Does human endometrial LGR5 gene expression suggest the existence of another hormonally regulated epithelial stem cell niche?

Tempest, Nicola; Baker, AM; Wright, Nicholas; Hapangama, D

doi:10.1093/humrep/dey083

Cited by 56 publications

(71 citation statements)

References 45 publications

(75 reference statements)

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“…The basalis markers described below (SSEA-1, nuclear SOX9, nuclear β-catenin) were the first basalis markers to be presented as epithelial ASC markers in 2013 [ 13 ]. Subsequent work has also suggested N-cadherin to be another basalis marker [ 84 ], but the very recent work using LGR5 in situ hybridisation challenges this hypothesis and proposes the existence of more than one epithelial stem cell niche in the human endometrium [ 85 ]. These studies, however, are based on the presumption that human endometrial glandular architectural arrangement is a single blunt-ended tube, which is disputed in 3D reconstruction studies [ 86 ].…”

Section: Identifying Markers That Are Expressed By Cells Located Imentioning

confidence: 99%

“…However, this study has not demonstrated any other stem cell properties of the SSEA1 + epithelial cells and their in vivo tissue reconstitution ability is also not yet known. More recent work has described some SSEA1 + cells to also be located in the LE, thus the expression is not strictly limited to the basalis [ 85 ]. The other criticism of SSEA1 + cells being progenitors is their relative abundance in the basalis and in the PM endometrium.…”

Section: Identifying Markers That Are Expressed By Cells Located Imentioning

confidence: 99%

“…To overcome the above deficiencies in the literature, earlier this year, the gold standard method of in situ hybridisation (ISH) was utilised alongside qRT-PCR, IHC and in silico analysis of published endometrial microarray datasets to conclusively examine the cellular location of LGR5 expression in full thickness normal human endometrium [ 85 ]. LGR5 expression was limited to the epithelial compartment of the endometrium, with high LGR5 expressing cells seen in the endometrial LE and in the stratum basalis; the LE expressed significantly higher levels of LGR5 than all other epithelial compartments.…”

Section: Examining Endometrium For the Expression Of Putative Stemmentioning

confidence: 99%

“…Data was further confirmed by analysing previously published microarray datasets. The epithelial compartment-specific expression pattern of LGR5 in the full thickness endometrium prompted the novel theory that more than one epithelial stem/progenitor cell pool could exist in the human endometrium; one residing in the basalis (SSEA-1 ++ /SOX9 ++ / LGR5 + ) supporting the massive regeneration of the functionalis after menstrual shedding or parturition; while the other ( LGR5 ++ / SSEA-1 + /SOX9 + ) supports the embryo-implantation process, and maintains the LE cells that are likely to be lost on a daily basis [ 85 ]. However, this study was an observational study without any functional data.…”

Section: Examining Endometrium For the Expression Of Putative Stemmentioning

confidence: 99%

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Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

Tempest

Maclean

Hapangama

2018

IJMS

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The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.

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Section: Identifying Markers That Are Expressed By Cells Located Imentioning

confidence: 99%

Section: Identifying Markers That Are Expressed By Cells Located Imentioning

confidence: 99%

Section: Examining Endometrium For the Expression Of Putative Stemmentioning

confidence: 99%

Section: Examining Endometrium For the Expression Of Putative Stemmentioning

confidence: 99%

See 2 more Smart Citations

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

Tempest

Maclean

Hapangama

2018

IJMS

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“…TCGA contained RNA sequencing data with patient follow up data for n = 200 of LGEC (grade I and II endometrioid EC) and n = 281 of HGEC (grade III endometrioid, serous, undifferentiated EC). Published microarray datasets from 3 further individual studies were examined with Illumina’s BaseSpace Correlation Engine application in BSCA and genes that perturbed AGR2 gene when mutated knocked down were identified with the Knockout atlas application as previously described [ 50 ] software; https://www.illumina.com/informatics/research/biological-data-interpretation/nextbio.html ; Illumina, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

High AGR2 protein is a feature of low grade endometrial cancer cells

et al. 2018

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BackgroundBiomarkers for identification of endometrial cancers (ECs) with high risk of recurrence are required to reduce the rising EC-related mortality. AGR2 is a prognostic marker in several hormonally-regulated cancers.AimTo assess the utility of AGR2 as a prognostic marker in EC.MethodsAGR2 immunoexpression was evaluated in 163 human endometrial samples. Change in AGR2 mRNA levels in response to oestrogen and dihydrotestosterone was studied in vitro.ResultsUpregulation of AGR2 (protein and mRNA) was seen in low grade EC, compared to the postmenopausal endometrium (P = 0.013) and to the high-grade EC (P < 0.0001). Elevated AGR2 protein expression-scores were associated with a high expression of estrogen alpha (ERα), progesterone, androgen receptors and early clinical stages. Metastatic lesions maintained higher AGR2 expression relative to matched-primary tumors. High-AGR2 protein levels were associated with better overall survival (P = 0.02) in all ECs, but in highly-ERα-expressing ECs, AGR2 associated with unfavourable patient outcome. Androgen through its receptor, downregulated AGR2 mRNA in the Ishikawa cells.ConclusionsAGR2 is overexpressed in low grade ECs and positively associated with hormone receptors. The association between high AGR2 and progressive disease within the high-ERα-expressing ECs suggests that in this group of patients, AGR2 might be a potential biomarker of poor prognosis.

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Generation of Human Endometrial Assembloids with a Luminal Epithelium using Air–Liquid Interface Culture Methods

Tian,

Yang,

Chen

et al. 2023

Advanced Science

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The endometrial lining of the uterus is essential for women's reproductive health and consists of several different types of epithelial and stromal cells. Although models such as gland‐like structures (GLSs) and endometrial assembloids (EnAos) are successfully established, they lack an intact luminal epithelium, which makes it difficult to recapitulate endometrial receptivity. Here, a novel EnAo model (ALI‐EnAo) is developed by combining endometrial epithelial cells (EnECs) and stromal cells (EnSCs) and using an improved matrix and air–liquid interface (ALI) culture method. ALI‐EnAos exhibit intact EnSCs and glandular and luminal epithelia, which recapitulates human endometrium anatomy, cell composition, hormone‐induced menstrual cycle changes, gene expression profiles, and dynamic ciliogenesis. The model suggests that EnSCs, together with the extracellular matrix and ALI culture conditions, contribute to EnAo phenotypes and characteristics reflective of the endometrial menstrual cycle. This enables to transcriptionally define endometrial cell subpopulations. It anticipates that ALI‐EnAos will facilitate studies on embryo implantation, and endometrial growth, differentiation, and disease.

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Does human endometrial LGR5 gene expression suggest the existence of another hormonally regulated epithelial stem cell niche?

Cited by 56 publications

References 45 publications

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

High AGR2 protein is a feature of low grade endometrial cancer cells

Generation of Human Endometrial Assembloids with a Luminal Epithelium using Air–Liquid Interface Culture Methods

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