Abstract
Nitric oxide (NO) is a gaseous biomolecule endogenously synthesized with an essential role in embryonic development and several physiological functions, such as regulating mitochondrial respiration and modulation of the immune response. The dual role of NO in embryonic stem cells (ESCs) has been previously reported, preserving pluripotency and cell survival or inducing differentiation with a dose-dependent pattern. In this line, high doses of NO have been used in vitro cultures to induce focused differentiation toward different cell lineages being a key molecule in the regenerative medicine field. Moreover, optimal conditions to promote pluripotency in vitro are essential for their use in advanced therapies. In this sense, the molecular mechanisms underlying stemness regulation by NO have been studied intensively over the current years. Recently, we have reported the role of low NO as a hypoxia-like inducer in pluripotent stem cells (PSCs), which supports using this molecule to maintain pluripotency under normoxic conditions. In this review, we stress the role of NO levels on stem cells (SCs) fate as a new approach for potential cell therapy strategies. Furthermore, we highlight the recent uses of NO in regenerative medicine due to their properties regulating SCs biology.
Highlights
We recently described the essential role of Nitric oxide (NO) inducing a cellular response to hypoxia in pluripotent stem cells (PSCs) [14]
We found that the treatment with low NO doses promotes Hypoxia-inducible factors ble factors (HIFs)-1α and HIF-2α protein accumulation in human PSCs (hPSCs) cultured under normoxic conditions (21% O2 ), mimicking the hypoxia response in cells cultured at 5% of O2 in a hypoxia incubator [14] (Figure 2B)
Concerning NO’s role in metabolic regulation, we reported an increase in glycolytic genes (HK2, LDHA, PDK1, and PKM2) and angiogenesis gene, vascular endothelial growth factor A (VEGF-A), in hPSCs after low dose of diethylenetriamine NO adduct (DETA-NO) treatment, showing comparable results in cells grown under hypoxia conditions (5% of O2 ) [14]
Summary
Nitric oxide (NO) is a highly reactive gas with a brief life span, synthesized by the enzyme nitric oxide synthase (NOS) through L-arginine oxidation to L-citrulline. High doses of NO can induce post-translational modifications through nitrosylation, or oxidation of protein thiol groups and cause the oxidation of iron (Fe2+ ) of the mitochondrial active centers in rat liver mitochondria, causing damage in all mitochondrial complexes [11]. This evidence indicates that NO could be a physiological regulator of cellular respiration and metabolism (Figure 1B). The potential role of NO in regulating the cellular response to hypoxia in vitro has been described [10,12–14] In these studies, the authors used an interval of oxygen pressure value around 1–5% of O2 to induce severe or physiological hypoxic conditions in vitro.
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