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Review
. 2022 Mar 3;11(3):497.
doi: 10.3390/antiox11030497.

The Role of Nitric Oxide in Stem Cell Biology

Estefanía Caballano-Infantes  1   2 , Gladys Margot Cahuana  1   3 , Francisco Javier Bedoya  1   3 , Carmen Salguero-Aranda  4   5   6 , Juan R Tejedo  1   3
Affiliations
Review

The Role of Nitric Oxide in Stem Cell Biology

Estefanía Caballano-Infantes et al. Antioxidants (Basel). .

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.

Keywords: biomaterials; cell differentiation; cell signaling; evolution; metabolism; nitric oxide; pluripotency; regenerative medicine; stem cell.

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Conflict of interest statement

The authors declare that they have no competing interest.

Figures

Figure 1
Figure 1
Nitric oxide synthesis and biological functions. (A) In normoxia conditions (21% O2), nitric oxide synthase (NOS) catalyzes the oxidation of the terminal guanidinyl nitrogen of the amino acid L-arginine to form L-citrulline and nitric oxide (NO) in presence of NADPH and cofactors such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), heme, and tetrahydrobiopterin (BH4) [3]. Once produced, NO readily interacts with O2, O2− anion, metals, nucleic acids, and proteins. (B) Left panel. NO at low concentration inhibits cytochrome c oxidase (CcO) activity by competing with O2. Adaptive responses to O2 concentration and cell survival genes are activated. Right panel. High concentrations of NO induce damage in all mitochondrial complexes, nitrosylation, or oxidation of protein thiol groups and induce cell death and differentiation.
Figure 2
Figure 2
Physiological human stem cell niches versus nitric oxide-based in vitro cultures. (A) Hypoxic niches of stem cells (SCs). The figure shows the O2 tensions characteristic of the biological niches of MSCs, NSCs, and HSCs. Various studies have determined by direct measurement or applying various mathematical models the O2 tension in bone marrow, adipose tissue, and the ventricular zone of the brain where the respective SCs reside. The results showed levels between 1 and 8% of O2, revealing an O2 tension lower than the atmospheric one (21% of O2). Direct measurements in the brain have not been carried out, but tensions of 0.55% O2 have been recorded in other attached regions in rodents, and conceptual translation to humans has been carried out. MSCs (mesenchymal SCs); NSCs (neural SCs); HSCs (hematopoietic SCs) [76]. (B) Low DETA-NO in normoxia (21% O2) encourages a response similar to hypoxia in PSCs. Therefore, exposure to 2 µM DETA-NO led to the accumulation of HIF-1α and HF-2α proteins, increased expression of pluripotency genes NANOG and OCT-4, and a shift towards the expression of genes favoring glycolitic metabolism. Mitochondrial functions and dynamics were also affected, with a decrease in OXPHOS, an increase in ECAR and DRP1 expression. These actions are not dependent on changes in mROS levels while GPX1 mRNA expression increase, which is compatible with the maintenance of pluripotency as it is described in the review. All in all, these outcomes indicate that NO induces a hypoxia-like response, regulating mitochondrial functionality and metabolic parameters in human PSCs, thus maintaining pluripotency [14]. In this context, the use of NO is proposed to supplement culture media for human PSCs (hPSCs) expansion. NO (nitric oxide); OCR (O2 consumption rate); ECAR (extracellular acidification rate), OXPHOS (oxidative phosphorylation).
Figure 3
Figure 3
Exogenous nitric oxide (NO) treatment in regenerative medicine. Recently, several strategies to release NO in a controlled manner have been designed to improve NO’s benefits in tissue repair derivate their physiological roles in stem cell biology. Significant advances in the tissue bioengineered field have been stated, highlighting NO roles in bone regeneration, cardiovascular repair, and wound healing.
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