Publications by authors named "Vincent Pasque"

The use of stem cells to model the early human embryo promises to transform our understanding of developmental biology and human reproduction. In this review, we present our current knowledge of the first 2 weeks of human embryo development. We first focus on the distinct cell lineages of the embryo and the derivation of stem cell lines.

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MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability.

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The advent of novel 2D and 3D models for human development, including trophoblast stem cells and blastoids, has expanded opportunities for investigating early developmental events, gradually illuminating the enigmatic realm of human development. While these innovations have ushered in new prospects, it has become essential to establish well-defined benchmarks for the cell sources of these models. We aimed to propose a comprehensive characterization of pluripotent and trophoblastic stem cell models by employing a combination of transcriptomic, proteomic, epigenetic, and metabolic approaches.

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Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer.

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Human cerebral organoids (COs) are self-organizing three-dimensional (3D) neural structures that provide a human-specific platform to study the cellular and molecular processes that underlie different neurological events. The first step of CO generation from human pluripotent stem cells (hPSCs) is neural induction, which is an simulation of neural ectoderm development. Several signaling pathways cooperate during neural ectoderm development and differentiation of hPSCs toward neural cell lineages is also affected by them.

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Studying human embryo development, most particularly around the time of implantation, is a challenge, yet it is necessary to improve assisted reproduction techniques. In this issue, Yu et al. and Karvas et al.

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The ability to study human post-implantation development remains limited owing to ethical and technical challenges associated with intrauterine development after implantation. Embryo-like models with spatially organized morphogenesis and structure of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (that is, the embryonic disc, the bilaminar disc, the yolk sac, the chorionic sac and the surrounding trophoblast layer) remain lacking. Mouse naive embryonic stem cells have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation structured stem-cell-based embryo models with spatially organized morphogenesis (called SEMs).

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Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA-sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks.

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Single-cell RNA sequencing (scRNA-seq) revolutionized our understanding of the molecular processes of early development and provided us with the means to capture biological heterogeneity and assess the cellular composition in early embryos. Comparative analysis of the transcriptional landscapes of embryos with single-cell resolution allows us to better understand and improve stem-cell-based embryo models. However, proper comparison between different single-cell datasets acquired by different laboratories and through different technologies is imperative for adequate analysis and findings.

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Our current understanding of early human development is limited. A study in PLOS Biology found a previously undefined group of cells that diverges from the main lineages and undergo apoptosis through the activity of young transposable elements.

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The human extraembryonic mesoderm (EXM) is an important tissue in the postimplantation embryo which is specified before gastrulation in primates but not in rodents. EXM is mesenchymal and plays an important role in embryogenesis, including early erythropoiesis, and provides mechanical support to the developing embryo. Recently, it has been shown that self-renewing extraembryonic mesoderm cells (EXMCs) can be modeled in vitro by using human naive pluripotent stem cells.

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Early during preimplantation development and in heterogeneous mouse embryonic stem cells (mESC) culture, pluripotent cells are specified towards either the primed epiblast or the primitive endoderm (PE) lineage. Canonical Wnt signaling is crucial for safeguarding naive pluripotency and embryo implantation, yet the role and relevance of canonical Wnt inhibition during early mammalian development remains unknown. Here, we demonstrate that transcriptional repression exerted by Wnt/TCF7L1 promotes PE differentiation of mESCs and in preimplantation inner cell mass.

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A hallmark of primate postimplantation embryogenesis is the specification of extraembryonic mesoderm (EXM) before gastrulation, in contrast to rodents where this tissue is formed only after gastrulation. Here, we discover that naive human pluripotent stem cells (hPSCs) are competent to differentiate into EXM cells (EXMCs). EXMCs are specified by inhibition of Nodal signaling and GSK3B, are maintained by mTOR and BMP4 signaling activity, and their transcriptome and epigenome closely resemble that of human and monkey embryo EXM.

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Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested.

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Human naive pluripotent stem cells have the remarkable ability to generate blastoids comprising trophectoderm, epiblast, and hypoblast-like cells. In this issue, Taubenschmid-Stowers et al. (2022) show that human naive pluripotent stem cell cultures contain cells that resemble the 8-cell human embryo, providing a model to study zygotic genome activation.

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Background: Precise gene dosage of the X chromosomes is critical for normal development and cellular function. In mice, XX female somatic cells show transcriptional X chromosome upregulation of their single active X chromosome, while the other X chromosome is inactive. Moreover, the inactive X chromosome is reactivated during development in the inner cell mass and in germ cells through X chromosome reactivation, which can be studied in vitro by reprogramming of somatic cells to pluripotency.

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Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage.

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Article Synopsis
  • Understanding how human embryos develop before implantation can enhance reproductive technologies and stem cell research.
  • The study uses advanced techniques like single-cell RNA sequencing to analyze mouse and human embryos' development over time, noting crucial changes in gene expression.
  • Key findings include the timing of different cell types forming and specific markers that indicate development stages, paving the way for better insights into embryonic development.
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Segregation of cells that form the embryo from those that produce the surrounding extra-embryonic tissues is critical for early mammalian development, but the regulatory layers governing these first cell fate decisions remain poorly understood. Recent work in The EMBO Journal identifies two chromatin regulators, Hdac3 and Dax1, that synergistically restrict the developmental potential of mouse embryonic stem cells and act as a lineage barrier to primitive endoderm formation.

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Totipotency is the ability of a single cell to give rise to all of the differentiated cell types that build the conceptus, yet how to capture this property in vitro remains incompletely understood. Defining totipotency relies on a variety of assays of variable stringency. Here, we describe criteria to define totipotency.

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Dosage compensation between the sexes results in one X chromosome being inactivated during female mammalian development. Chromosome-wide transcriptional silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a process termed X-chromosome reactivation (XCR), which has emerged as a paradigm for studying the reversal of chromatin silencing. XCR is linked with germline development and induction of naive pluripotency in the epiblast, and also takes place upon reprogramming somatic cells to induced pluripotency.

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Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) involves the reactivation of endogenous pluripotency genes and global DNA demethylation, but temporal resolution of these events using existing markers is limited. Here, we generate murine transgenic lines harboring reporters for the 5-methylcytosine dioxygenase Tet1 and for Oct4. By monitoring dual reporter fluorescence during pluripotency entry, we identify a sequential order of Tet1 and Oct4 activation by proximal and distal regulatory elements.

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Dosage compensation between XX female and XY male cells is achieved by a process known as X chromosome inactivation (XCI) in mammals. XCI is initiated early during development in female cells and is subsequently stably maintained in most somatic cells. Despite its stability, the robust transcriptional silencing of XCI is reversible, in the embryo and also in a number of reprogramming settings.

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The establishment and validation of reliable induced pluripotent stem cell (iPSC)-derived in vitro models to study microglia and monocyte/macrophage immune function holds great potential for fundamental and translational neuro-immunology research. In this study, we first demonstrate that ramified CXCR1 iPSC-microglia (cultured within a neural environment) and round-shaped CXCR1 iPSC-macrophages can easily be differentiated from newly established murine CXCR1CCR2 iPSC lines. Furthermore, we show that obtained murine iPSC-microglia and iPSC-macrophages are distinct cell populations, even though iPSC-macrophages may upregulate CXCR1 expression when cultured within a neural environment.

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