Biology subjects

Cousins, F. L.

Publications and source records attributed to Cousins, F. L..

2 recordsLinked to original sources

bioRxiv2025

Molecular signature of human endometrial stem/progenitor cells at the single cell level

Human endometrium sheds and regenerates each month during the menstrual cycle. N-cadherin+ (CDH2) glandular epithelial progenitors and SUSD2+ MSC and their niches have been identified but their signaling interactions remain unknown. SSEA1+ epithelial cells resurface the endometrium generating a new luminal epithelium each cycle. Based on these markers, we characterised the gene expression of human endometrial stem/progenitor cell-enriched populations derived from FACSorted hysterectomy endometrium by scRNAseq. Two of 10 epithelial clusters contained CDH2+SOX9+ cells with high TRH and IHH expression. N-cadherin and IHH, and SSEA1 and Hedgehog coreceptor BOC immunocolocalised in the basal layer of endometrial glands from which the new functional layer glands regenerate each menstrual cycle. Two of six mesenchymal clusters contained SUSD2+ MSC, one with high MUSTN1 expression. Epithelial progenitors and endometrial MSC transitioned to their respective progeny. We provide new insights into human endometrial stem/progenitor cell signaling pathways and niche interactions regulating their function. HighlightsO_LIEnriching cell suspensions of human endometrial cells from hysterectomy tissues with CDH2+ epithelial progenitors, SSEA-1+ basalis epithelial cells and SUSD2+ perivascular MSC enabled their gene profiling at the single cell level. C_LIO_LIMultiple cell fate trajectory analyses showed that CDH2+SOX9+ epithelial cells and SUSD2+MYH11+MCAM+MUSTN1+ MSC are the progenitors for human endometrial glandular and luminal epithelial cells, and stromal vascular cells, respectively. C_LIO_LIEnriched TRH expression in human endometrial epithelial progenitors suggests a role in their progenitor function. C_LIO_LIInteraction between IHH of SOX9+ human endometrial epithelial progenitors with basalis fibroblasts and decidualized stroma and co-receptor BOC suggests IHH signalling may have a role in basalis epithelial migration to repair the luminal epithelium during menses. C_LI eTOC blurbGargett and colleagues provide a molecular signature of human endometrial stem/progenitor cells by enriching 4 stem/progenitor populations from hysterectomies using known markers for scRNAseq analysis. The two epithelial and two MSC progenitor states identified transitioned to their differentiated progeny. IHH was validated as a key signalling molecule of epithelial progenitors in basal glands that interacted with BOC co-receptors.

molecular biology↗

bioRxiv2022

A Role for Steroid 5 alpha-reductase 1 in Vascular Remodelling During Endometrial Decidualisation

Decidualisation is the hormone-dependent process of endometrial remodelling that is essential for fertility and reproductive health. It is characterised by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodelling. Deficits in decidualisation are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-eclampsia. Androgens are key regulators of decidualisation that promote optimal differentiation of stromal fibroblasts and activation of downstream signalling pathways required for endometrial remodelling. We have shown that androgen biosynthesis, via 5-reductase-dependent production of dihydrotestosterone, is required for optimal decidualisation of human stromal fibroblasts in vitro, but whether this is required for decidualisation in vivo has not been tested. In the current study we used steroid 5-reductase type 1 (SRD5A1) deficient mice (Srd5a1-/- mice) and a validated model of induced decidualisation to investigate the role of SRD5A1 and intracrine androgen signalling in endometrial decidualisation. We measured decidualisation response (weight/proportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5-reductase deficiency on the decidualisation response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signalling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualisation restored decidualisation responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signalling is required for optimal decidualisation in vivo and confirm a major role for androgens in the development of the vasculature during decidualisation through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signalling in the endometrium.

physiology↗