ArticleStem cell research2014
Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency.
Article in Stem cell research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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Who cites it
32 citing papers in PubMed, 47 citations in OpenAlex.
- The integrated developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.Scientific reports · 2026Article
- Trophoblast adaptation to hypoxia: balance and dysfunction.Cell communication and signaling : CCS · 2025Review
- Nicotinamide Riboside, an NAD + Precursor, Protects Against Cardiac Mitochondrial Dysfunction in Fetal Guinea Pigs Exposed to Gestational Hypoxia.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- Determinants of Embryo Implantation: Roles of the Endometrium and Embryo in Implantation Success.Reproductive sciences (Thousand Oaks, Calif.) · 2023Review
- Using high throughput screens to predict miscarriages with placental stem cells and long-term stress effects with embryonic stem cells.Birth defects research · 2022Review
- Using Live Imaging and Fluorescence Ubiquitinated Cell Cycle Indicator Embryonic Stem Cells to Distinguish G1 Cell Cycle Delays for General Stressors like Perfluoro-Octanoic Acid and Hyperosmotic Sorbitol or G2 Cell Cycle Delay for Mutagenic Stressors like Benzo(a)pyrene.Stem cells and development · 2022Article
- Bioenergetics adaptations and redox homeostasis in pregnancy and related disorders.Molecular and cellular biochemistry · 2021Review
- Placental Mitochondrial Abnormalities in Preeclampsia.Reproductive sciences (Thousand Oaks, Calif.) · 2021Article
- Predicted rat interactome database and gene set linkage analysis.Database : the journal of biological databases and curation · 2020Article
- Transcriptomic analysis reveals differential gene expression, alternative splicing, and novel exons during mouse trophoblast stem cell differentiation.Stem cell research & therapy · 2020Article
- Extracellular glucose levels in cultures of undifferentiated mouse trophoblast stem cells affect gene expression during subsequent differentiation with replicable cell line-dependent variation.The Journal of reproduction and development · 2019Article
- Stress Forces First Lineage Differentiation of Mouse Embryonic Stem Cells; Validation of a High-Throughput Screen for Toxicant Stress.Stem cells and development · 2019Article
- Sexual dimorphism of mitochondrial function in the hypoxic guinea pig placenta.Biology of reproduction · 2019Article
- Reduced Uteroplacental Perfusion Pressure (RUPP) causes altered trophoblast differentiation and pericyte reduction in the mouse placenta labyrinth.Scientific reports · 2018Article
- Regulation of energy metabolism during early mammalian development: TEAD4 controls mitochondrial transcription.Development (Cambridge, England) · 2018Article
- Effects of Gravity, Microgravity or Microgravity Simulation on Early Mammalian Development.Stem cells and development · 2018Review
- Magnesium Deprivation Potentiates Human Mesenchymal Stem Cell Transcriptional Remodeling.International journal of molecular sciences · 2018Article
- Review
- Effects of selenium on the survival and invasion of trophoblasts.Clinical and experimental reproductive medicine · 2018Article
- CoQ10 increases mitochondrial mass and polarization, ATP and Oct4 potency levels, and bovine oocyte MII during IVM while decreasing AMPK activity and oocyte death.Journal of assisted reproduction and genetics · 2017Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. In an implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor 4 (FGF4) enabled the highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24h despite exposure to FGF4. However, hypoxic stress supported differentiation poorly after 4-7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential and maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited optimum differentiation at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5-2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.