During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting immuno-acceptance of the fetal allograph. Global cross-talk between the trophoblast and the decidua has not been elucidated to date, and the current study used a functional genomics approach to investigate these paracrine interactions.
Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators.
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View SamplesPlacental trophoblasts are key determinants of in utero development. Mouse trophoblast stem cells (mTSCs), which were first derived over a decade ago, are a powerful cell culture model for studying their self-renewal or differentiation. Our attempts to isolate an equivalent population from the trophectoderm of human blastocysts generated colonies that quickly differentiated in vitro. This finding suggested that the human placenta has another progenitor niche. Here we show that the chorion is one such site. Initially, we immunolocalized pluripotency factors and trophoblast fate determinants in the early-gestation placenta, amnion and chorion. Immunoreactive cells were numerous in the chorion. We isolated these cells and plated them in medium containing FGF and an inhibitor of activin/nodal signaling, which is required for human embryonic SC self-renewal. Colonies of polarized cells with a limited lifespan emerged. Trypsin dissociation yielded continuously self-replicating monolayers. Colonies and monolayers formed the two major human trophoblast lineagesmultinucleate syncytiotrophoblasts and invasive cytotrophoblasts (CTBs). Transcriptional profiling experiments revealed the factors associated with the self-renewal or differentiation of human chorionic trophoblast progenitor cells (TBPCs). They included imprinted genes, NR2F1/2, HMGA2 and adhesion molecules that were required for TBPC differentiation. Together, the results of these experiments suggested that the chorion is one source of epithelial CTB progenitors. These findings explain why CTBs of fully formed chorionic villi have a modest mitotic index and identify the chorionic mesoderm as a niche for TBPCs that support placental growth.
Establishment of human trophoblast progenitor cell lines from the chorion.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
Sex, Age, Specimen part
View SamplesIn preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placentas role has been a focus. We hypothesized that decidual defects are an important determinant of the placental phenotype. We isolated (human) endometrial stromal cells (hESCs) from non-pregnant donors with a prior pregnancy that was complicated by severe PE (sPE). Versus controls, they failed to decidualize as demonstrated by morphological criteria and the analysis of stage-specific antigens. These results were bolstered by showing that they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal-fetal interface. Transcriptional profiling revealed sPE-associated defects in gene expression. Also, decidual cells from sPE patients, which de-differentiated in vitro, failed to re-decidualize in culture. Immediately following isolation they released factors that inhibited CTB invasion, linking a possible cause to a known effect. These data suggested that failed decidualization is an important contributor to down regulated CTB invasion in sPE. Diagnosis of this defect prior to pregnancy would enable therapies that are designed to improve decidualization, a novel strategy for prevention.
Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sex, Age, Specimen part, Disease
View SamplesDuplication of the genome in mammalian cells occurs in a defined temporal order referred as its replication-timing program (RT). RT is regulated in units of 400-800 Kb referred as replication domains (RDs) and changes dynamically during development. Changes in RT are generally coordinated with transcriptional competence and changes in sub-nuclear position. We generated genome-wide RT profiles for 29 distinct human cell types including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures). Surprisingly, transcriptome data revealed that, despite an overall correlation between early replication and transcriptional activity, most genes that switched RT during differentiation can be expressed when late replicating. Intriguingly, this class of genes was nonetheless induced to high expression levels prior to a late to early RT switch and down-regulated after the switch back to late replication. These results clarify the complex relationship between transcription and RT and identify classes of genes that behave as potential drivers of the RT switch vs. those that may depend upon an RT switch for transcriptional induction.
Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification.
No sample metadata fields
View SamplesGene expression profiling of liver biopsies collected from 33 healthy liver donors ranging from 13 to 90 years old. The Affymetrix HG-U133 Plus 2.0 GeneChip platform was used to evaluate gene-expression.
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sex, Age, Specimen part, Disease
View SamplesWe introduce a microfluidic platform that enables off-chip single-cell RNA-seq after multigenerationa lineage tracking under controlled culture conditions. Overall design: Examination of lineage and cell cycle dependent transcriptional profiles in two cell types
A microfluidic platform enabling single-cell RNA-seq of multigenerational lineages.
Specimen part, Cell line, Subject
View SamplesFacioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.
DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.
Specimen part
View SamplesVanin1, a regulator of vitamin B5 metabolism, is expressed by sarcoma tumors. We evaluated its impact on sarcoma growth by using sarcoma cell lines derived from p16p19Vnn1-deficient mice and further transduced with an oncogenic RasV12 oncogene (R tumors) in the presence or not of a catalytically active (VR tumors) or mutated (VdR tumors) Vnn1 isoform.
Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity.
Specimen part, Cell line
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