Abstract
ABSTRACTTwo recently developed models, trophoblast organoids and trophoblast stem cells (TSCs), are useful tools to further the understanding of human placental development. Both differentiate from villous cytotrophoblast (VCT) to either extravillous trophoblast (EVT) or syncytiotrophoblast (SCT). Here, we compare the transcriptomes and miRNA profiles of these models to identify which trophoblast they resemble in vivo. Our findings indicate that TSCs do not readily undergo SCT differentiation and closely resemble cells at the base of the cell columns from where EVT derives. In contrast, organoids are similar to VCT and undergo spontaneous SCT differentiation. A defining feature of human trophoblast is that VCT and SCT are human leukocyte antigen (HLA) null, whereas EVT expresses HLA-C, -G and -E molecules. We find that trophoblast organoids retain these in vivo characteristics. In contrast, TSCs express classical HLA-A and HLA-B molecules, and maintain their expression after EVT differentiation, with upregulation of HLA-G. Furthermore, HLA expression in TSCs differs when grown in 3D rather than in 2D, suggesting that mechanical cues are important. Our results can be used to select the most suitable model for the study of trophoblast development, function and pathology.
Highlights
The placenta has many biological functions to support the developing fetus
Expression patterns of HLA class I molecules in trophoblast models cultured in vitro We first investigated the expression HLA class I molecules by the trophoblast models as this is a defining feature of human trophoblast (Faulk and Temple, 1976; King et al, 2000) with a clear difference between villous cytotrophoblast (VCT), SCT and extravillous trophoblast (EVT) (Fig. 1A) (Apps et al, 2009; Lee et al, 2016)
This is shown using serial sections of first trimester human placenta stained with a monoclonal antibody, W6/32 (Brodsky, Bodmer and Parham, 1979), which recognizes all HLA class I molecules, and G233, an HLA-G specific mAb (Loke et al, 1997) (Fig. 1B)
Summary
The placenta has many biological functions to support the developing fetus. Trophoblast, the main cell type of the placenta, arise from the trophectoderm of the implanting blastocyst. Placental villi are surrounded by a layer of cytotrophoblast cells (VCT) that fuse to form a multi-nucleated layer of syncytiotrophoblast (SCT). This syncytium is in direct contact with maternal blood and is the principal site of nutrient and oxygen exchange. A possible location for trophoblast progenitors is at the base of these cell columns (the “column niche”), marked by ITGA2/NOTCH1 expression (Haider et al, 2016; Lee et al, 2018). At their distal ends the columns merge to form the cytotrophoblastic shell that initially encapsulates the conceptus at the maternal-fetal interface. Endovascular EVT migrate down the inside of the spiral arteries and transiently replace the endothelium
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