Kaldhusdal Vilde, Boger Mathias Franzen, Tjernlund Annelie, Burgener Adam D, Bradley Frideborg, Lajoie Julie, Omollo Kenneth, Kimani Joshua, Fowke Keith, Czarnewski Paulo, Broliden Kristina
Department of Medicine Solna, Division of Infectious Diseases, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Bioclinicum J7:20, 171 76, Solna, Sweden.
Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA.
Sci Rep. 2025 Jan 6;15(1):1014. doi: 10.1038/s41598-024-83775-9.
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.
注射用避孕药醋酸甲羟孕酮长效避孕针（DMPA）与宫颈黏膜屏障受损有关。本文应用高分辨率空间转录组学来揭示这些改变的分子标记物的空间定位。对使用DMPA或非激素避孕药的肯尼亚性工作者的宫颈外口组织样本进行了空间转录组学和基因集富集分析。来自更大队列的综合全身雌二醇水平和大块组织基因表达数据扩大了该研究的范围。无监督聚类揭示了四个上皮层和七个黏膜下层，展示了空间受限且多样的功能性上皮反应，以及结构较松散的黏膜下空间排列。DMPA与全黏膜免疫球蛋白基因上调有关，经CD20 B细胞免疫染色验证，并与基底膜附近的免疫标记物上调有关。下调的基因代表空间受限的上皮屏障完整性破坏和黏膜下细胞外基质功能障碍。转录谱与雌激素调节标记物有关。总体而言，我们的研究结果揭示了与使用DMPA相关的雌激素调节的不同宫颈外口转录谱。虽然免疫球蛋白基因在整个黏膜中上调，但先天免疫反应的激活和屏障完整性标记物的失调在空间上是受限的。这些结果扩展了先前使用大块转录组学的分析，并提供了对受DMPA影响的分子格局的见解，揭示了避孕效果和健康影响。
