Stromal Heterogeneity in the Human Proliferative Endometrium—A Single-Cell RNA Sequencing Study

Queckbörner, Suzanna; Grothusen, Carolina von; Boggavarapu, Nageswara Rao; Francis, Roy Mathew; Davies, Lindsay C.; Gemzell‐Danielsson, Kristina

doi:10.3390/jpm11060448

Cited by 41 publications

(45 citation statements)

References 61 publications

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“…S1 A and Table S2 ). Stromal cells were the most abundant cell type and made up the mass of the regenerative endometrial functionalis ( 9 ) as evidenced by HAND2 and WT1. The immunostaining of HAND2 and WT1 with CD45 revealed many stromal cells dispersed with some CD45-positive immune cells in between ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Deciphering the endometrial niche of human thin endometrium at single-cell resolution

Zhao

Jiang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Thin endometrium is the most common reason for uterine infertility and refractory gynecological diseases due to its complexity in pathogenesis and adverse pregnancy outcomes. Here, we profile cells from normal and thin endometrium at single-cell resolution to investigate the sophisticated alterations in the local microenvironment that occur in thin endometrium. Increased cellular senescence, collagen overdeposition, and significant down-regulation of gene expression related to cell proliferation are observed and confirmed. Moreover, we demonstrate aberrant activation of the SEMA3 pathway accompanied by dampened EGF, PTN, and TWEAK signaling pathways in thin endometrium. These findings aid in understanding the mechanisms of thin endometrium and provide new tools to rejuvenate the atrophic endometrium for female fertility preservation and successful pregnancy.

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Section: Resultsmentioning

confidence: 99%

Deciphering the endometrial niche of human thin endometrium at single-cell resolution

Zhao

Jiang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…In the first PCA dimension, which separates stromal from epithelial cells, the most specific ST cells’ gene was the Wilms’ tumor suppressor gene 1 ( WT1 ), previously reported as specifically expressed in woman endometrial ST cells [ 39 ]. This was also the case of smooth muscle cell markers ( TAGLN ; ACTA2 ; CNN1 ; TPM2 ), also specifically detected in the endometrial stromal compartment of healthy women [ 40 ]. Additionally, STRA6 and SFRP1 , encoding a receptor for retinol uptake and a soluble modulator of Wnt signalling, respectively, were highly expressed in ST cells, as previously described in woman’s endometrium [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Progesterone differentially affects the transcriptomic profiles of cow endometrial cell types

et al. 2022

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Background The endometrium is a heterogeneous tissue composed of luminal epithelial (LE), glandular epithelial (GE), and stromal cells (ST), experiencing progesterone regulated dynamic changes during the estrous cycle. In the cow, this regulation at the transcriptomic level was only evaluated in the whole tissue. This study describes specific gene expression in the three types of cells isolated from endometrial biopsies following laser capture microdissection and the transcriptome changes induced by progesterone in GE and ST cells. Results Endometrial LE, GE, and ST cells show specific transcriptomic profiles. Most of the differentially expressed genes (DEGs) in response to progesterone are cell type-specific (96%). Genes involved in cell cycle and nuclear division are under-expressed in the presence of progesterone in GE, highlighting the anti-proliferative action of progesterone in epithelial cells. Elevated progesterone concentrations are also associated with the under-expression of estrogen receptor 1 (ESR1) in GE and oxytocin receptor (OXTR) in GE and ST cells. In ST cells, transcription factors such as SOX17 and FOXA2, known to regulate uterine epithelial-stromal cross-talk conveying to endometrial receptivity, are over-expressed under progesterone influence. Conclusions The results from this study show that progesterone regulates endometrial function in a cell type-specific way, which is independent of the expression of its main receptor PGR. These novel insights into uterine physiology present the cell compartment as the physiological unit rather than the whole tissue.

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“…The generation of these scRNAseq datasets have allowed us to make some preliminary comparisons to results from studies using this technique to explore cell heterogeneity in human endometrium and human endometrial cells (Wang et al, 2020, Queckborner et al, 2021, Cao et al, 2021, Garcia-Alonso et al, 2021). Queckborner and colleagues focused their analysis cells from 3 donors obtained during in the proliferative phase of their menstrual cycle (6864 cells) using a protocol that enriched for stromal cells (Queckborner et al, 2021). They subtyped two populations of perivascular/pericyte cells with different expression levels of MY11D and CSPG4 both of which we have previously mapped to perivascular populations in the mouse endometrium (Kirkwood et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Single cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation

Kirkwood

Gibson

Shaw

et al. 2021

Preprint

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The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study we used a validated mouse model of endometrial repair in combination with three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the cycling endometrium. Using scRNAseq we identified a novel population of PDGFRb+ cells that arose in the endometrium in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they arose from stromal fibroblasts and were in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2+). We demonstrate for the first time that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to restoration of tissue integrity during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Ashermans syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.

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Stromal Heterogeneity in the Human Proliferative Endometrium—A Single-Cell RNA Sequencing Study

Cited by 41 publications

References 61 publications

Deciphering the endometrial niche of human thin endometrium at single-cell resolution

Deciphering the endometrial niche of human thin endometrium at single-cell resolution

Progesterone differentially affects the transcriptomic profiles of cow endometrial cell types

Single cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation

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