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Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell Analysis

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Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell Analysis International Journal of Molecular Sciences Article Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell Analysis Yi Yang 1, Jia-Peng He 2 and Ji-Long Liu 2,* 1 College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; [email protected] 2 Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; [email protected] * Correspondence: [email protected] Abstract: As a crucial step for human reproduction, embryo implantation is a low-efficiency process. Despite rapid advances in recent years, the molecular mechanism underlying embryo implantation remains poorly understood. Here, we used the mouse as an animal model and generated a single- cell transcriptomic atlas of embryo implantation sites. By analyzing inter-implantation sites of the uterus as control, we were able to identify global gene expression changes associated with embryo implantation in each cell type. Additionally, we predicted signaling interactions between uterine luminal epithelial cells and mural trophectoderm of blastocysts, which represent the key mechanism of embryo implantation. We also predicted signaling interactions between uterine epithelial-stromal crosstalk at implantation sites, which are crucial for post-implantation development. Our data provide a valuable resource for deciphering the molecular mechanism underlying embryo implantation. Keywords: embryo implantation; mouse; single-cell RNA-seq; transcriptional changes Citation: Yang, Y.; He, J.-P.; Liu, J.-L. Cell–Cell Communication at the Embryo Implantation Site of Mouse Uterus Revealed by Single-Cell 1. Introduction Analysis. Int. J. Mol. Sci. 2021, 22, Embryo implantation is a crucial step for human reproduction. This is a low-efficiency 5177. https://doi.org/10.3390/ process and the implantation failure rate per menstrual cycle is approximately 70% [1,2]. ijms22105177 In assisted reproductive technologies, despite a high success rate of in vitro fertilization, implantation rate remains very low [3]. Additionally, an emerging concept is that early Academic Editor: Chaya Kalcheim pregnancy loss and various pregnancy complications are rooted in suboptimal embryo implantation [4]. Therefore, it is imperative to understand the molecular mechanism of Received: 23 April 2021 embryo implantation. Accepted: 10 May 2021 Published: 13 May 2021 Due to ethical restrictions and experimental difficulties, in vivo analysis of embryo im- plantation heavily relies on mice. By using uterus-specific gene knockout mice, a number of Publisher’s Note: MDPI stays neutral genes have been proven to be required for embryo implantation [5]. Alternatively, several with regard to jurisdictional claims in studies have analyzed global gene expression changes between implantation sites and published maps and institutional affil- inter-implantation sites of mouse uterus using high-throughput transcriptomic approaches, iations. providing a useful candidate gene list for further study of embryo implantation [6–8]. The limitation of these studies is that the whole uterus is used. The uterus has a complex struc- ture consisting of three layers, namely the endometrium, myometrium and perimetrium, and many cell types, including luminal and glandular epithelial cells, stromal cells, smooth muscle cells, endothelial cells and various immune cells. Thus, a whole uterus bulk RNA- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. seq approach is unable to accurately capture cell-type-specific gene expression changes. This article is an open access article In addition to whole uteri, isolated uterine luminal epithelium from implantation sites distributed under the terms and and inter-implantation sites by enzymes [9] and laser-capture microdissection (LCM) [10] conditions of the Creative Commons have been subjected to high-throughput transcriptomic analysis. It is undoubtedly true Attribution (CC BY) license (https:// that the use of isolated uterine luminal epithelium was a better choice than the whole creativecommons.org/licenses/by/ uterus. However, the limitation is that the contributions of cell types, other than luminal 4.0/). epithelium, and signaling crosstalk between different cell types were not considered. Int. J. Mol. Sci. 2021, 22, 5177. https://doi.org/10.3390/ijms22105177 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 5177 2 of 13 With advances in single-cell RNA-seq techniques, it is now possible to analyze global gene expression profiles within highly heterogeneous tissues at the single-cell level [11]. In the present study, by using the-state-of-the-art single-cell RNA-seq approach, we resolved all cell types at implantation sites and inter-implantation sites of the mouse uterus on gestational day 5. Consequently, we were able to identify different expression changes associated with embryo implantation in all cell types. Additionally, we predicted that cell– cell communication is involved in embryo implantation. Our study provides a valuable resource for understanding the molecular mechanisms underlying embryo implantation in mice. 2. Results 2.1. Single-Cell Analysis of Embryo Implantation Site in Mouse Uterus Embryo implantation takes place on gestational day 5 in mice. The implantation site in the uterus can be visualized after an intravenous injection of Chicago Blue B dye solution (Figure1A). In order to capture a cell-type resolved map of mouse embryo implantation, single-cell RNA-seq data were generated from the implantation site (IS) and the inter- implantation site (IIS, served as control) by using a 10x Genomics platform. The whole uterus, which consists of the endometrium, myometrium and perimetrium, was used. The blastocyst at IS was also kept. After quality control, a total of 8421 cells (2606 for IS and 5815 for IIS) were obtained. Unsupervised clustering analysis revealed 19 distinct cell clusters for IS and IIS combined (Figure1B). Major cell types were defined using the expression of known cell-type-specific genes, with stromal cells expressing Hoxa11 [12], epithelial cells expressing Krt8 [13], smooth muscle cells expressing Acta2 [14], pericytes expressing Rgs5 [15], endothelial cells expressing Vwf or Prox1 [16] and immune cells expressing Ptprc [17] (Figure1C). We found four stromal cell clusters, S1, S1p, S2 and S2p. Cells in S1/S1p but not S2/S2p expressed high levels of Hand2, implying that S1/S1p were inner stromal cells and S2/S2p were outer stromal cells [18]. S1p and S2p expressed high level of Mki67, suggesting that S1p and S2p were a subset of proliferating S1 and S2 cells, respec- tively. There were two epithelial cell clusters, LE and GE. LE contained luminal epithelial cells expressing Tacstd2, and GE was composed of glandular epithelial cells expressing Foxa2 [19]. Only one smooth muscle cell cluster and one pericyte cluster were identi- fied. Endothelial cells had four clusters: VEC and its proliferating subset VECp were vascular endothelial cells expressing Vwf, while LEC and its proliferating subset LECp were lymphatic endothelial cells expressing Prox1 [16]. The seven immune cell clusters were macrophages (M, Ptprc+Adgre1+)[20], a proliferating subset of macrophages (Mp, Ptprc+Adgre1+Mki67+), dendritic cells (DC, Ptprc+Cd209a+Siglech−)[20], plasmacytoid dendritic cells (pDC, Ptprc+Cd209a+Siglech+)[21], mixed natural killer cells and T cells (NK/T, Ptprc+Nkg7+ or Ptprc+Cd3e+)[22], a proliferating subset of natural killer cells (NKp, Ptprc+Nkg7+Cd3e−Mki67+) and B cells (B, Ptprc+Cd79a+)[22]. We next aimed to discover novel markers for each cell type. We selected genes that were expressed significantly higher in the cell type of interest than the other cell types by Wilcoxon rank sum test. A heatmap depicting the top 10 marker genes for each cell type is shown in Figure1D. The complete lists of marker genes are presented in Supplementary Table S1. Int. J. Mol. Sci. 2021, 22, 5177 3 of 13 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 13 FigureFigure 1. 1.Single-cell Single-cell transcriptome transcriptome analysis analysis of of the the implantation implantation site site in in mouse mouse uterus uterus on on gestational gestational day day 5: (5:A )(A A) photographA photo- ofgraph mouse of uterus mouse on uterus gestational on gestational day 5. day The 5. position The position of embryo of embryo implantation implantation sites sites was was marked marked with with an an arrow. arrow. (B ()B The) The t-stochastic neighbor embedding (tSNE) representation of single-cell RNA-seq data obtained from implantation sites t-stochastic neighbor embedding (tSNE) representation of single-cell RNA-seq data obtained from implantation sites (IS) and (IS) and inter-implantation sites (IIS). Single cells were grouped by cellular origin (left) and cell clusters (right). LE: lu- inter-implantationminal epithelial cells; sites (IIS).GE: glandular Single cells epithelial were grouped cells; S1: by superf cellularicial origin stromal (left) cells; and S2: cell deep clusters stromal (right). cells; LE: S1p: luminal proliferati epithelialng cells;superficial GE: glandular stromal epithelial cells; S2p: cells; proliferating S1: superficial deep stromalstromal cells;cells; S2:SMC: deep smooth stromal muscle cells; S1p:cells; proliferatingPC: pericytes; superficial VEC: vascular stromal cells;endothelial S2p: proliferating cells; VECp: deep proliferating stromal cells; vascular SMC: smoothendothelial muscle cells; cells;
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