Differential Expression of Nitric Oxide Signaling Components in Undifferentiated and Differentiated Human Embryonic Stem Cells

Mujoo, Kalpana; Krumenacker, Joshua S.; Wada, Yoshiko; Murad, Ferid

doi:10.1089/scd.2006.15.779

Cited by 36 publications

(31 citation statements)

References 26 publications

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“…Therefore, based on these previous observations, we hypothesized that the NOcGMP pathway should influence the differentiation of ES cells into cells of various lineages such as myocardial cells, neural precursor cells, and possibly cells of other lineages. Our previous studies clearly indicate the involvement of NO signaling components in the differentiation of both mouse and human ES cells into cardiomyocytes (18,19).…”

Section: Figmentioning

confidence: 59%

“…Based on our previous studies with mouse and human ES cells (18,19), in addition to the preliminary studies of others with mouse ES cells, we believe that the NO-cGMP signaling system has a significant role in the differentiation of mouse and human stem cells into cells of various lineages including cardiomyocytes. Although the inherent heterogeneity of cell population in differentiating stem cells obviously complicates the correlation of biochemistry with cell biology with our studies and others, important clues are forthcoming that may permit us and others to pharmacologically influence stem cell differentiation, tissue engineering, and transplantation biology.…”

Section: Figmentioning

confidence: 92%

“…In addition, although the slow-release NO donor NOC-18 alone did not show stimulation of cGMP levels, when it was combined with BAY 41-2272 there was a 4-fold increase in cGMP accumulation compared with BAY 41-2272 alone, demonstrating the presence of an activatable sGC as has been described (24) in isolated rat cardiomyocytes. BAY 41-2272 by itself shows some increase in cGMP levels, possibly because of increased NOS-2 and NOS-3 levels in differentiated cells (18,19).…”

Section: Figmentioning

confidence: 99%

“…(Magnification: 20ϫ.) detectable sGC (18,19); therefore, the levels of cGMP in undifferentiated cells are probably caused by particulate guanylyl cyclase. In contrast, although differentiated cells exhibited 7-fold lower levels of basal cGMP compared with undifferentiated cells, a 13-fold stimulation in cGMP accumulation was observed with 100 M NOC-22, demonstrating that differentiated cells acquire the ability to be stimulated with NO.…”

Section: Figmentioning

confidence: 99%

“…Compared with NOS-1, NOS-2, and NOS-3 mRNA and protein levels were also induced during ES cell differentiation (18,19), thereby demonstrating the involvement of NO signaling components during differentiation of ES cells into cardiac cells. Previous studies by other investigators (20) have shown increased cardiomyogenesis with NO donors and by delivery of the NOS-2 gene in mouse ES cells.…”

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confidence: 93%

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Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells

Mujoo

Sharin

Bryan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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cardiomyogenesis ͉ cyclic GMP ͉ soluble guanylyl cyclase ͉ NO donors ͉ sGC activators E mbryonic stem (ES) cells are derived from the inner cell mass of the preimplantation embryo, and because of their selfrenewal and pluripotency, they are thought to revolutionize the field of regenerative medicine (1-3). Although transplantation of stem cells into animal models of cardiac injury and Parkinson's disease has revealed some beneficial effects, a better understanding of the role of specific signaling pathways involved in proliferation and differentiation of ES cells is necessary to improve their use in clinical medicine (4-6). Components of a number of signaling pathways such as Wnt/␤-catenin (7), phosphotidyle-inosital 3-kinase (8, 9), MAPK (10), and NO (11) have been shown to regulate proliferation and differentiation of stem cells.NO is a diffusible short-lived free radical and a signaling molecule with a number of important physiological functions such as smooth muscle relaxation, neurotransmission, and inhibition of platelet aggregation and host defense mechanisms (12). It also plays a role in the pathology of several inflammatory diseases and other pathological conditions such as cancer, diabetes, and neurodegenerative diseases (13,14). NO plays an important role in the control of heart rate, contractibility, coronary perfusion, and cardiac development (15, 16). It is synthesized by enzymes called nitric oxide synthases such as NOS-1 (neuronal NOS), NOS-2 (inducible NOS), and NOS-3 (endothelial NOS) that catalyze the oxidation of L-arginine into L-citruline with the release of NO. NO can also be measured in biological systems as metabolites of NO and as nitrites and nitrates (17). The NO receptor soluble guanylyl cyclase (sGC) is a heme-containing heterodimer with ␣ and ␤ subunits (12). Binding of NO to the heme prosthetic group of sGC catalyzes the conversion of GTP into the second messenger cGMP that can exert many physiological effects, such as mediating vascular smooth muscle tone and motility, phototransduction, and maintenance of fluid and electrolyte homeostasis by interaction of cGMP with downstream effectors such as a family of cGMP-dependent protein kinases, cGMP-dependent phosphodiesterases, and cyclic nucleotide gated channels (11).Our previous studies with mouse and human ES cells demonstrated a time-dependent increase in mRNA and protein levels of different subunits of sGC (with the exception of ␤2 mRNA in H-9 cells) during both mouse and human ES cell differentiation into cells of cardiac lineage. Compared with NOS-1, NOS-2, and NOS-3 mRNA and protein levels were also induced during ES cell differentiation (18,19), thereby demonstrating the involvement of NO signaling components during differentiation of ES cells into cardiac cells. Previous studies by other investigators (20) have shown increased cardiomyogenesis with NO donors and by delivery of the NOS-2 gene in mouse ES cells.In this study, we demonstrate the role of NO and cGMP in differentiation of human and mouse ES cells by regulating t...

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Section: Figmentioning

confidence: 59%

Section: Figmentioning

confidence: 92%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 93%

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Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells

Mujoo

Sharin

Bryan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Nitric Oxide Determines Mesodermic Differentiation of Mouse Embryonic Stem Cells by Activating Class IIa Histone Deacetylases: Potential Therapeutic Implications in a Mouse Model of Hindlimb Ischemia

et al. 2010

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In human endothelial cells, nitric oxide (NO) results in class IIa histone deacetylases (HDACs) activation and marked histone deacetylation. It is unknown whether similar epigenetic events occur in embryonic stem cells (ESC) exposed to NO and how this treatment could influence ESC therapeutic potential during tissue regeneration. This study reports that the NO-dependent class IIa HDACs subcellular localization and activity decreases the global acetylation level of H3 histones in ESC and that this phenomenon is associated with the inhibition of Oct4, Nanog, and KLF4 expression. Further, a NO-induced formation of macromolecular complexes including HDAC3, 4, 7, and protein phosphatase 2A (PP2A) have been detected. These processes correlated with the expression of the mesodermalspecific protein brachyury (Bry) and the appearance of several vascular and skeletal muscle differentiation markers. These events were abolished by the class IIa-specific inhibitor MC1568 and by HDAC4 or HDAC7 short interfering RNA (siRNA). The ability of NO to induce mesodermic/ cardiovascular gene expression prompted us to evaluate the regenerative potential of these cells in a mouse model of hindlimb ischemia. We found that NO-treated ESCs injected into the cardiac left ventricle selectively localized in the ischemic hindlimb and contributed to the regeneration of muscular and vascular structures. These findings establish a key role for NO and class IIa HDACs modulation in ESC mesodermal commitment and enhanced regenerative potential in vivo. STEM CELLS 2010;28:431-442 Disclosure of potential conflicts of interest is found at the end of this article.

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sGC-cGMP Signaling: Target for Anticancer Therapy

Bian

Murad

2014

Advances in Experimental Medicine and Biology

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The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The α1β1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe(2+)) heme at histidine 105 of the β1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment.

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Differential Expression of Nitric Oxide Signaling Components in Undifferentiated and Differentiated Human Embryonic Stem Cells

Cited by 36 publications

References 26 publications

Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells

Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells

Nitric Oxide Determines Mesodermic Differentiation of Mouse Embryonic Stem Cells by Activating Class IIa Histone Deacetylases: Potential Therapeutic Implications in a Mouse Model of Hindlimb Ischemia

sGC-cGMP Signaling: Target for Anticancer Therapy

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