Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies

Abstract

Background: Human endometrium remains a poorly understood tissue of the female reproductive tract. The superficial endometrial functionalis, the site of embryo implantation, is repeatedly shed with menstruation, and the stem cell-rich deeper basalis is postulated to be responsible for the regeneration of the functionalis. Two recent manuscripts have demonstrated the 3D architecture of endometrial glands. These manuscripts have challenged and replaced the prevailing concept that these glands end in blind pouches in the basalis layer that contain stem cells in crypts, as in the intestinal mucosa, providing a new paradigm for endometrial glandular anatomy. This necessitates re-evaluation of the available evidence on human endometrial regeneration in both health and disease in the context of this previously unknown endometrial glandular arrangement.

Objective and rationale: The aim of this review is to determine if the recently discovered glandular arrangement provides plausible explanations for previously unanswered questions related to human endometrial biology. Specifically, it will focus on re-appraising the theories related to endometrial regeneration, location of stem/progenitor cells and endometrial pathologies in the context of this recently unravelled endometrial glandular organization.

Search methods: An extensive literature search was conducted from inception to April 2021 using multiple databases, including PubMed/Web of Science/EMBASE/Scopus, to select studies using keywords applied to endometrial glandular anatomy and regeneration, and the references included in selected publications were also screened. All relevant publications were included.

Outcomes: The human endometrial glands have a unique and complex architecture; branched basalis glands proceed in a horizontal course adjacent to the myometrium, as opposed to the non-branching, vertically coiled functionalis glands, which run parallel to each other as is observed in intestinal crypts. This complex network of mycelium-like, interconnected basalis glands is demonstrated to contain endometrial epithelial stem cells giving rise to single, non-branching functionalis glands. Several previous studies that have tried to confirm the existence of epithelial stem cells have used methodologies that prevent sampling of the stem cell-rich basalis. More recent findings have provided insight into the efficient regeneration of the human endometrium, which is preferentially evolved in humans and menstruating upper-order primates.

Wider implications: The unique physiological organization of the human endometrial glandular element, its relevance to stem cell activity and scarless endometrial regeneration will inform reproductive biologists and clinicians to direct their future research to determine disease-specific alterations in glandular anatomy in a variety of endometrial pathological conditions.

Keywords: 3D microarchitecture; adenomyosis; endometrial polyps; endometrial stem progenitor cells; endometriosis; endometrium; fertility; placenta accreta spectrum; regeneration.

Figure 1.

Architecture of human endometrial glands: past and present. (A) Haematoxylin and eosin stained human endometrial section at ×400 and ×20 magnification (scale bars = 50 and 500 μm, respectively). (B) 2D schematic of the pre-2020 consensus view of endometrial glandular architecture, with functionalis glands running a vertical course to the basalis glands and terminating in blind pouches. (C) 3D schematic of the novel endometrial gland arrangement based on recent findings, with basalis glands exhibiting a branching, mycelium-like configuration running perpendicular to functionalis glands.

Figure 2.

Endometrial epithelial stem cell niche. (A) Chromogenic immunostaining of cytochrome C oxidase (CCO) in the human endometrium highlighting the extent of CCO-deficient clonal expansion (blue glands). ×20 magnification (scale bar = 500 μm). (B) 2D rendering of the hypothetical origin of partially CCO-deficient functionalis glands arising from basalis-resident stem cells. Adapted from Tempest et al. (2020). (C) Putative stem cell niches in the endometrial lumen (leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5⁺⁺), stage-specific embryonic-antigen 1 (SSEA-1⁺), SRY-box 9 (SOX9⁺) and basalis (LGR5⁺, SSEA-1⁺⁺, SOX9⁺⁺, N-cadherin⁺, nuclear β-catenin⁺).

Figure 3.

Proposed endometrial epithelial regeneration. (A) Schematic of the full-thickness endometrium highlighting the potential locations of epithelial stem/progenitor cells within the different zones of the basalis. (B) Maintenance of the luminal epithelium by resident stem/progenitor cells following daily shedding, desquamation events and (C) blastocyst implantation. (D) Model of epithelial regeneration via progenitors following complete destruction of the superficial and basalis layers of the endometrium. The mycelium-like configuration of the stem cell rich basalis will allow rapid replenishment of the lost basalis glands by horizontal spread in a way that would not be possible with a blind singular glandular conformation.

Figure 4.

Relevance of epithelial histoarchitecture to endometrial pathologies. (A) Schematics show the ant colony-like structure of adenomyotic lesions containing epithelial glands with multiple branch points (Yamaguchi et al., 2021). Lesions may be connected directly to the endometrial basalis, supporting the theory of eutopic glandular invasion of the myometrium, or isolated lesions, hinting at an alternative origin. The glandular architecture of endometrial polyps and endometriotic lesions (including superficial, ovarian and deep-infiltrating endometriosis) remain to be elucidated. They may have a complex-branching or non-branching glandular conformation. (B) Proposed model of endometrial regeneration in Asherman’s syndrome; following surgical removal of intrauterine adhesions and barrier insertion to inhibit recurrence, basalis networks from neighbouring skip lesions are able to expand parallel to the myometrium in a horizontal plane by means of resident stem/progenitor cells, subsequently restoring the whole glandular element.