Abstract
The placenta is crucial for a successful pregnancy and the health of both the fetus and the pregnant woman. However, how the human trophoblast lineage is regulated, including the categorization of the placental cell subtypes is poorly understood. Here we performed single-cell RNA sequencing (RNA-seq) on sorted placental cells from first- and second-trimester human placentas. New subtypes of cells of the known cytotrophoblast cells (CTBs), extravillous trophoblast cells (EVTs), Hofbauer cells, and mesenchymal stromal cells were identified and cell-type-specific gene signatures were defined. Functionally, this study revealed many previously unknown functions of the human placenta. Notably, 102 polypeptide hormone genes were found to be expressed by various subtypes of placental cells, which suggests a complex and significant role of these hormones in regulating fetal growth and adaptations of maternal physiology to pregnancy. These results document human placental trophoblast differentiation at single-cell resolution and thus advance our understanding of human placentation during the early stage of pregnancy.
Highlights
The first cell fate decision during human embryo development divides the embryonic cells into two lineages, i.e., the inner cell mass (ICM) and the trophectoderm, which further develop into the embryo proper and the main part of the placenta, respectively.[1]The placenta is a transient organ that is essential for anchoring the conceptus, preventing its rejection by the maternal immune system, and transporting nutrients and waste between the fetus and the mother.[2]
We examined the main signaling pathways involved in trophoblast cell fusion by Gene Set Enrichment Analysis (GSEA) using the database from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the top-ranked signaling pathways are illustrated in Supplementary information, Figure S3c
This study, focusing on the first and second trimester human placenta, identified new subtypes of placental cells (Figs. 1f and 7): (1) We found three subtypes of CTBs: a proliferative subtype, which may serve as the pool that replenishes the CTB pool; a non-proliferative, Syncytin-2-positive cell subtype, which proved to be the progenitor cells of the STB; and a non-proliferative, Syncytin-2-negative subtype
Summary
The first cell fate decision during human embryo development divides the embryonic cells into two lineages, i.e., the inner cell mass (ICM) and the trophectoderm, which further develop into the embryo proper and the main part of the placenta, respectively.[1]The placenta is a transient organ that is essential for anchoring the conceptus, preventing its rejection by the maternal immune system, and transporting nutrients and waste between the fetus and the mother.[2]. The villus is the functional unit of the placenta and consists of an outer epithelial trophoblast layer and a stromal cell core, derived from the trophectoderm and the extraembryonic mesoderm, respectively.[6] The stromal cell core contains fetal endothelial cells, mesenchymal stromal cells (MSCs), Hofbauer cells[7] amongst others. MSCs in the human placenta have been reported to be fibroblast-like cells with differentiation capabilities and immunomodulatory properties.[8] Hofbauer cells are fetal macrophages that may be involved in the phagocytosis of cellular debris and the modulation of human placental development by enhancing villous branching.[9,10]
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