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Role of progesterone receptor in inguinal hernia formation via skeletal muscle fibrosis [Hernia_Xenium]

ABSTRACT: Inguinal hernia development has been linked to fibrosis and atrophy of the lower abdominal muscle (LAM). We have shown that exogenous adminstration of estradiol (E2) and progesterone (P4) in mice can induce LAM fibrosis, muscle atrophy, and hernia development in mice, and that concurrent inhibition of progesterone receptor signaling using the drug RU486 can prevent this process. Utilizing a combination of single-nuclear transcriptomics and epigenomics, we analyzed the effects of E2 and P4 on the different cell types in the LAM to determine how these compounds contribute to hernia development. Xenium spatial transcriptomics of LAM tissue of treated WT mice allowed for validation of cell type colocalization and differential gene analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE288663 | GEO | 2025/06/03

REPOSITORIES: GEO

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Project description:The myometrium is an important reproductive tissue composed primarily of smooth muscle cells. Contractility of the myometrial smooth muscle cells during pregnancy and labour is modulated by hormones. Despite much research, little is known about the molecular mechanism by which estrogen and progesterone regulate myometrial contractility. This study investigates global gene expression profile of cultured human uterine smooth muscle cells (hUtSMCs) following 17Î²-estradiol (E2) and/or progesterone treatments using cDNA microarray technology. Furthermore the effects of addition of the progesterone inhibitor RU486 were investigated. Many genes were regulated in the presence of P4 or E2 alone but almost six times these numbers were regulated in the presence of the combination. The majority of these genes returned to near baseline levels (control samples) on addition of RU486. In total 796 annotated genes were significantly differentially expressed in the combined presence of P4 and E2 (relative to untreated levels). Furthermore, 666 annotated genes were significantly regulated by the addition of RU486 to the P4/E2 combination (relative to P4/E2 levels). Gene ontology analysis of these differentially expressed genes revealed a strong association of P4/E2 treatment with the downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response and differentiation. Upregulated processes included cell survival (anti-apoptosis), gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling and cell growth. Functional withdrawal of progesterone using RU486 effectively reversed the processes induced by P4/E2 treatment. The hUtSMC system is an additional useful model to investigate steroid effects on smooth muscle cells in isolation from other myometrial cell types. In this study human myometrial smooth muscle cells (hUtSMCs) purchased from Lonza were cultured and treated with 17beta estradiol and progesterone either alone or in combination. In addition the 17beta estradiol and progesterone combined treated samples were also treated with the progesterone inhibitor RU486 (mifepristone). RNA was isolated after 72h from both treated and untreated control cells. The experiment was repeated 3 times. Please note that slides were scanned three times successively (i.e. 3 .gpr files per sample) and the median raw values were used as input raw data for GeneSpring analysis (Median_Table_InputRAW.xlsx).

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Role of progesterone receptor in inguinal hernia formation via skeletal muscle fibrosis [Hernia_Xenium]

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