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The effects of hypoxia, HIF, and Notch in regulating early hemangioblast development
Author(s) -
RamirezBergeron Diana L,
Kuang ShuZhen,
Hernandez Encarnacion Flores
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a185-b
Subject(s) - hemangioblast , notch signaling pathway , microbiology and biotechnology , embryoid body , embryonic stem cell , hypoxia (environmental) , biology , progenitor cell , mesoderm , stem cell , haematopoiesis , signal transduction , chemistry , induced pluripotent stem cell , genetics , gene , organic chemistry , oxygen
Adaptive responses to low oxygen (O 2 ) tension (hypoxia) are integral to embryogenesis, tumorigenesis, and tissue ischemia. Mutations in members of the Hypoxia Inducible Factor (HIF) family, important transcriptional mediators of these adaptations, lead to multiple cardiovascular defects. Our model system utilizes embryonic stem (ES) cells differentiated into embryoid bodies (EBs) mimicking early development, which can be cultured under physiologic O 2 conditions. We showed that hypoxia promotes mesoderm formation and its differentiation into hemagioblasts (angiogenic and hematopoietic progenitors cells) analyzed by enumerating colonies (BL‐CFCs) or assaying for the expression of Flk‐1 (VEGF‐R2). Recent data show that hypoxia's contribution to the maintenance of undifferentiated stem cells is associated with Notch. Our data demonstrate that hypoxia influences the expression of Notch receptors ( Notch‐1 and ‐4 ), ligands ( Delta‐4 ) and downstream targets ( Hrt‐1 and ‐2 ). Furthermore, using γ‐secretase inhibitors that block Notch signaling results in decreased production of Flk‐1 + cells. Our current hypothesis is that hypoxia influences Notch signaling and early cardiovascular differentiation and our present studies are designed to understand these developmental events. (Supported by NIH HL‐02‐022 and AHA 0‐665412U)