Endometrial Stem/Progenitor Cells–Their Role in Endometrial Repair and Regeneration

Abstract

The human endometrium is a remarkable tissue, undergoing ~450 cycles of proliferation, differentiation, shedding (menstruation), repair, and regeneration over a woman's reproductive lifespan. Post-menstrual repair is an extremely rapid and scar-free process, with re-epithelialization of the luminal epithelium completed within 48 h of initiation of shedding. Following menstruation, the functionalis grows from the residual basalis layer during the proliferative phase under the influence of rising circulating estrogen levels. The regenerative capacity of the endometrium is attributed to stem/progenitor cells which reside in both the epithelial and stromal cell compartments of the basalis layer. Finding a definitive marker for endometrial epithelial progenitors (eEPCs) has proven difficult. A number of different markers have been suggested as putative progenitor markers including, N-cadherin, SSEA-1, AXIN2, SOX-9 and ALDH1A1, some of which show functional stem cell activity in in vitro assays. Each marker has a unique location(s) in the glandular epithelium, which has led to the suggestion that a differentiation hierarchy exists, from the base of epithelial glands in the basalis to the luminal epithelium lining the functionalis, where epithelial cells express different combinations of markers as they differentiate and move up the gland into the functionalis away from the basalis niche. Perivascular endometrial mesenchymal stem cells (eMSCs) can be identified by co-expression of PDGFRβ and CD146 or by a single marker, SUSD2. This review will detail the known endometrial stem/progenitor markers; their identity, location and known interactions and hierarchy across the menstrual cycle, in particular post-menstrual repair and estrogen-driven regeneration, as well as their possible contributions to menstruation-related disorders such as endometriosis and regeneration-related disorder Asherman's syndrome. We will also highlight new techniques that allow for a greater understanding of stem/progenitor cells' role in repair and regeneration, including 3D organoids, 3D slice cultures and gene sequencing at the single cell level. Since mouse models are commonly used to study menstruation, repair and regeneration we will also detail the mouse stem/progenitor markers that have been investigated in vivo.

Frequent PIK3CA mutation in normal endometrial gland drives spheroid formation and may be involved in stem cell propagation

“…Next, IHC was carried out to characterize the properties of the spheroids. First, the expression of ALDH1A1, Axin2, and SOX9, previously reported stem cell marker of endometrial epithelium, 17 was examined in spheroids after grown in stem‐cell media for over 3 months. As shown in Figure 4A, the predominant expressions of cytoplasmic ALDH1A1, nuclear Axin2, and SOX9 were confirmed in all the spheroids examined, suggesting that spheroids were mainly composed of cells with stem‐like characteristics through long‐term culture.…”

The role of human endometrial stem cells application in endometrial-factor induced infertility

“…These ndings ful l the minimal criteria to de ne human MSCs proposed by Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) [45][46][47]. The ndings negate the uncertainty about endometrium scratching usage for stem cells collection and lead us to clearly con rm that not only stratum basalis, but, also, stratum functionalis could be used for the isolation of stem cells with high proliferation, self-renewal and differentiation potential characteristics of hEnSCs [48][49][50][51]. The evidence that hEnSCs can be easily and repeatedly isolated without leading to major technical problems or causing inconvenience to patientssuch as the need for hospitalization or anaesthesia -is worthwhile for stem cells-based therapy implementation in clinical practise [52,53].…”

Modeling Endometrium Biology and Disease

“…Finally, to construct ‘a uterus in a dish’, at least comprising endometrium and myometrium mimics, not only the different cell types need to be included, but also the complex architectural organization needs to be recapitulated, such as basalis and functionalis layers with differing gland configurations [ 52 , 120 ], and stem/progenitor cell hierarchies [ 121 ]. Eventual faithful modeling will strongly help to enhance our understanding of uterus biology and pathology.…”