Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

Abstract

Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders.

Does culture condition of reduced oxygen pressure helps in embryo quality? A prospective randomized study

“…Early stages of embryonic growth are hastened by reduced oxygen tension. 7 This was the basis of shifting to culturing embryos in reduced oxygen pressure. Increased production of ROS are blamed to cause decreased fertilization rate, reduced cleavage rate and reduced blastulation.…”

Cellular senescence or stemness: hypoxia flips the coin

“…This means that the preimplemented embryo is adapted to a low oxygen atmosphere. In humans, it has been shown that low oxygen atmospheres can produce high-quality embryos and improve implementation from developing zygotes [181]. Additionally, placental development is associated with hypoxia, as cytotrophoblasts, which are stem cells forming placenta, proliferate better at low oxygen concentrations in vitro [182,183].…”

“…MYC, OCT4, SOX2 and NANOG are upregulated by HIF2a in these conditions, promoting pluripotency. Additionally, it has been shown that HIF2a can increase glycolytic flux under 5% oxygen, upregulating CTBP1 and CTBP2 to promote self-renewal [181].…”

“…This is probably because of the variability generated by multiple factors, such as the maturation state of the stem cells, hypoxia exposure time or oxygen levels used [8,[186][187][188]. Hypoxia culture can promote the differentiation of mESCs toward endothelial cells, simulating the physiological process of embryonic vascular differentiation [181]. Indeed, the pluripotency markers Oct3/4, Tra1-60, Nanog and Sox2 are downregulated under high levels of ROS.…”

Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism

“…A growing body of evidence suggests that low oxygen concentration, in combination with appropriate differentiation stimuli, promotes hiPSC differentiation into cells of mesodermal origin, such as endothelial cells, CMs, or chondrocytes [105,[113][114][115]. The effect of low oxygen tension on the endothelial differentiation potential of hPSCs was extensively reviewed in a recent paper by Podkalicka et al [116]. Briefly, the available data indicated that endothelial specification is enhanced under hypoxia.…”