NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

Abstract

Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes. The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation of lineage committed precursor cells to be used for regenerative therapies.

Molecular analysis, developmental function and heavy metal-induced expression of ABCC5 in zebrafish

“…As the second messenger of nitrite oxide (NO) signaling system, cGMP serves as signals for regulating diverse cellular and physiological processes (Arnold et al, 1977). At the cellular level, NO and cGMP regulate important processes such as growth, survival, differentiation, proliferation, migration, axon guidance and other processes through a variety of downstream signaling cascades (Madhusoodanan and Murad, 2007). Efflux of cGMP by ABCC5 may be viewed as either controlling the intracellular concentration of cGMP in addition to the well-established metabolic degradation by phosphodiesterases, or providing an extracellular signal that may act in either an autocrine or paracrine fashion at specific receptors.…”

Effect of muscle‐derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat

“…If they are, this may open up a complementary approach to MDSC implantation, by the potential modulation of endogenous stem cells to achieve similar effects. Interestingly, both nitric oxide and cGMP, physiological mediators of penile erection whose levels can be increased pharmacologically, have been shown to trigger stem cell differentiation [44][45][46], and therefore they could constitute new approaches to awaken dormant stem cells.…”

Interactions between the NO-Citrulline Cycle and Brain-derived Neurotrophic Factor in Differentiation of Neural Stem Cells

“…There are three NOS isoforms: NOS1 or neuronal NOS (nNOS), which is primarily found in the brain, although its expression is also observed in skeletal muscle and other tissues; NOS2 or inducible NOS; and NOS3 or endothelial NOS (eNOS), which was first observed in endothelial cells but is also present in other cell types (reviewed in Ref. 6). L-Arginine is the only substrate of NOS for NO synthesis.…”