ArticleBMC biology2022
Hypoxia is fine-tuned by Hif-1α and regulates mesendoderm differentiation through the Wnt/β-Catenin pathway.
Article in BMC biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Higher expression of SOX1, miR-155, and miR-21 in the colostrum of SARS-CoV-2-infected mothers.Scientific reports · 2026Article
- Metabolic programming in tooth development: a regulatory network from energy substrates to signaling instructions.Frontiers in cell and developmental biology · 2026Review
- A Boolean network model of hypoxia, mechanosensing and TGF-β signaling captures the role of phenotypic plasticity and mutations in tumor metastasis.PLoS computational biology · 2025Article
- Construction and application of pancreatic exocrine organoid and spheroid for drug screening and precision medicine.Frontiers in cell and developmental biology · 2025Review
- Identification of PDLIM1 as a glioblastoma stem cell marker driving tumorigenesis and chemoresistance.Cell death discovery · 2024Article
- Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice.Molecular metabolism · 2024Article
- PHD2 safeguards modest mesendoderm development.Communications biology · 2024Article
- Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions.Developmental cell · 2024Article
- Comprehensive insights into the understanding of hypoxia in ameloblastoma.Histology and histopathology · 2024Review
- Wnt7a Decreases Brain Endothelial Barrier Function Via β-Catenin Activation.Molecular neurobiology · 2024Article
- Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus.Developmental cell · 2023Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHypoxia naturally happens in embryogenesis and thus serves as an important environmental factor affecting embryo development. Hif-1α, an essential hypoxia response factor, was mostly considered to mediate or synergistically regulate the effect of hypoxia on stem cells. However, the function and relationship of hypoxia and Hif-1α in regulating mesendoderm differentiation remains controversial.
resultsWe here discovered that hypoxia dramatically suppressed the mesendoderm differentiation and promoted the ectoderm differentiation of mouse embryonic stem cells (mESCs). However, hypoxia treatment after mesendoderm was established promoted the downstream differentiation of mesendoderm-derived lineages. These effects of hypoxia were mediated by the repression of the Wnt/β-Catenin pathway and the Wnt/β-Catenin pathway was at least partially regulated by the Akt/Gsk3β axis. Blocking the Wnt/β-Catenin pathway under normoxia using IWP2 mimicked the effects of hypoxia while activating the Wnt/β-Catenin pathway with CHIR99021 fully rescued the mesendoderm differentiation suppression caused by hypoxia. Unexpectedly, Hif-1α overexpression, in contrast to hypoxia, promoted mesendoderm differentiation and suppressed ectoderm differentiation. Knockdown of Hif-1α under normoxia and hypoxia both inhibited the mesendoderm differentiation. Moreover, hypoxia even suppressed the mesendoderm differentiation of Hif-1α knockdown mESCs, further implying that the effects of hypoxia on the mesendoderm differentiation were Hif-1α independent. Consistently, the Wnt/β-Catenin pathway was enhanced by Hif-1α overexpression and inhibited by Hif-1α knockdown. As shown by RNA-seq, unlike hypoxia, the effect of Hif-1α was relatively mild and selectively regulated part of hypoxia response genes, which fine-tuned the effect of hypoxia on mESC differentiation.
conclusionsThis study revealed that hypoxia is fine-tuned by Hif-1α and regulates the mesendoderm and ectoderm differentiation by manipulating the Wnt/β-Catenin pathway, which contributed to the understanding of hypoxia-mediated regulation of development.
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