The Elusive Endometrial Epithelial Stem/Progenitor Cells

Abstract

The human endometrium undergoes approximately 450 cycles of proliferation, differentiation, shedding and regeneration over a woman's reproductive lifetime. The regenerative capacity of the endometrium is attributed to stem/progenitor cells residing in the basalis layer of the tissue. Mesenchymal stem cells have been extensively studied in the endometrium, whereas endometrial epithelial stem/progenitor cells have remained more elusive. This review details the discovery of human and mouse endometrial epithelial stem/progenitor cells. It highlights recent significant developments identifying putative markers of these epithelial stem/progenitor cells that reveal their in vivo identity, location in both human and mouse endometrium, raising common but also different viewpoints. The review also outlines the techniques used to identify epithelial stem/progenitor cells, specifically in vitro functional assays and in vivo lineage tracing. We will also discuss their known interactions and hierarchy and known roles in endometrial dynamics across the menstrual or estrous cycle including re-epithelialization at menses and regeneration of the tissue during the proliferative phase. We also detail their potential role in endometrial proliferative disorders such as endometriosis.

Keywords: adul stem cell; endometrium; epithelial cells; human; lineage tracing; mouse; progenitor cell; stem cell niche.

FIGURE 1

Scanning electron microscopy of human endometrial microarchitecture during menstruation. (A) Day 2, basalis glandular epithelial stump protrudes into the uterine lumen. (B) Day 4, newly formed luminal epithelium progressively covering fibrin-coated denuded areas. (C) Day 7, re-epithelialization has been completed. Adapted with permission from Ludwig and Spornitz (1991).

FIGURE 2

Human endometrial epithelial location and hierarchy. (A) Full-thickness proliferative and secretory stage premenopausal endometrium. Functionalis and basalis delineated by dotted line. Glands (g) extend from the luminal epithelium to the endometrial-myometrial junction, showing branching and horizontal gland profiles in the deep basalis. (B) Epithelial stem/progenitor hierarchy. Adapted with permission from Gargett et al. (2012) and Filby et al. (2020).

FIGURE 3

Mouse endometrium and epithelial unit. (A) Longitudinal section of estrous cycling endometrium, hematoxylin, and eosin stained. (B) A representative uterine epithelial unit stained with CD326 (EpCAM, epithelial marker, green) is composed of LE, duct and single gland labeled by FOXA2 (red) in adult wild-type uterine tissue section. The dotted line shows the intersection zone between luminal and gland epithelial compartments. Scale bar: 5 μm.