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

Abstract

Human-induced pluripotent stem cells (hiPSCs) offer numerous possibilities in science and medicine, particularly when combined with precise genome editing methods. hiPSCs are artificially generated equivalents of human embryonic stem cells (hESCs), which possess an unlimited ability to self-renew and the potential to differentiate into any cell type of the human body. Importantly, generating patient-specific hiPSCs enables personalized drug testing or autologous cell therapy upon differentiation into a desired cell line. However, to ensure the highest standard of hiPSC-based biomedical products, their safety and reliability need to be proved. One of the key factors influencing human pluripotent stem cell (hPSC) characteristics and function is oxygen concentration in their microenvironment. In recent years, emerging data have pointed toward the beneficial effect of low oxygen pressure (hypoxia) on both hiPSCs and hESCs. In this review, we examine the state-of-the-art research on the oxygen impact on hiPSC functions and activity with an emphasis on their niche, metabolic state, reprogramming efficiency, and differentiation potential. We also discuss the similarities and differences between PSCs and cancer stem cells (CSCs) with respect to the role of oxygen in both cell types.

Integrating Oxygen and 3D Cell Culture System: A Simple Tool to Elucidate the Cell Fate Decision of hiPSCs

“…This study also showed the correlation between the cellular metabolism and the maintenance of pluripotency. The lactate production rate was higher, indicating the anaerobic metabolism to meet the energy requirements, in turn upregulating NANOG expression, mainly in 5% O 2 [35]. E-cad/N-cad confirmed the exit from pluripotency.…”

“…2022, 23, x FOR PEER REVIEW 6 of 14 higher in the case of 5% O2. The shift from epithelial to mesenchymal cells is crucial in cell fate decisions and aids in the dynamics of cell differentiation [35]. Furthermore, the epithelial-mesenchymal transition was observed by staining with E-cadherin and N-cadherin (Figure 4C), and the gene expression of E-cadherin and Ncadherin in different oxygen levels aligned with 5% O 2 and 10% O 2 , respectively (Figure 4D).…”

“…The production of lactate by the aggregates utilizing the glucose was more rapid in 5% O 2 (1.309) and 2.5% O 2 (1.21), higher than that in 10% O 2 (1.04) and 20% O 2 (1.123), indicating that 5% and 2.5% O 2 relied more on the anaerobic metabolic pathway for obtaining energy, as shown in Figure 3E, more significantly at Day 5 in the cases of 5% and 2.5% O 2 . The anaerobic metabolism under a hypoxic environment plays a role in the maintenance of pluripotency [35].…”

“…We hypothesized that the pluripotency was maintained while the segregated region entered the differentiated state, which was specifically higher in the case of 5% O 2 . The shift from epithelial to mesenchymal cells is crucial in cell fate decisions and aids in the dynamics of cell differentiation [35].…”

Hypoxia facilitates proliferation of smooth muscle cells derived from pluripotent stem cells for vascular tissue engineering

“…Developmental biology research shows that, during embryonic development, the entire vascular system has not yet been formed and cannot provide adequate oxygen supply (Nit et al., 2021). The combined data in this study highlight the benefits of culture at reduced oxygen tension for amplifying hiPSC‐VSMCs, enhancing ECM deposition capacity for further vascular tissue engineering development.…”