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Received Jun 12, 2017; Accepted Oct 2, 2017
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1. Introduction
During early mammalian development, embryonic cells are localized into the microenvironment of the uterus, where the embryo is able to survive and grow in hypoxia (low oxygen tension) before the functional vascular system is formed and oxygen and nutrition are supplied to embryonic tissue [1]. The impact of hypoxia (ranging from 21.6 to 36 mm Hg, 3–5% O2) on normal early embryonic development has been emphasized by several research groups [2, 3]. Intriguingly, most embryonic and adult stem cell populations, including hematopoietic, mesenchymal, and neural stem cells, are naturally present in hypoxic conditions and oxygen level plays a crucial role in the determination of stem cell fate [4–6]. Besides the oxygen gradient, developmental morphogens including ligands of the Wnt family have a relevant impact on the temporal and spatial induction as well as specification of all germ layers [7–10]. However, the effect of low oxygen tension and morphogens on stem cell fate remains controversial, especially in the context of ESC self-renewal and differentiation.
Cellular responses to hypoxia are mainly mediated via hypoxia-inducible factors (HIF). These transcription factors are master regulators of adaptation processes in response to decreased oxygen supply, including angiogenesis, glycolysis, and red blood cell production [11]. Besides their role in the regulation of metabolic and angiogenic responses, HIFs are involved in the control of the proliferation and differentiation of most stem cell populations [12]. Importantly, the specific ablation of the HIF1