Endometrial stem/progenitor cells: Properties, origins, and functions

Abstract

The endometrium is the inner mucosal lining of the uterus that undergoes extensive cyclic growth, regeneration, differentiation, and shedding throughout the menstrual cycle in response to steroid hormones. It repeatedly undergoes approximately 450 cycles of degeneration and regeneration in a woman's lifetime. Endometrial abnormalities can be associated with repeated embryo implantation failure, recurrent spontaneous abortion, and other physiological features responsible for female infertility. This significant regenerative capacity may occur as a result of tissue-resident stem cell populations within the endometrium. Indeed, the existence of endometrial stem cells was only observed in humans and rodents through several isolation and characterization methods in the last few years. Although endometrial stem cells share various biological characteristics with other types of mesenchymal stem cells, they also show some differences in phenotype, self-renewal, and multilineage differentiation potential. Extensive studies over many years on endometrial stem cells will provide new insights into the physiology and mechanisms underlying various gynaecological diseases related to endometrial abnormalities such as female infertility, endometriosis, and endometrial cancer. Here we summarized recent studies about cellular origins and biological characteristics of endometrial stem cells. We also reviewed various recent studies to improve our understanding of their physiological roles. Many preclinical studies on their potential therapeutic applications to various endometrial diseases that could lead to reproductive dysfunction were also reviewed.

Keywords: CD146; LGR5; OCT-4; SOX9; SSEA-1; SUSD2; Side population; Wnt/β-catenin.

Figure 1

Schematic diagram of the dynamic endometrial tissue and the location of endometrial stem cells. Endometrium repeatedly undergoes approximately 450 cycles of degeneration and regeneration in ovarian hormones, estrogen and progesterone. The functional endometrial layer is cyclically regenerated from the basalis, which is not shed during menstruation. This cyclic regeneration of endometrium may is mediated by tissue-resident endometrial stem cells located in the basal layer.

Figure 2

Schematic diagram of two hypotheses about the endogenous origin of human endometrial stem cells. Stromal-type endometrial stem cells are found around the luminal and glandular epithelia within both functional and basal endometrial layers. Stromal-like stem cells are known to express multiple markers such as CD90, CD133, CD146, LGR5, NTPDase2, Stro-1, and SUSD2. Epithelial-like stem cells are known to exist mainly at the base of glands or blood vessels located in the basal endometrial layer and express various specific genes such as DNMT3B, GDF3, GABR3, NANOG, N-cadherin, OCT-4, and SSEA-1.

Figure 3

Schematic diagram of two hypotheses about the exogenous origin (bone marrow-derived stem cells) of human endometrial stem cells. Enhanced estrogen secretion is known to stimulate the translocation of circulating endothelial progenitor cells into endometrial blood vessels through CXCL12/CXCR4 signaling cascade.

Figure 4

Schematic diagram of the characteristics of endometrial stem cells. Current studies on biomarkers of endometrial stem cells have been focused on certain genes known to be associated with some critical functions of other stem cell types, such as self-renewal capacity, pluripotency, and multilineage differentiation potential.