Dataset Information

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

ABSTRACT:

Background

Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization.

Results

We observed a unique IGF1⁺ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B⁺ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell-cell communication for decidualization was developed. An aberrant ratio conversion of IGF1⁺ stromal cells to IGF1R⁺ stromal cells is observed in unexplained RIF patients.

Conclusions

Overall, a unique subpopulation of IGF1⁺ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.

SUBMITTER: Shi JW

PROVIDER: S-EPMC9733393 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

Shi Jia-Wei JW Lai Zhen-Zhen ZZ Yang Hui-Li HL Zhou Wen-Jie WJ Zhao Xiao-Ya XY Xie Feng F Liu Song-Ping SP Chen Wei-Dong WD Zhang Tao T Ye Jiang-Feng JF Zhou Xiang-Yu XY Li Ming-Qing MQ

BMC biology 20221208 1

<h4>Background</h4>Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly assoc ...[more]

PMID: 36482461

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Project description:Endometrial decidualization is a decidual tissue formed by the proliferation and re-differentiation of endometrial stroma stimulated by decidualization inducing factors. It is very important for the proper maintenance of pregnancy. Previous studies speculated that Golgi phosphoprotein 3 (GOLPH3) may have a regulatory role in the process of endometrial decidualization, while the specific molecular mechanisms of GOLPH3 is unclear. In this part, GOLPH3 was silenced in human endometrial stromal cells (hESCs), and the transcriptome data (RNA-seq) by GOLPH3 knockdown (siGOLPH3) was obtained by high-throughput sequencing technology so as to analyze the potential targets of GOLPH3 at expression and alternative splicing levels in hESCs. Through bioinformatics analysis, we found that siGOLPH3 can significantly affect the overall transcriptional level of hESCs. A total of 6,025 differentially expressed genes (DEGs) and 4,131 differentially alternative splicing events (DASEs) were identified. Through functional cluster analysis of these DEGs and genes where differential alternative splicing events are located, it is found that they are enriched in the PI3K/Akt signaling pathway, RNA splicing and processing, transcription factors and other pathways related to endometrial decidualization and important biological processes, indicating the important biological function of GOLPH3. At the same time, we focused on the analysis of the transcription factors regulated by GOLPH3, including gene expression regulation and the regulation of variable splicing. We found that GOLPH3can regulate the expression of transcription factors such as LD1, FOSL2, GATA2, CSDC2 and CREB3L1. At the same time, it affects the variable splicing mode of FOXM1 and TCF3. The function of these transcription factors is directly related to decidualization of endometrium. Therefore, we infer that GOLPH3 may participate in endometrial de membrane by regulating expression and alternative splicing levels of transcription factors. We further identified the role of GOLPH3 in the transcriptional mechanism. At the same time, it also expands the function mode of GOLPH3 protein molecule, and provides a theoretical basis for downstream targeted drug research and development and clinical application.

Project description:Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal cellular compartments of the human endometrium during the proliferative and secretory phase of the menstrual cycle as well as in cultured HESCs. We also found that SRC-3 depletion in cultured HESCs results in a significant attenuation in the induction of a wide-range of established biomarkers of decidualization, despite exposure of these cells to a deciduogenic stimulus and normal progesterone receptor expression. These molecular findings are supported at the cellular level by the inability of HESCs to morphologically transform from a stromal fibroblastoid cell to an epithelioid decidual cell when endogenous SRC-3 levels are markedly reduced. To identify genes, signaling pathways and networks that are controlled by SRC-3 and potentially important for hormone-dependent decidualization, we performed RNA-sequencing on HESCs in which SRC-3 levels were significantly reduced at the time of administering the deciduogenic stimulus. Comparing HESC controls with HESCs deficient in SRC-3, gene enrichment analysis of the differentially expressed gene set revealed an overrepresentation of genes involved in chromatin remodeling, cell proliferation/motility, and programmed cell death. These predictive bioanalytic results were confirmed by the demonstration that SRC-3 is required for the expansion, migratory and invasive activities of the HESC population, cellular properties that are required in vivo in the formation or functioning of the decidua. Collectively, our results support SRC-3 as an important coregulator in HESC decidualization. Since perturbation of normal homeostatic levels of SRC-3 is linked with common gynecological disorders diagnosed in reproductive age women, this endometrial coregulator-along with its new molecular targets described here-may open novel clinical avenues in the diagnosis and/or treatment of a non-receptive endometrium, particularly in patients presenting non-aneuploid early pregnancy loss.

Dataset Information

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

Background

Results

Conclusions

Publications

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

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