Unveiling urethral cellular heterogeneity in menopause through single-nucleus RNA sequencing

Area of Science:

• Urology
• Molecular Biology
• Genomics

Background:

• Estrogen is vital for urethral structure and function.
• Estrogen deprivation, seen in menopause or ovariectomy, can cause urethral dysfunction.
• The precise molecular mechanisms behind these changes are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular changes in the rat urethra during estrogen deprivation.
• To identify key genes and pathways affected by menopause-associated hormonal changes.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was performed on urethras from ovariectomized (OVX) and Sham control rats.
• Unsupervised clustering (UMAP) and differential gene expression analysis were used to identify cell types and transcriptional changes.
• Functional enrichment analysis explored biological pathways and cellular interactions.

Main Results:

• snRNA-seq revealed significant cellular heterogeneity and transcriptional reprogramming in the OVX rat urethra.
• Fos was identified as a key transcription factor in epithelial cell communication and differentiation under low estrogen.
• Basal epithelial cells showed epithelial-to-mesenchymal transition (EMT) programs, and Tmem233 was linked to muscle contraction; immune cells, especially T cells, exhibited increased inflammation.

Conclusions:

• This study provides a comprehensive snRNA-seq analysis of the female rat urethra during menopause.
• It elucidates critical cellular and molecular alterations, including EMT and inflammatory responses, driven by estrogen deficiency.