Biology subjects

Van de Velde, H.

Publications and source records attributed to Van de Velde, H..

6 recordsLinked to original sources

bioRxiv2025

SMARCA2/4-Dependent Chromatin Remodelling Establishes Gene Regulatory Programs in Early Human Embryos and Blastoids

Establishment of cell lineages during development is regulated by transcription factors binding at cis-regulatory elements to activate gene regulatory programs. Many transcription factors require chromatin remodellers for accessibility at their target sites. Although these key principles of gene regulation in mammalian development have emerged, the contribution of chromatin remodellers to early human embryogenesis remains unknown. Here, we show that the SWI/SNF ATPases SMARCA2 and SMARCA4 are required for establishing the epiblast and trophectoderm fates during human pre-implantation development and facilitate accessibility at regulatory elements. We find that degradation of SWI/SNF ATPases disrupts epiblast formation in blastoids and enhances trophectoderm specification, while also showing transcriptional and chromatin misregulation in TE-like cells. In human embryos, SWI/SNF perturbation impaired blastocyst formation and the establishment of the inner cell mass. Single-nucleus chromatin accessibility and transcriptome profiling in blastoids reveals that the SWI/SNF complex safeguards the naive epiblast and trophectoderm programs and facilitates enhancer and transcription factor motif accessibility. These findings identify SWI/SNF chromatin remodellers as critical regulators of embryonic lineage specification during human pre-implantation development.

developmental biology↗

bioRxiv2024

Stalling of the endometrial decidual reaction determines the recurrence risk of miscarriage risk

In each menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction - implantation and decidualization - pivot on the time-sensitive loss of progesterone-resistant stromal cells that form a transient implantation niche and reciprocal expansion of progesterone-responsive pre-decidual cells. In parallel, proliferation and differentiation increase the abundance of immunotolerant uterine natural killer (uNK) cells. Examination of pre-pregnancy endometrial biopsies from 924 women revealed that the frequency of cycles culminating in a blunted or stalled decidual reaction closely aligns with the age-independent recurrence risk of miscarriage. Further, analysis of 632 biopsies obtained in different cycles from 316 women indicated that prior miscarriages disrupt intercycle endometrial homeostasis, an observation supported by modelling the impacts of prolonged decidual inflammation in three-dimensional endometrial assembloids. Although stalling of the decidual reaction is often accompanied by a poor expansion of immunotolerant uNK cells, miscarriages do not impact intercycle uNK cell dynamics. Our findings indicate that intrinsic uterine mechanisms hardwire the recurrence risk of miscarriage, underscoring the need for pre-pregnancy diagnostics and therapeutics. One Sentence SummaryThe frequency of menstrual cycles culminating in a suboptimal decidual reaction determines the recurrence risk of miscarriage.

physiology↗

bioRxiv2022

Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1

We know that polarity and YAP1 play a key role in trophectoderm initiation in compacted human embryos, however we know little about the TEAD family of transcription factors that become activated by YAP1 and especially if they play a role during epiblast and primitive endoderm formation. Here we show that compaction occurs heterogeneously between the 8- and 16-cell stages. While 8-cell stage blastomeres are not yet polarized, polarized outer cells and non-polarized inner cells arise in compacted 16-cell stage embryos. While trophectoderm specifiers TEAD1, YAP1 and GATA3 mostly co-localise in the nuclei of polarized outer/trophectoderm cells, they are also found in some cells of compacting embryos before polarity is established indicating that differentiation into trophectoderm cells can be initiated independently of polarity. In the inner cell mass, TEAD1 and YAP1 also distinguish GATA4 positive cells in a salt-and-pepper distribution and in the sorted primitive endoderm cells. Our detailed roadmap on polarization, compaction, position and lineage segregation events during human preimplantation development paves the road for further functional studies. Fundamental knowledge of lineage segregation events will eventually explain how and why embryos fail to develop further before or during implantation.

developmental biology↗

bioRxiv2022

Aneuploidy triggers autophagy and p53-mediated apoptosis and impairs second lineage segregation in human preimplantation embryos

About 70% of human cleavage stage embryos show chromosomal mosaicism, falling to 20% in blastocysts. Chromosomally mosaic human blastocysts can implant and lead to healthy new-borns with normal karyotypes. Studies in mouse embryos and human gastruloids have shown that aneuploid cells show proteotoxic stress, autophagy and p53 activation and that they are eliminated from the epiblast by apoptosis while being tolerated in the trophectoderm. These observations suggest a selective loss of aneuploid cells from human embryos, but the underlying mechanisms are not yet fully understood. In this study we investigated the cellular consequences of aneuploidy in a total of 125 human blastocysts. RNA-sequencing of trophectoderm cells showed transcriptional signatures of activated p53 pathway and apoptosis, which was proportionate to the level of chromosomal imbalance. Immunostaining corroborated that aneuploidy triggers proteotoxic stress, autophagy, p53-signalling, and apoptosis independent from DNA damage. Total cell numbers were lower in aneuploid embryos, due to a decline both in trophectoderm and in epiblast/primitive endoderm cell numbers. While lower cell numbers in trophectoderm may be attributed to apoptosis, it appeared that aneuploidy impaired the second lineage segregation, particularly primitive endoderm formation. This might be reinforced by retention of NANOG in aneuploid embryos. Our findings might explain why fully aneuploid embryos fail to further develop and we hypothesize that the same mechanisms lead to removal of aneuploid cells from mosaic embryos. This hypothesis needs further study as we did not analyze chromosomal mosaic embryos. Finally, we demonstrated a few differences with previous findings in the mouse, emphasizing the need for human embryo research to understand the consequences of aneuploidy.

developmental biology↗

bioRxiv2022

A conserved role of Hippo signaling in initiation of the first lineage specification event across mammals

Our understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have recently shown that the establishment of cell polarity via aPKC is a conserved event in the initiation of the trophectoderm (TE) placental program in mouse, cow, and human embryos. However, the molecular mechanisms transducing cell polarity into cell fate in cow and human embryos is unknown. Here, we have examined the evolutionary conservation of the molecular cascade downstream of aPKC in four different mammalian species: mouse, rat, cow, and human. Surprisingly, by morphokinetic and immunofluorescence analyses, we observe that rat embryos more closely recapitulate human and cow developmental dynamics, in comparison to the mouse. Nevertheless, in all four species, inhibition of the Hippo pathway by targeting LATS kinases is sufficient to drive ectopic TE initiation and downregulation of SOX2, a marker of the inner cell mass. Our comparative embryology approach uncovered intriguing differences as well as similarities in a fundamental developmental process among mammals, reinforcing the importance of cross-species investigations.

developmental biology↗

bioRxiv2021

Mitochondrial DNA variants segregate during human preimplantation development into genetically different cell lineages that are maintained postnatally

Humans present remarkable mitochondrial DNA (mtDNA) variant mosaicism, not only across tissues but even across individual cells within one person. The timing of the first appearance of this mosaicism has not yet been established. In this study, we hypothesized it occurs during preimplantation development. To investigate this, we deep-sequenced the mtDNA of 254 oocytes from 85 donors, 158 single blastomeres of 25 day-3 embryos, 17 inner cell mass and trophectoderm samples of 7 day-5 blastocysts, 142 bulk DNA and 68 single cells of different adult tissues. We found that day-3 preimplantation embryos already present blastomeres that carry variants unique to that cell, showing that the first events of mtDNA mosaicism happen very early in human development. We classified the mtDNA variants based on their recurrence or uniqueness across sibling oocytes and embryos, and between single cells and samples from the same embryos or adult individuals. Variants that recurred across samples had higher heteroplasmic loads and more frequently resulted in synonymous changes or were located in non-coding regions than variants that were unique to one oocyte or single embryonic cell. These differences were maintained through developmental stages, suggesting that the mtDNA mosaicism arising in preimplantation development is maintained into adulthood. Further, the results support a model in which close clustering of mitochondria carrying specific mtDNA variants in the ooplasm leads to asymmetric distribution of these mitochondria throughout the cell divisions of the preimplantation embryo, resulting in the appearance of the first form of mtDNA mosaicism in human development.

genetics↗