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Effect of Aging on the Human Myometrium at Single-Cell Resolution

ABSTRACT: The myometrial dysfunction associated with aging can prompt complications during pregnancy and labor, causing a 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty peri- and post-menopausal women. We identified 23 myometrial cell subpopulations, including novel contractile capillary, venous capillary, immune-modulated fibroblasts, and nervous system regulatory fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observed altered myometrial cell-to-cell communication as an aging hallmark associated with the loss of 25/229 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older women during pregnancy and labor

ORGANISM(S): Homo sapiens

PROVIDER: GSE236660 | GEO | 2023/12/12

REPOSITORIES: GEO

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Project description:Changes in cell phenotype are thought to occur through the expression of groups of co-regulated genes within Topologically Associated Domains (TADs). In this paper we locate genes expressed within the myometrium of the human uterus during the onset of term labor into TADs. Transformation of the myometrial cells of the uterus into a contractile phenotype during term human labor is the result of a complex interaction of different epigenomic and genomic layers. Recent work suggests that the transcription factor RelA lies at the top of this regulatory network. Using deep RNAseq analysis of myometrial samples obtained at term from women undergoing caesarean section prior to or after the onset of labor we have identified evidence for how other gene expression regulatory elements interact with transcription factors in the labor phenotype transition. Gene set enrichment analysis of our RNAseq data identified three modules of enriched genes (M1, M2 and M3) which in gene ontology studies are linked to matrix degradation, smooth muscle and immune gene signatures. These genes were predominantly located within chromosomal TADs suggesting co-regulation of expression. Our transcriptomic analysis also identified significant differences in the expression of long-non-coding RNAs (lncRNA), microRNAs (miRNA) and transcription factors that were predicted to target genes within the TADs. Additionally, network analysis revealed 14 new lncRNA (MCM3AP-AS1, TUG1, MIR29B2CHG, HCG18, LINC00963, KCNQ1OT1, NEAT1, HELLPAR, SNHG16, NUTM2B-AS1, MALAT1, PSMA3-AS1, GABPB1-AS1, NORAD, NKILA) and 4 miRNA (mir-145, mir-223, mir-let-7a, mir-132) as top gene hubs with 4 transcription factors (NFKB1, RELA, ESR1) as master regulators. Together, these factors are likely to be involved in co-regulatory networks driving a myometrial transformation to generate an estrogen sensitive phenotype. We conclude that lncRNA and miRNA targeting the ESR1 and NFKB pathways play a key role in the initiation of human labor. For the first time we perform an integrative analysis to present a multi-level genomic signature in the myometrium for spontaneous term labor.

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Effect of Aging on the Human Myometrium at Single-Cell Resolution

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