Abstract
In humans, the maternal endometrium participates in the physical and physiological interaction with the blastocyst to begin implantation. A bidirectional crosstalk is critical for normal implantation and then a successful pregnancy. While several studies have used animal models or cell lines to study this step, little knowledge was acquired to address the role of endometrial cells in humans. Here, we analyzed single-cell sequencing data from a previous study including 24 non-coculture endometrial stromal cells (EmSCs) and 57 EmSCs after coculture with embryos. We further explored the transcriptomic changes in EmSCs and their interactions with trophoblast cells after coculture. Differentially expressed gene (DEG) analysis showed 1783 upregulated genes and 569 downregulated genes in the cocultured embryos. Weight gene coexpression network and gene ontology analysis of these DEGs showed a higher expression of RAMP1, LTBP1, and LRP1 in EmSCs after coculture, indicating the enrichment of biological processes in blood vessel development and female pregnancy. These data imply that EmSCs start blood vessel development at the implantation stage. Compared with endometrium data in vivo at the implantation window, key pathways including epithelial cell development and oxygen response were involved at this stage. Further analysis using CellphoneDB shed light on the interactions between EmSCs and embryonic trophoblasts, suggesting the important role of integrins and fibroblast growth factor pathways during implantation. Taken together, our work reveals the synchronization signaling and pathways happening at the implantation stage involving the acquisition of receptivity in EmSCs and the interaction between EmSCs and trophoblast cells.
Highlights
Implantation is a key event for embryos to continue development [1]
Among the total of 2352 Differentially expressed gene (DEG) in endometrial stromal cells (EmSCs) found between the “PRE” group and “POST” group using DEG analysis (false discovery rate (FDR) < 0.05 and fold change ≥ 2), 1783 genes, e.g., LRP1, MUC15, and COL15A1, were upregulated and 569 genes, e.g., TMSB4X, STMN1, and GOLIM4, were downregulated in the “POST” group (Figure 2B and Table S1, Supplementary Materials), followed by downstream single-cell transcriptomic analysis (Figure 1)
These results suggest the activation of extracellular matrix pathways in EmSCs to support embryo implantation
Summary
Implantation is a key event for embryos to continue development [1]. Successful implantation relies on the synchronized development of the endometrium and embryo [2]. Human embryos penetrate and begin to invade into endometrial cells during the “window of implantation” (WOI) [3]. This process requires delicate spatiotemporal coordination by feto-maternal crosstalk, whose failure is considered as the major reason for implantation failure [4]. Two studies developed a new in vitro culture system for human post-implantation embryos [7,8]. Our group and Zhou et al [10,11] recently published studies focusing on the development of the trophectoderm in peri-implantation conceptuses using coculture and single-cell RNA sequencing methods, respectively. We compared EmSCs and trophectoderm cells before and after coculture using the coculture model in vitro, whereby the implantation progress mimicked that in vivo. The underlying interactions between embryos and EmSCs at these stages were explored to gain insight into the implantation process and identify potential biomarkers for diagnosis, prognosis, and drug targeting for pregnancy-related malfunctions
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