, or non-hormonal contraceptives, underwent spatial transcriptomics and gene set enrichment analyses. Integrated systemic estradiol levels and bulk tissue gene expression data from a larger cohort enhanced the study’s scope. Unsupervised clustering unveiled four epithelial and seven submucosal layers, showcasing spatially restricted and diverse functional epithelial responses, and a less structured submucosal spatial ordering. DMPA associated with mucosal-wide immunoglobulin gene upregulation, verified by CD20+ B-cell immunostaining, and upregulated immune markers adjacent to the basal membrane. Downregulated genes represented spatially restricted disrupted epithelial barrier integrity and submucosal extracellular matrix dysfunction. The transcriptional profile was associated with markers of estrogen regulation. Collectively, our findings reveal estrogen-modulated distinct ectocervical transcriptional profiles associated with DMPA usage. While upregulation of immunoglobulin genes occurs throughout the mucosa, activation of innate immune responses and dysregulation of barrier integrity markers are spatially restricted. These results extend previous analyses using bulk transcriptomics and provide insights into the molecular landscape influenced by DMPA, shedding light on contraceptive effects and health implications. |
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| id | doaj-art-d9ddf925d3fc4483b70f7ec6e88f86b8 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-d9ddf925d3fc4483b70f7ec6e88f86b82025-01-12T12:14:57ZengNature PortfolioScientific Reports2045-23222025-01-0115111610.1038/s41598-024-83775-9Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate usersVilde Kaldhusdal0Mathias Franzen Boger1Annelie Tjernlund2Adam D. Burgener3Frideborg Bradley4Julie Lajoie5Kenneth Omollo6Joshua Kimani7Keith Fowke8Paulo Czarnewski9Kristina Broliden10Department of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetDepartment of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetDepartment of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetDepartment of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetDepartment of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetDepartment of Medical Microbiology and Infectious Diseases, University of ManitobaDepartment of Medical Microbiology and Immunology, University of Nairobi, Kenyatta National Hospital CampusDepartment of Medical Microbiology and Infectious Diseases, University of ManitobaDepartment of Medical Microbiology and Infectious Diseases, University of ManitobaScience for Life Laboratory, Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Stockholm UniversityDepartment of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstitutetAbstract The injectable contraceptive, depot medroxyprogesterone acetate (DMPA), is associated with compromised cervical mucosal barriers. High-resolution spatial transcriptomics is applied here to reveal the spatial localization of these altered molecular markers. Ectocervical tissue samples from Kenyan sex workers using DMPA, or non-hormonal contraceptives, underwent spatial transcriptomics and gene set enrichment analyses. Integrated systemic estradiol levels and bulk tissue gene expression data from a larger cohort enhanced the study’s scope. Unsupervised clustering unveiled four epithelial and seven submucosal layers, showcasing spatially restricted and diverse functional epithelial responses, and a less structured submucosal spatial ordering. DMPA associated with mucosal-wide immunoglobulin gene upregulation, verified by CD20+ B-cell immunostaining, and upregulated immune markers adjacent to the basal membrane. Downregulated genes represented spatially restricted disrupted epithelial barrier integrity and submucosal extracellular matrix dysfunction. The transcriptional profile was associated with markers of estrogen regulation. Collectively, our findings reveal estrogen-modulated distinct ectocervical transcriptional profiles associated with DMPA usage. While upregulation of immunoglobulin genes occurs throughout the mucosa, activation of innate immune responses and dysregulation of barrier integrity markers are spatially restricted. These results extend previous analyses using bulk transcriptomics and provide insights into the molecular landscape influenced by DMPA, shedding light on contraceptive effects and health implications.https://doi.org/10.1038/s41598-024-83775-9DMPASpatial transcriptomicsEctocervixHypoestrogenemiaMucosaEstrogen |
| spellingShingle | Vilde Kaldhusdal Mathias Franzen Boger Annelie Tjernlund Adam D. Burgener Frideborg Bradley Julie Lajoie Kenneth Omollo Joshua Kimani Keith Fowke Paulo Czarnewski Kristina Broliden Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users Scientific Reports DMPA Spatial transcriptomics Ectocervix Hypoestrogenemia Mucosa Estrogen |
| title | Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| title_full | Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| title_fullStr | Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| title_full_unstemmed | Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| title_short | Spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| title_sort | spatial transcriptomics unveils estrogen modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users |
| topic | DMPA Spatial transcriptomics Ectocervix Hypoestrogenemia Mucosa Estrogen |
| url | https://doi.org/10.1038/s41598-024-83775-9 |
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