期刊
EXPERIMENTAL BIOLOGY AND MEDICINE
卷 233, 期 8, 页码 1044-1057出版社
SAGE PUBLICATIONS LTD
DOI: 10.3181/0709-RM-263
关键词
human embryonic stem cell; embryoid body; hematopoiesis; hypoxia; hypoxic inducible factor (HIF)
资金
- NHLBI NIH HHS [R01 HL77923, R21 HL72000] Funding Source: Medline
Oxygen tension can provide an important determinant for differentiation and development of many cells and tissues. Genetic regulation of hemato-endothelial commitment is known to respond to oxygen deprivation via stimulation of hypoxia inducible factors (HIFs). Here, we use a closed bioreactor system to monitor and control the dissolved oxygen during differentiation of human embryonic stem cells (hESCs) via formation of embryoid bodies (hEBs). Exposing hESC-derived EBs to ambient oxygen at or below 5% results in stabilization of HIF-1 alpha and increased transcription of hypoxic responsive genes. Interestingly, we find that rather than HIF-1a expression being stable over prolonged (7-16 days) culture in hypoxic conditions, HIF-1 alpha expression peaks after approximately 48 hours of hypoxic exposure, and then declines to near undetectable levels, despite constant hypoxic exposure. This transient stabilization of HIF-1a during hESC-derived EB culture is demonstrated for four distinct stages of differentiation. Furthermore, we demonstrate hEB cell expansion is slowed by hypoxic exposure, with increased apoptosis. However, hEB cell proliferation returns to normal rates upon return to normoxic conditions. Therefore, although hypoxia effectively stimulates hypoxic responsive genes, this single variable was not sufficient to improve development of hemato-endothelial cells from hESCs.
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