VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development
- University of Pennsylvania, United States
- University of South Florida, United States
Abstract
During formation of the mammalian placenta trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts. The genetic and molecular basis of endovascular invasion remains poorly defined, however, and whether trophoblasts utilize specialized endothelial proteins in an analogous manner to create vascular channels remains untested. Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of EC junctions. VE-cadherin is also expressed in invasive trophoblasts and is a prime candidate for a molecular mechanism of endovascular invasion by those cells. Here, we show that the VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua in the mouse. VE-cadherin deficiency results in loss of spiral artery remodeling that leads to decreased flow of maternal blood into the placenta, fetal growth restriction, and death. These studies identify a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs.
Data availability
Source Data files have been included for Figure 1, Figure 1-Supplemental Figure 1, Figure 1-Supplemental Figure 2, Figure 1-Supplemental Figure 3, Figure 2, Figure 3, Figure 4-Supplemental Figure 1, and Figure 4-Supplemental Figure 2. All reagents have been listed in the Methods section in this paper.The RNA-seq data set has been deposited in the NCBI GEO under accession ID number GSE189408. Investigators interested in the animals used in this study should contact Dr. Jeremy Veenstra-Vanderweele (Columbia University), Dr. Gustsavo Leone (Medical University of South Carolina), and Dr. Joshua Scallan (University of South Florida).
Article and author information
Author details
Funding
National Institutes of Health (T32 HL007439)
- Derek C Sung
National Institutes of Health (F30 HL158014)
- Derek C Sung
American Heart Association (Postdoctoral Fellowship 35200213)
- Xiaowen Chen
National Institutes of Health (T32 HL007971)
- Thomas C Stevenson Keller
American Heart Association (Postdoctoral fellowship 836238)
- Thomas C Stevenson Keller
National Institutes of Health (HL142905)
- Joshua P Scallan
National Institutes of Health (HL145397)
- Ying Yang
National Institutes of Health (HL142976)
- Mark L Kahn
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were conducted using an approved animal protocol (806811) in accordance with the University of Pennsylvania Institutional Animal Care and Use Committee.
Copyright
© 2022, Sung et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,481
- views
-
- 538
- downloads
-
- 21
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development
eLife 11:e77241.
https://doi.org/10.7554/eLife.77241
Further reading
-
- Developmental Biology
The evolutionary introduction of asymmetric cell division (ACD) into the developmental program facilitates the formation of a new cell type, contributing to developmental diversity and, eventually, species diversification. The micromere of the sea urchin embryo may serve as one of those examples: an ACD at the 16-cell stage forms micromeres unique to echinoids among echinoderms. We previously reported that a polarity factor, activator of G-protein signaling (AGS), plays a crucial role in micromere formation. However, AGS and its associated ACD factors are present in all echinoderms and across most metazoans. This raises the question of what evolutionary modifications of AGS protein or its surrounding molecular environment contributed to the evolutionary acquisition of micromeres only in echinoids. In this study, we learned that the GoLoco motifs at the AGS C-terminus play critical roles in regulating micromere formation in sea urchin embryos. Further, other echinoderms’ AGS or chimeric AGS that contain the C-terminus of AGS orthologs from various organisms showed varied localization and function in micromere formation. In contrast, the sea star or the pencil urchin orthologs of other ACD factors were consistently localized at the vegetal cortex in the sea urchin embryo, suggesting that AGS may be a unique variable factor that facilitates ACD diversity among echinoderms. Consistently, sea urchin AGS appears to facilitate micromere-like cell formation and accelerate the enrichment timing of the germline factor Vasa during early embryogenesis of the pencil urchin, an ancestral type of sea urchin. Based on these observations, we propose that the molecular evolution of a single polarity factor facilitates ACD diversity while preserving the core ACD machinery among echinoderms and beyond during evolution.
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
A major challenge in the stem cell biology field is the ability to produce fully functional cells from induced pluripotent stem cells (iPSCs) that are a valuable resource for cell therapy, drug screening, and disease modelling. Here, we developed a novel inducible CRISPR-mediated activation strategy (iCRISPRa) to drive the expression of multiple endogenous transcription factors (TFs) important for in vitro cell fate and differentiation of iPSCs to haematopoietic progenitor cells. This work has identified a key role for IGFBP2 in developing haematopoietic progenitors. We first identified nine candidate TFs that we predicted to be involved in blood cell emergence during development, then generated tagged gRNAs directed to the transcriptional start site of these TFs that could also be detected during single-cell RNA sequencing (scRNAseq). iCRISPRa activation of these endogenous TFs resulted in a significant expansion of arterial-fated endothelial cells expressing high levels of IGFBP2, and our analysis indicated that IGFBP2 is involved in the remodelling of metabolic activity during in vitro endothelial to haematopoietic transition. As well as providing fundamental new insights into the mechanisms of haematopoietic differentiation, the broader applicability of iCRISPRa provides a valuable tool for studying dynamic processes in development and for recapitulating abnormal phenotypes characterised by ectopic activation of specific endogenous gene expression in a wide range of systems.
