Spatial Transcriptomics Unveils Estrogen-modulated Immune Responses and Structural Alterations in the Ectocervical Mucosa of Depot Medroxyprogesterone Acetate Users

Overview

Journal Sci Rep

Specialty Science

Date 2025 Jan 6

PMID 39762272

Authors

Vilde Kaldhusdal

Mathias Franzen Boger

Annelie Tjernlund

Adam D Burgener

Frideborg Bradley

Julie Lajoie

Kenneth Omollo

Joshua Kimani

Keith Fowke

Paulo Czarnewski

Kristina Broliden

Affiliations

Soon will be listed here.

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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