Human embryonic stem cells contribute to embryonic and extraembryonic lineages in mouse embryos through inhibition of apoptosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100862 | GEO | 2017/11/10
SECONDARY ACCESSION(S): PRJNA393309
REPOSITORIES: GEO
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Project description:BackgroundPrevious attempts to isolate pluripotent cell lines from rat preimplantation embryo in mouse embryonic stem (ES) cell culture conditions (serum and LIF) were unsuccessful, however the resulting cells exhibited the expression of such traditional pluripotency markers as SSEA-1 and alkaline phosphatase. We addressed the question, which kind of cell lineages are produced from rat preimplantation embryo under "classical" mouse ES conditions.ResultsWe characterized two cell lines (C5 and B10) which were obtained from rat blastocysts in medium with serum and LIF. In the B10 cell line we found the expression of genes known to be expressed in trophoblast, Cdx-2, cytokeratin-7, and Hand-1. Also, B10 cells invaded the trophectodermal layer upon injection into rat blastocysts. In contrast to mouse Trophoblast Stem (TS) cells proliferation of B10 cells occurred independently of FGF4. Cells of the C5 line expressed traditional markers of extraembryonic-endoderm (XEN) cells, in particular, GATA-4, but also the pluripotency markers SSEA-1 and Oct-4. C5 cell proliferation exhibited dependence on LIF, which is not known to be required by mouse XEN cells.ConclusionsOur results confirm and extend previous findings about differences between blastocyst-derived cell lines of rat and mice. Our data show, that the B10 cell line represents a population of FGF4-independent rat TS-like cells. C5 cells show features that have recently become known as characteristic of rat XEN cells. Early passages of C5 and B10 cells contained both, TS and XEN cells. We speculate, that mechanisms maintaining self-renewal of cell lineages in rat preimplantation embryo and their in vitro counterparts, including ES, TS and XEN cells are different than in respective mouse lineages.
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Project description:Genomic imprinting and X chromosome inactivation (XCI) require epigenetic mechanisms to encode allele-specific expression, but how these specific tasks are accomplished at single loci or across chromosomal scales remains incompletely understood. Here, we systematically disrupt essential epigenetic pathways within polymorphic embryos in order to examine canonical and non-canonical genomic imprinting as well as XCI. We find that DNA methylation and Polycomb group repressors are indispensable for autosomal imprinting, albeit at distinct gene sets. Moreover, the extraembryonic ectoderm relies on a broader spectrum of imprinting mechanisms, including non-canonical targeting of maternal endogenous retrovirus (ERV)-driven promoters by the H3K9 methyltransferase G9a. We further identify Polycomb-dependent and -independent gene clusters on the imprinted X chromosome, which appear to reflect distinct domains of Xist-mediated suppression. From our data, we assemble a comprehensive inventory of the epigenetic pathways that maintain parent-specific imprinting in eutherian mammals, including an expanded view of the placental lineage.
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Project description:Retinoblastoma (Rb)-deficient embryos show severe defects in neurogenesis, erythropoiesis, and lens development and die at embryonic day 14.5. Our recent results demonstrated a drastic disorganization of the labyrinth layer in the placenta of Rb-deficient embryos, accompanied by reduced placental transport function. When these Rb-/- embryos were supplied with a wild-type placenta by using either tetraploid aggregation or genetic approaches, animals survived until birth. Here we analyze the role of extraembryonic Rb in regulating proliferation, apoptosis, and differentiation in the rescued animals at different developmental stages. Many of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-/- animals, including the ectopic apoptosis in the CNS, were virtually absent in rescued Rb-/- pups. However, rescued animals died at birth with severe skeletal muscle defects. Like in Rb knockout embryos, rescued animals showed a marked increase in DNA replication and cell division in the CNS. In sharp contrast, the typical widespread neuronal apoptosis was absent in Rb-deficient embryos reconstituted with a normal placenta. In lens fiber cells, however, the inappropriate proliferation and apoptosis that is normally observed in Rb-/- embryos continued unabated in rescued animals. These results demonstrate that Rb function in extraembryonic lineages plays an important role in the survival of neuronal cells and in the differentiation of the erythroid lineage, providing mechanistic insight into the cell autonomous and nonautonomous functions of Rb during development.
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Project description:The cell movements underlying the morphogenesis of the embryonic endoderm, the tissue that will give rise to the respiratory and digestive tracts, are complex and not well understood. Using live imaging combined with genetic labeling, we investigated the cell behaviors and fate of the visceral endoderm during gut endoderm formation in the mouse gastrula. Contrary to the prevailing view, our data reveal no mass displacement of visceral endoderm to extraembryonic regions concomitant with the emergence of epiblast-derived definitive endoderm. Instead, we observed dispersal of the visceral endoderm epithelium and extensive mixing between cells of visceral endoderm and epiblast origin. Visceral endoderm cells remained associated with the epiblast and were incorporated into the early gut tube. Our findings suggest that the segregation of extraembryonic and embryonic tissues within the mammalian embryo is not as strict as believed and that a lineage previously defined as exclusively extraembryonic contributes cells to the embryo.
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Project description:The histiocytoses [Erdheim-Chester Disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman-Destombes disease (RDD)] are characterized by the infiltration of monocytes, macrophages, and dendritic cells in normal tissues, leading to significant morbidity due to disruption of critical organ systems. While their pathogenesis involves MAPK-ERK pathway mutations, their epigenetic landscape remains poorly understood. Epigenetic mechanisms such as DNA methylation, histone modification, and non-coding RNA are crucial in gene expression regulation and cancer development. We previously identified a distinct non-coding RNA profile in histiocytosis patients compared to controls. We analyzed the DNA methylation profile of 30 patients and found significant alterations in 23,322 methylation sites compared to controls, independent of age, gender, mutation type, or disease site. We observed a significant hypermethylation in the let-7b transcript, resulting in decreased let-7b expression. This led to the lack of regulation on the anti-apoptotic proteins BCL2L1, which was overexpressed in 21/21 (100%) patients' biopsies and BCL2 in 11/21 biopsies (52%). Treatment with the hypomethylating agent, 5-Azacytidine, restored let-7b expression, reduced BCL2L1 levels, and induced apoptosis in BRAFV600E mutant cells. Additionally, BCL2L1 and BCL2 inhibitors also induced apoptosis. This novel epigenetic mechanism suggests that hypomethylating agents or BH3 mimetic drugs may offer new therapeutic targets for histiocytosis.
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