1. Hypoxia affects mesoderm and enhances hemangioblast specification during early development
- Author
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Karen D. Cowden Dahl, M. Celeste Simon, Anja Runge, Diana L. Ramírez-Bergeron, Hans Joerg Fehling, and Gordon Keller
- Subjects
Fetal Proteins ,Vascular Endothelial Growth Factor A ,Mesoderm ,medicine.medical_specialty ,Cellular differentiation ,medicine.medical_treatment ,Cell Count ,Bone Morphogenetic Protein 4 ,Biology ,Mice ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Progenitor cell ,Growth Substances ,Hypoxia ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Stem Cells ,Growth factor ,Aryl Hydrocarbon Receptor Nuclear Translocator ,Nuclear Proteins ,Cell Differentiation ,Hypoxia-Inducible Factor 1, alpha Subunit ,Vascular Endothelial Growth Factor Receptor-2 ,Embryonic stem cell ,Coculture Techniques ,Cell biology ,DNA-Binding Proteins ,Kinetics ,Haematopoiesis ,Phenotype ,medicine.anatomical_structure ,Endocrinology ,Receptors, Aryl Hydrocarbon ,Hypoxia-inducible factors ,Bone Morphogenetic Proteins ,Hemangioblast ,Hypoxia-Inducible Factor 1 ,T-Box Domain Proteins ,Cell Division ,Gene Deletion ,Transcription Factors ,Developmental Biology - Abstract
Hypoxia Inducible Factor (HIF), consisting of HIF1alpha and ARNT (HIF1beta) subunits, activates multiple genes in response to oxygen (O(2)) deprivation. Arnt(-/-) mice exhibit substantial defects in blood cell and vessel development. We demonstrate that hypoxia accelerates the expression of Brachyury (a mesoderm-specific transcription factor), BMP4 (a mesoderm-promoting growth factor) and FLK1 (a marker of hemangioblasts, the bipotential progenitor of endothelial and hematopoietic cells) in differentiating ES cell cultures. Significantly, proliferation of embryonic hemangioblasts (BL-CFCs) is regulated by hypoxia, as Arnt(+/+) ES cells generate increased numbers of FLK1(+) cells, and BL-CFCs with accelerated kinetics in response to low O(2). This response is HIF-dependent as Arnt(-/-) ES cells produce fewer FLK1(+) cells and BL-CFCs, under both normoxic and hypoxic conditions. Interestingly, this defect is rescued when Arnt(-/-) ES cells are co-cultured with Arnt(+/+) ES cells. Vegf(+/-)or Vegf(-/-) ES cells generate proper numbers of FLK1(+) cells but fewer BL-CFCs, suggesting that additional factors regulated by HIF (other than VEGF) are involved in these early events. Thus, hypoxic responses are important for the establishment of various progenitor cells, including early mesoderm and its differentiation into hemangioblasts. Together these data suggest that ineffective responses to hypoxia in Arnt(-/-) embryos abrogate proper cardiovascular development during early embryogenesis, including the pathways controlling hemangioblast differentiation.
- Published
- 2004
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