Effects of nitric oxide on stem cell therapy

    Effects of nitric oxide on stem cell therapy Wuchen Wang, Yugyung Lee, Chi H. Lee PII: DOI: Reference:

S0734-9750(15)30037-9 doi: 10.1016/j.biotechadv.2015.09.004 JBA 6972

To appear in:

Biotechnology Advances

Received date: Revised date: Accepted date:

10 February 2015 14 September 2015 18 September 2015

Please cite this article as: Wang Wuchen, Lee Yugyung, Lee Chi H., Effects of nitric oxide on stem cell therapy, Biotechnology Advances (2015), doi: 10.1016/j.biotechadv.2015.09.004

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Effects of Nitric Oxide on Stem Cell Therapy

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Review Wuchen Wang, 1 Yugyung Lee, 2 Chi H Lee*1

Institution:

1. School of Pharmacy University of Missouri, Kansas City 2. School of Computing and Engineering, University of Missouri, Kansas City

Journal:

Biotechnology Advances

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* Correspondence Chi H. Lee, Ph.D.

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Authors:

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Professor 2464 Charlotte St Division of Pharmaceutical Sciences University of Missouri at Kansas City Kansas City, MO 64108, USA (816) 235 2408 (Tel) (816) 235 5779 (Fax) [email protected]

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Abstract The use of stem cells as a research tool and a therapeutic vehicle has demonstrated their great potential in the treatment of various diseases. With unveiling of nitric oxide synthase (NOS) universally present at various levels in nearly all types of body tissues, the potential therapeutic implication of nitric oxide (NO) has been magnified, and thus scientists have explored new treatment strategies involved with stem cells and NO against various diseases. As the functionality of NO encompasses cardiovascular, neuronal and immune systems, NO is involved in stem cell differentiation, epigenetic regulation and immune suppression. Stem cells trigger cellular responses to external signals on the basis of both NO specific pathways and concerted action with endogenous compounds including stem cell regulators. As potency and interaction of NO with stem cells generally depend on the concentrations of NO and the presence of the cofactors at the active site, the suitable carriers for NO delivery is integral for exerting maximal efficacy of stem cells. The innovative utilization of NO functionality and involved mechanisms would invariably alter the paradigm of therapeutic application of stem cells. Future prospects in NOinvolved stem cell research which promises to enhance drug discovery efforts by opening new era to improve drug efficacy, reduce drug toxicity and understand disease mechanisms and pathways, were also addressed. Key Words: Nitric oxide, Stem Cell Therapy, Novel platforms for NO delivery 1. Introduction 2. Stem cells and their therapeutic properties 2.1. Adipose-derived mesenchymal stem cells (ADSCs) 2.2. Neuronal stem cells (NSCs) 2.3. Endothelial progenitor cells (EPCs) 2.4. Mesenchymal stem cells (MSCs) 2.5. Hematopoietic stem cells (HSCs) 3. The involvement of NO in the regulation of stem cells 3.1. NO involvement in stem cell differentiation 3.2. NO involvement in stem cell epigenetic regulation 3.3. NO involvement in stem cell immune suppression 4. Characterization of stem cell regulation mediated by NO 4.1. The modulators of stem cell therapeutic efficacy 4.2. NO concentration dependent regulation 4.3. The combinatory effects of cofactors and exogenous compounds 4.4. The combinatory effects with the external stimuli 4.5. Nitrosylation signaling mediated regulation 5. Novel platforms for NO delivery to stem cells 5.1. Internal NO production 5.1.1. eNOS gene based production 5.1.2. Induction of eNOS expression 5.2. External NO supply 5.2.1. Exogenous NO-releasing compounds 5.2.2. Novel NO carriers 6. Future prospects in NO-involved stem cell therapy 6.1. Recent progress in drug screening via stem cell models 6.2. Future prospects for clinical application of stem cell therapy 2

ACCEPTED MANUSCRIPT 1. Introduction In the past decades, nitric oxide (NO) has been a major research interest in biomedical,

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basic biology and translational research fields (Moncada and Higgs, 2006). NO provides

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sustained vascular tone maintenance and supplies enhanced blood flow to ventricular cell and various organs including particular regions of the brain (Ji et al., 2009, Lee, 2011, Nuñez C,

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2014). The vessel dilator and neural transmitter functions lend credence to its becoming a

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primary target for the treatment of cardiovascular and neural diseases (Acharya et al., 2012, Liu et al., 2011). Cardiovascular malfunctions, such as hypertension, acute myocardial infarction and

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atherosclerosis, are generally attributed to an insufficient supply of NO to blood vessel (Lepic et al., 2006). On the other hand, the universal presence of cerebral palsy among neonates is due to

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the effects of a constant over-supply of NO during the formation of the brain (Ji et al., 2009). These findings suggested that NO is a key element in both cardiovascular tuning and brain

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development, albeit in an opposite way.

Numerous inducers are known to enhance the levels NO and act to produce several diseases including fibromyalgia and posttraumatic stress disorder (Pall, 2007). These short-term triggers are acting primarily through the nitric oxide product, peroxynitrite, and considered to switch on a complex malicious cycle, known as the NO/ONOO- cycle that is responsible for the onset of pathological symptoms (Radi, 2013). As the understanding of the biological property of peroxynitrite provides a framework to elucidate the molecular mechanisms of oxidant-mediated cell and tissue injury in NO-producing systems, elevated peroxynitrite/NO ratio and consequent oxidative stress seem to be integral to produce various pathological conditions including heart failure and other cardiovascular diseases (Pall, 2013; Bianco and Fukuto, 2015).

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ACCEPTED MANUSCRIPT Various investigations on neurogenesis have demonstrated that NO is involved with the bidirectional regulation of both neuronal stem cells (NSCs) and normal neurons (Luo et al.,

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2010). With unveiling of nitric oxide synthase (NOS) universally present at various levels in

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nearly all types of body tissues (Buono et al., 2012, Purcell et al., 1999), there are sufficient evidences that NO promotes cardiomyogenesis via converting embryonic stem cells (ESCs) into

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the cardiac-specific phenotype (Chen et al., 2010, Kanno et al., 2004). The inhibition of nNOS in

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NSCs results in impaired neurogenesis, whereas removal of nNOS in neurons promotes NSCs proliferation (Luo et al., 2010), which subsequently lead to the utility of NOS inhibitors as a

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therapeutic agent against the arrested commitment of ESCs (Bartsch et al., 2011). Although the mechanisms of these intertwined regulation pathways have yet to be elucidated, the involvement

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of NO in stem cells therapy and readiness in adopting stem cell therapy towards corresponding tissue defects and diseases were widely acknowledged.

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In specific types of stem cells, NOS is constituently present within them. For instance, all three isoforms of NOS are found in skin-derived mesenchymal stem cells (MSCs), which is indicative of the implication of NO in MSCs mediated skin regeneration (Salvolini E, 2010). MSCs populated vessel prosthetics managed to induce bioactive NOS expression and exerted self-supporting NO dilating functions, suggesting that stem cells possess the ability to produce viable NO under structured stimulations (Kanki-Horimoto et al., 2006). NO can also be externally provided to stem cells through gene insertion (Kanki-Horimoto et al., 2006) or preconditioning with NO donors (Masoud et al., 2012). As the potential therapeutic implication of stem cells and NO against various diseases has been magnified, the innovative utilization of NO functionality and involved mechanisms would invariably alter the paradigm of therapeutic application of stem cells. Subsequently, stem cell research promises to enhance drug discovery

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ACCEPTED MANUSCRIPT efforts by opening new era to improve drug efficacy and reduce toxicity, discover novel target, and understand disease mechanisms and pathways.

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This review article focuses on the NO mediated regulation of the therapeutic properties of

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stem cells, the mechanisms behind their regulations, and novel platforms for NO delivery to stem

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cells. Future prospects in NO-involved stem cell therapy were also discussed.

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2. Stem cells and therapeutic properties

The use of stem cells as a research tool and a therapeutic vehicle has demonstrated the

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great potential for treatment of numerous diseases (Song et al., 2014). Stem cells with a scope of origin from human body are capable of migrating and integrating into new translational medicine

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(Sareen et al., 2014), and have been utilized to remedy existing defects of specific tissues (Li et al., 2014a, Piltti et al., 2013). Among the most pursued topics in recent research and

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development fields, regenerative medicine invariably holds its valuable position and can be categorized into the following sub-types as shown in Table 1.

2.1. Adipose-derived mesenchymal stem cells (ADSCs) Being extracted firstly from human adipose tissues, ADSCs maintain the fibroblast-like morphology, and are prone to differentiate into connective tissue under the conditions where the growth factors are stimulated (Yang et al., 2015). In canine models, ADSCs implantation was effective for the treatment of vocal fold injury via improvement of smoothness and morphological concaveness mediated by secreted ECM components, such as fibronectin, decorin and elastin de novo (Hu et al., 2014). The use of ADSCs for connective tissue repair has guaranteed continuous studies on rare defects and a wide range of injuries including surgical

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ACCEPTED MANUSCRIPT suture wound healing, calvarial defect and articular cartilage (Laverdet et al., 2014, Lu et al.,

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2014, Reckhenrich et al., 2014).

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2.2. Neuronal stem cells (NSCs)

Along with their differential capabilities under various stimuli, neuronal stem cells serve

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as an excellent candidate to replace existing non-regenerative neural cells in Parkinson’s disease

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and stroke (Purcell et al., 2009). Among stem cell platforms for degenerative tissues, neural progenitors (NPs) were frequently explored due to the greatest behavioral improvement and

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survival rate in the aphakia mouse model. Grafting of NPs has not only restored the functional loss caused by degenerative neural damage, but also redeemed the amount of neurons existing in

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the substantia nigra of the experimental mouse (Moon et al., 2013). The life expectancy of patients with neurodegenerative diseases can be further extended, once the successful translation

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of animal study to clinical trial is completed.

2.3. Endothelial progenitor cells (EPCs) The regulation of NO has been the primary focus in the elucidation of the mechanisms involved with vascular diseases not only due to its basic role in vasodilation but also its complex interaction with neuronal progenitor cells and synaptic messaging (Yang et al., 2013). As blood vessels heavily rely on endothelial cells aligned inside for NO-mediated vasomotor function, the maintenance of the precursors of endothelial cells in both cardiovascular system and neural system is integral to their homeostasis function (Marcelo et al., 2013). An enhanced accumulation of amyloid β peptides, a major component of extracellular amyloid plaques and cleavage product, was detected in brain tissue of the eNOS-deficient mice, suggesting that a

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ACCEPTED MANUSCRIPT substantial supply of NO to endothelial cells is required for normal functions in the central nervous system (Katusic and Austin, 2014).

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The outcomes of therapeutic approaches to improve the function of endothelial cells

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depend on the appropriate utilization of EPCs from cardiovascular origin. Endothelial progenitor cells naturally mobilize themselves from bone marrow in response to cardiovascular damage,

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whereas, in atherosclerosis, the progression of plaque was reversed in the presence of EPC

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mobilizers (Yao et al., 2012), which is due to the suppression of hyperglycemia via enhanced NO release from EPCs. Future studies on EPCs function in neuronal repair and cardiovascular

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through the NO involved mechanism.

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diseases will reveal the connection between two systems that seems to be partially mediated

2.4. Mesenchymal stem cells (MSCs)

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Being derived from bone marrow, MSCs possessed multi-lineage differentiation potential as well as high malleability to adapt themselves to various modifications, which make them a suitable candidate for both neuronal damages and cardiovascular diseases. MSCs modified with a brain derived neurotrophic factor (BDNF) displayed the high recovery rate in the brain cells as compared to non-treated groups (Jeong et al., 2014). Differentiation of MSCs into neuronal stem cells using cerebrospinal fluids (CSF) was considered as a viable option for clinical treatment of neuronal diseases (Ren C, 2013). It was found that MSCs exert its tissue repair function by differentiation of both neurons and glial cells in response to neurotrophic factors. Studies employing MSCs as a cytoprotective and tissue repair agent demonstrated that a small portion of MSCs have made a significant impact on the complication of diabetes mellitus (El-Tantawy and Haleem, 2014). It was also shown that benign functionality of cardiac muscle

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ACCEPTED MANUSCRIPT was significantly enhanced after migration of the intravenously infused MSCs to the heart in myocardial infraction rat model (Tong et al., 2013). Myogenic stem cells transfected with eNOS

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gene were able to consistently produce NO for endothelial growth and formation of new vessels

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(Janeczek et al., 2013), offering a practical solution to repair the post infarction scar, and thus serving as a suitable candidate for cell therapy. It was duly expected that a more delicate and

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advanced delivery system for MSCs could lay the foundation for a novel treatment strategy.

2.5. Hematopoietic stem cells (HSCs)

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Initially being employed to treat leukemia, HSCs have been efficiently used for treatment of various diseases (Sachs, 1996). The bone marrow is easily accessible and harbors two types of

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stem cells, one of which is HSCs whose transplantation has become a standard treatment option for leukemia multiple myeloma (Cherry et al., 2013).

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Despite their established clinical applications, the role of HSCs in promoting platelet formation has not been fully elucidated. Megakaryocytopoiesis is the process of the platelet production and involves the diversification of multi-potent HSCs. NO autocrine was reported to positively trigger HSCs megakaryocyte progress and thereafter platelet development stimulated by autocrine-synthesized NOS (Dai et al., 2006). An incorporation of EPCs derived from HSCs into retinal vasculature promotes neovascularization in the preclinical study (Guo et al., 2012). As EPCs and HSCs are not specific to any existing lineages, this approach can be translated into the clinical treatment against ischemic injury in numerous types of vascular systems.

3. The involvement of NO in the regulation of stem cells 3.1. NO involvement in stem cell differentiation

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ACCEPTED MANUSCRIPT The involvement of NO in stem cell differentiation has been mediated via several working mechanisms as shown in Figure 1. NO has been involved with the regulation of

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neuronal cells derived from subventricular zone which is responsible for building the genesis of

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stem/precursor cell populations (Keilhoff, 2011). Neurons and astrocytes were differentiated from NSCs in the cultured conditions, and this process is largely dependent on the result of NO

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signaling produced during the neuron development (Tao Li et al., 2010), being positively

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regulated by NO, and reversely regulated by NOS inhibitors (Sa et al., 2010). Endothelial differentiation of embryonic stem cells (ESCs) largely depends on both

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external and endogenous NO, and is substantiated by the presence of significantly enhanced ECs markers, such as CD144, eNOS and FLK1(Huang et al., 2010, Mujoo et al., 2008). Bone marrow

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stem cells (BMSCs) also expressed cardiac makers that could be suppressed by either NOS inhibitors or sGC inhibitors (Ybarra et al., 2011). The deficiency of eNOS was the major source

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of lacking matrix metallopeptidase 9 (MMP-9) signaling in rodent bone marrow, and these symptoms were alleviated by the treatment of pharmacological agents, such as NO donors or inserting eNOS genes, to bone marrow cells (Aleksinskaya et al., 2013). Pre-conditioning of adipose-derived mesenchymal stem cells (ADSCs) with an NO-donor allowed them to enter the differentiation state faster, and enhanced their ability to produce von Willebrand factors and troponins for cardiac repair (Berardi et al., 2011). Therefore, the cytoprotective effects of NO on ESC derived cardiomyocytes could be explored as a preconditioning strategy of stem cells (Gorbe et al., 2014).

3.2. NO involvement in stem cell epigenetics regulation

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ACCEPTED MANUSCRIPT Epigenetic mechanisms reflect the final outcome in the transcriptional hierarchy mediated by transcriptional factors and are designated to alter the gene function without causing any

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changes to DNA sequence. Epigenetic mechanisms include modifications of the histones and

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histone variants incorporation, changes in DNA methylation and Adenosine-5′-triphosphatedependent chromatin remodeling, implementation of RNAi pathways and non-protein-coding

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RNAs (ncRNA) (Cheong and Lufkin, 2010). The epigenetics of histone proteins are the major

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contributor to the responses to environmental cues, bring up the neuronal transcriptional expression. NO regulates epigenetics of cells by mediating the post-translational demethylation

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of histone lysine residues (KDMs). A nitrosyl iron complex formed with the radical of NO at the catalytic cite directly inhibits KDM3A, altering the transcription outcome of the related proteins

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(Hickok et al., 2013).

There was a positive correlation between reduced availability of NO and cardiovascular

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pathology, and this finding led to the research towards discovering the various possible paths of ESCs involved with the vascular development process (Huang et al., 2010, Tejedo et al., 2010). ESCs used in early embryonic epigenetics studies confirmed that stem cell factors, such as Nanog and Sox 2, are potential negative cues in histone modification and control the epigenetic markers, whereas the roles of gene-specific promoters including Mixl1, Brachyury and GATA are still unidentified (Cheong and Lufkin, 2010).

3.3. NO involvement in stem cell immune suppression The transplantation of NSCs or NPCs caused immune system suppression (Sauer et al., 2011, Wang et al., 2009), which is utilized for the treatment of immunopathology in the brain. NSCs suppress the function of T lymphocytes by producing the high level of NO and

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ACCEPTED MANUSCRIPT prostaglandin E2 (Janeczek et al., 2013, Sauer et al., 2011, Wang et al., 2009). The inhibition of nNOS in NSCs resulted in suppression of T cells intracellular Ca (2+) oscillation, substantiating

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the function of NO in immunopathology (Sato et al., 2007).

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It was suggested that the logarithmic increase of iNOS expression is the basis of MSCs immune suppression (Xu et al., 2013). In certain circumstances, however, T-cell proliferation

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can be up-enhanced by MSCs due to inhibition of iNOS production or iNOS gene ablation,

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indicating that NO acts as a switch in MSC-mediated immunomodulation (Li et al., 2012). It was also found from biological assessment of MSCs that the targeting of TAK-1 binding protein

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(TAB2) significantly contributes to the reduced iNOS expression, hence yielding a low immunosuppression capacity exhibited by MSCs.

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The MSCs immune suppression mediated by NO works in conjunction with pro-

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inflammatory cytokines, such as interferon-γ (INF- γ) and tumor necrosis factor α (TNF-α),

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which also serve as a trigger of tumor growth at influential organs (Han et al., 2011, Ren et al., 2008). MSCs immune suppression can also be regulated by cytokine signaling 1 (SOCS1) suppressors, whose absence significantly reduced the expression of iNOS (Zhang et al., 2014) and subsequently restricted the general usage of MSCs to tumor patients.

4. Characterization of stem cells regulation mediated by NO The effects NO released from the body on the growth and differentiation of stem cells depend on several variables, such as the source of NO, its local concentration and the presence of cofactors. Stem cells trigger cellular responses to external signals on the basis of both NO specific pathways and concerted action with endogenous compounds including stem cell regulators as shown in Figure 2.

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4.1. The modulators of stem cell therapeutic efficacy

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The mobilization of hematopoietic stem (HSCs) and progenitor cells originated from

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bone marrow was stimulated by NO mediated regulators, such as G-CSF and SCF (de Resende et al., 2007). Stem cell factor (SCF) is found to be a significant mediator in gametogenesis,

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hematopoiesis and melanogenesis, and responsible for the modulation of vascular permeability.

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The NO production by eNOS isoforms distinctively enabled SCF induced internalization of endothelial cadherin (Kim et al., 2014b), indicating that the neutralization of SCF is considered

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as a potential target for the treatment of hyper-permeable vascular diseases. An external NO exposure affects neural progenitor cell (NPC) population by modulating

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neuro-inflammatory conditions. An excessive NO-donor promotes the transition from neuronal cells to glial cells in vitro, which is dependent on the amount of transcription factors including

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Neuron-Restrictive Silencing Factor (NRSF) and Repressor Element Silencing Transcription (REST). This finding suggested that the high level of NO exposure does not work independently towards neural signaling, but relies on collaborative chromatin modifications provided by NRSF/REST (Bergsland et al., 2014). The mechanistic study has identified the involvement of NO and cytokines including hepatocyte growth factor (HGF) and granulocyte colony-stimulating factor (G-CSF) in the MSCs repair process against acute lung fibrosis (ALF) (Lee et al., 2010, Ortiz et al., 2003). A decrease in the levels of NO metabolites in MSC is exposure-time dependent, suggesting that MSCs acted on the microenvironment of the lung by suppressing iNOS activity and modulating immune responses of the adjacent immune cells (Hung et al., 2013).

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ACCEPTED MANUSCRIPT NO-donors were shown to up-regulate the release profiles of stromal cell derived factor1α (SDF-1α), a product from embryonic neurons, and its chemokine receptors (CXCR4)

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(Petkovic et al., 2013, Sachewsky and Morshead, 2014), subsequently promoting the migration

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of bone marrow derived stem cells (BMSCs) (Cui et al., 2007) and sustaining the self-renewal rate of neuronal stem cells and their efficacy against the ischemic conditions (Addington et al.,

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2014). These results highlight the importance of NO as a modulator of stem cell therapy and

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were further augmented by the similar approach to that achieved from the stimulated eNOS

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expression induced by inserting eNOS genes to MSCs (Ali et al., 2012).

4.2. NO concentration dependent regulation

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It was shown that the capacity of NO interaction with stem cells hinges on the intracellular concentration of NO (Fuseler and Valarmathi, 2012). For instance, glioma stem

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cells (GSCs) sustain their self-expansion through elevated intracellular iNOS expression (Eyler et al., 2011, Kim et al., 2013), suggesting that NOS inhibition can be used as a new regimen against glioma.

The external NO has varying effects on stem cells depending on their types, doses and sources. Embryonic stem cells (ESCs) were protected from apoptosis in the presence of NO at the low levels (2-20 μM), however, their progress to the next level was also delayed as a consequence of NO exposure (Tejedo et al., 2010). The high concentration of NO generally suppresses stem cells metabolism, however, promotes the differentiation of ESCs (Mora-Castilla et al., 2010). The down-regulation of gene Nanog and Oct4 were observed from ESCs treated with NO-donors (1.0 mM) in the mouse model.

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ACCEPTED MANUSCRIPT The recent study confirmed that over-expression of myocardial iNOS following coronary ligation is the potential cause of cell loss associated with post-transplantation (Li et al., 2014b).

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HSCs isolated from human blood cells treated with high level NO-donor yielded induced self-

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renewal and altered replication potential of cells via enhancement of telomerase activity (Deezagi, 2012). The apoptosis of cells was induced by the excessive NO produced during the

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transplantation process and thus, the selective inhibition of iNOS in the initial stage of MSCs

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myocardial transplantation seems to be a viable option to regulate the apoptosis process.

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4.3. The combinatory effects of cofactors and exogenous compounds It was postulated that NO modulates stem cells efficacy not only individually but also on

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a collaborative basis with other neural mediators or other exogenous compounds (Napoli et al., 2013). Programmed cell death of mesenchymal progenitor cells (MPCs) was stimulated by the

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high concentrations of NO-donors and expedited by acrylamide through a different pathway from that mediated by NO (Szewczyk et al., 2012). MPCs exposed to the high doses of NOdonors and acrylamides were disrupted and intoxicated, and subsequently prone to the loss of their osteogenic property.

NO-donors along with NSAID, such as ibuprofen, indomethacin (IDO) and NCX320, were tested on human trials for the mitigation effects on muscular dystrophy (Sciorati et al., 2011). NSAID lowered local inflammation, while NO-donors substituted the delocalized nNOS occurred in dystrophies. There was a report on a concerted action of NO with atorvastatin (LIPITOR), a cholesterol lowering statin drug, during the MSCs transplantation for myocardial infarction post protection (Song et al., 2013). This enhanced efficacy of MSCs was due to the activation of NOS subtypes by atorvastatin, allowing for a longer retention period of MSCs on

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ACCEPTED MANUSCRIPT cardiac tissues. The key effectors in immune suppression by MSCs also include indomethacin (IDO) that stimulated adipogenesis of MSC (Sato et al., 2007, Su et al., 2014).

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It was found that nicotine is the major neuro-teratogen chemical to brain dysfunction

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(Roy et al., 1998), and negatively affects neural stem cells by directly up-regulating the production of NO in the neurospheres (Lee et al., 2014). HSCs from mouse exposed to nicotine

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showed the elevated level of histone deacetylatase 1 (HDAC1), which is proportional to the

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doses of nicotine. Subsequently, it was speculated that targeting the concerted action of NO and HDAC1 may serve as a potential therapeutic strategy against neurodegenerative disorders caused

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by cigarette smoking.

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4.4. The combinatory effects with the external stimuli Rats with vigorous physical activity displayed a consistently high differentiation rate

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regardless of the NO concentrations (Ocarino et al., 2008). It was suggested that the activation of vascular stem cells and enhanced vessel density under the persistent shear stress could be resulted from NO mediated VEGF production (Bassaneze et al., 2010). There are also reports on shear stress triggered VEGF-R2 and P13K/Akt/mTOR activation in EPCs (Obi et al., 2012), which is indicative of the involvement of external stimuli in vasculogenesis. It was demonstrated that physical activity rather than NO production has a greater impact on the osteogenic differentiation of MSCs. MSCs are known to exert paracrine effects on surrounding microenvironment, which is associated with the ability to produce vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) (Bluguermann et al., 2013, Boomsma and Geenen, 2012), both of which significantly decreased as MSCs were treated with the NO donor, FK409 (Wang et al., 2008). The cells in the presence of NO repressed

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ACCEPTED MANUSCRIPT themselves from exerting its function in a paracrine manner, while spending more resources in

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committing to new lineage under the external stimuli.

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4.5. Nitrosylation signaling mediated regulation

The post-translational modification, S-nitrosylation, is known as the selective

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modification process of cysteine residues in protein to form S-nitrosocysteine (Sunico et al.,

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2013). The molecular pathway by which NO accomplishes functional diversity has a direct impact on protein function, location and stability, as well as viability and differentiation of stem

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cells (Gould et al., 2013).

MSCs and EPCs adopt different paths to vasculogenesis according to their responses to

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nitrosylation signaling. NO exerts nitrosative stress on mesencephalic cells, inducing s-

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nitrosylation of transcriptional factors and neuronal death notably in Parkinson’s disease. S-

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nitrosylation of target proteins, whether in HDAC2 or other cysteine residues of the protein, elicits biological functions including chromatin alteration. S-nitrosylation of parkin, a neuroprotective protein, up-regulated p53 gene expression (Sunico et al., 2013), which is known to be mediated by not only endogenous NO, but also a few regulating enzymes, such as a GSNO reductase (GSNOR).

In cardiovascular systems, the nitrosylation of crucial anti-inflammatory proteins, such as dynamin, N-ethylmaleimide sensitive factors and caspases, down-grades the inflammatory process (Calvert et al., 2007). Vasculogenesis is closely regulated by the S-nitrosylation process mediated by GSNOR. Maturation of EPCs and postnatal angiogenesis are functional consequences of S-nitrosylation, however, in a negative way. The animal study with the ligation of artery (i.e., knock-out of GSNOR in mice) showed an enhanced infarct size (Lima et al., 2009)

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ACCEPTED MANUSCRIPT and a consistent elevated number of HSCs (Gomes et al., 2013), indicating that S-nitrosylation has a crucial role in defining the stem cells response to vascular injury.

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In addition to vascular generation, S-nitrosylation of beta-Catenin was found to promote

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vascular permeability to macromolecules via stimulation of platelet-activating factor (PAF). It was demonstrated that the proteins in adherens junctions were S-nitrasylated during the eNOS

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translocation process (Marin et al., 2012), suggesting that NO signaling in endothelial cells has a

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direct impact on not only guanyl cyclases (GCs) related muscle relaxation but also vascular

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permeability.

5. Novel platforms for NO delivery to stem cells

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Due to a short half-life and diffusive nature of NO, currently available strategies used to deliver NO into stem cells have an inherently limited capacity to accurately control the quantity

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and extent (Diring et al., 2013). As potency and interaction of NO with stem cells generally depend on the concentrations of NO and the presence of the cofactors at the active site, the suitable carriers for NO delivery seems to be critical for exerting maximal efficacy of stem cells.

5.1. Internal NO production

5.1.1. eNOS gene based production The functions of three subtypes of NOS isoforms ultimately differ on their capacity and rates of arginine conversion. iNOS is a subtype of NOS enzyme whose function lies in the defense against xenobiotics. The over-expression of iNOS in stem cells under certain conditions was counterproductive due to the relatively massive production of NO (Li et al., 2014b). Subsequently, stimulated NO expression through insertion of iNOS or eNOS gene into various

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ACCEPTED MANUSCRIPT types of stem cells seems to be a viable option to produce in situ NO (Kanki-Horimoto et al., 2006).

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Muscle stem cells responsible for skeletal muscle regeneration heavily rely on

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macrophage population involved with the expression of iNOS subtypes. In muscle injury, the infiltration of macrophages is mediated through iNOS rather than more prevalent nNOS. The

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involvement of iNOS in muscle regeneration seems to be not directly correlated with myogenic

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precursor cells, even though some studies using iNOS knockout mice did not provide sufficient evidences (Rigamonti et al., 2013).

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Adipose-derived stem cells (ADSCs) in the absence of eNOS transfection distinctively lack NO production, subsequently producing a minimal EC-like phenotype (Fischer et al., 2009).

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Such inadequate supply contributes to hyperplasia, when the ADSCs were engineered as endothelial cell substitutes against coronary artery disease. The enhancement of the NO level in

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differentiated ADSCs greatly alleviate this symptom through their protective effects on the vascular grafts (McIlhenny et al., 2013). 5.1.2. Induction of eNOS expression Aside from the direct transfection with NOS genes, stem cells possess the capability to produce viable NO under micro or nano-structured stimulations (Martinez et al., 2009). ADSCs adsorbed on cobalt chrome (CoCr) surface produced an endothelial-like surface and up-regulated their eNOS gene levels (Shi et al., 2013). In another study, progenitor cells free of surface proteins differentiated to possess CD141 surface proteins as well as eNOS, successfully accomplishing self-regulated production of NO in tissue engineered heart valves (Schmidt et al., 2007).

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ACCEPTED MANUSCRIPT There is an evidence of NOS residing in hematopoietic stem cells (Aleksinskaya et al., 2013), subsequently achieving the peak level of NO production during stem cell commitment

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(Tiribuzi et al., 2013). The NO production in these cells was depleted by an universal NOS

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inhibitor, NG-monomethyl-l-arginine monoacetate (L-NMMA), and the differentiation process of HSCs was significantly delayed until the efficacy of the inhibitor expired. However, the

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cellular markers for stemness of HSCs (i.e., Capthesins S and D) remained in their precursor

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forms, which is indicative of the lack of commitment signaling to proceed. It was also demonstrated that argininosuccinate synthase (AS) expression in neural stem

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cells as well as the differentiation of NSCs into astrocytes are closely correlated with the production of NO (Lameu et al., 2012). An addition of brain-derived neurotrophic factor (BDNF)

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reversed the delayed differentiation of stem cells in the absence of eNOS, indicating that the

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neural differentiation process is partially maintained by BDNF.

5.2. External NO supply

5.2.1. Exogenous NO-releasing compounds Due to the unique function of NO donors on various types of stem cells, pre-conditioning with NO donors as shown in Figure 3 has been frequently adapted to stem cell therapy (Campelo et al., 2012). The survival rate of MSCs applied for the protection of renal ischemic injury after kidney damage was significantly enhanced upon being pre-conditioned with the moderate level (100 μM) of the NO-donor (Masoud et al., 2012). The pre-clinical test demonstrated that external NO-donors are a potential initiator of stem cell therapeutics on ischemic diseases. An external application of NO-releasing drugs has been widely used for cardiovascular protection for decades, but only until recently researchers started to employ conjugating NO-

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ACCEPTED MANUSCRIPT donors on the surface of polymer coated implants to control stem cell attachment (Xing et al., 2013). The local release of NO suppressed the grafting of stem cells seeded on the gelatin coated

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formation of MSCs through site-specific regulation of T-cells.

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implants, indicating that the high concentration of NO (200 µM) prohibits the cytoskeleton

One of nonsteroidal anti-inflammatory drugs (NSAID), HCT 1026, a derivative of

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flurbiprofen, contains an NO-releasing moiety, producing NO in situ in the presence of

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hemolytics (Maffia et al., 2002). When they were combined with stem cell treatment, NO releasing NSAID enhanced the satellite cell number and activity via inhibiting inflammation and

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securing the mesoangioblasts (Brunelli et al., 2007). 5.2.2. Novel NO carriers

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5.2.2.1. Scaffold formulations

The NO-releasing platforms intended for cell therapy consist of several prototypes as

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shown in Table 2. The novel platform aimed for on-demand liberation of NO in response to light irradiation was developed by incorporating Photo-reactive nitro-containing imidazole into crystalline coordinated frameworks (Diring et al., 2013). Microcrystals of porous coordination polymers (PCPs) embedded in tissue adhesive matrix formed a three-dimensional (3D) scaffold that allows for the precise control over the local delivery of NO-donor conjugates at the cellular level An adequate delivery of NO is the key to maintain the sustained survival rate of local stem cells. Pin to hole spark discharge (PHD) plasma was used to produce the relatively high NO concentration for the topical delivery through the skin (Dobrynin et al., 2011). This approach achieved the biocompatibility of plasma generated NO equivalent to natural NO, exerting the

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The ability to deliver NO to cells under the spatial and temporal control in vitro has long

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been pursued for enhancement of biological action of NO in stem cells. Light emitting diode (LED) triggered release of NO pro-drugs from polydimethylsiloxane has been used for uniform

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delivery of NO to various types of stem cells including MSCs, SMCs and HEK293 cells

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(Romanowicz et al., 2013). The LED device regulated by fixed light source provided an unhindered supply of external NO and seems to have a huge potential to be adapted for

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numerous biomedical applications. 5.2.2.2. Nanoparticles

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Stem cell-based delivery of drug-loaded nanoparticles offers a viable option to overcome such issues related with nano-carriers as inefficient distribution and failure to target disseminated

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sites including brain and tumor (Stuckey and Shah, 2014). The ability of stem cells to incorporate nanoparticles and migrate through interstitial barriers along with their inherent tumor-tropic properties and synergistic anti-tumor effects make stem cells a suitable carrier for such combined therapy (Aleynik et al., 2014). The delivery of NO in a combination with chemotherapeutic drugs at their low concentrations has been a great facilitator of tumor apoptosis (Kim et al., 2014a). Glioma stem cells induced in tumor sites promoted the level of iNOS, whose process was suppressed by the high concentrations of NO (Eyler et al., 2011). Nanoparticles made of self-assembled di-block polymers and incorporated with GSNO (i.e., NO prodrug) were developed to improve NO stability in aqueous media, and achieved the sustained release of NO in neuroblastoma cells and enhanced anti-tumor activity of brain-specific chemotherapeutics (Duong et al., 2013).

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eNOS (Nishikawa et al., 2009). This study supports that the switching of enzyme activity of

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eNOS and subsequent induction of NO release is achievable by targeting caveolae with nanoparticles. Caveolae are flask-shaped functional compartments in plasma membrane of cells

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and transport cargo to the basal side of the monolayer. They can be further tailored for

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personalized medicine because they can serve as the targeted cells in pathological tissue (Wang and Malik, 2013).

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When considering the limitations of current nano-carrier systems, further research seems to be needed on interactions between stem cells, the inflammatory milieu in which they reside,

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and the therapeutic compounds including NO they can carry. Mesenchymal stem cells (MSCs) have been successfully studied and discussed as a vehicle for cancer gene therapy (Gao et al.,

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2013). MSCs suppressed the excessive immune responses of B cells, T cells, macrophages, natural killer cells and dendritic cells via combined activities of numerous immunosuppressive mediators (Han et al., 2012), and most mediators are inducible by inflammatory stimuli including nitric oxide (NO) (Ren et al., 2008). The use of MSCs as drug-loaded nano-carrier systems has demonstrated the potent efficacy for cancer treatment and will also have a major impact on the bioengineering and tissue regeneration fields. 5.2.2.3. Nanofiber/Hydrogel Nanostructured materials produced by electrospinning technology have been used to generate nanofibrous scaffolds made of synthetic polymers or native matrix molecules. A tubular scaffold (2 mm in diameter) with a microstructure of nonwoven fibers produced by electrospinning of poly (propylene carbonate) (PPC) was used for the growth of bone marrow

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amount of NO produced by grafts seeded with eNOS-modified MSCs was comparable to that

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produced by native blood vessels, and significantly higher than that in the grafts seeded with non-modified MSCs, improving vessel regeneration and cardiovascular functions.

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The nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP), was conjugated to the

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gelatin hydrogel, which showed a rapid nitric oxide release in the first 2 hr and then a slower but sustained release in the next 70 hr (Xing et al., 2013). As compared with the control, the nitric

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oxide–releasing gelatin hydrogel demonstrated significantly lower human mesenchymal stem cells (hMSCs) attachment and proliferation rate after 72 hr incubation, providing a promising

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therapeutic approach in enhancing the cell attachment and proliferation of biomedical implants. The nanofiber-hydrogel blend containing NO donors (i.e. GSNO) and reactive oxygen

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species (ROS) scavengers (Edaravone: EDV) was explored as an advanced strategy for stabilization of Mast cells (MCs) to achieve efficient immune-suppressive effects (Oh and Lee, 2014). A mixture of GSNO and EDV significantly lowered the degranulation rate of activated Mast cells (a-MCs), indicating that NO plays an integral role in degranulation of a-MCs and nanofibers containing a mixture of nitric oxide donors and ROS scavengers could be used as a promising platform to stabilize MCs from the ROS-mediated immune responses.

6. Future prospects in NO-involved stem cell therapy 6.1. Recent progress in drug screening via stem cell models Stem cell models offer new advanced opening for pharmaceutical companies to identify and discover new drugs (Guo et al., 2013). While stem cell-derived hepatocytes still express

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ACCEPTED MANUSCRIPT immature markers, such as growth factors and nitric oxide synthase (NOS), cardiac differentiation from stem cells has made the most progress. Even though the ability to

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differentiate embryonic stem cells (ESCs) into functional and differentiated cells has relatively

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well established (Jensen et al., 2009), there still needs new proficiencies surrounding stem cell differentiation and proliferation, and proper efficacy assays to make successful use of stem cells

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in drug design.

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The discovery of induced pluripotent stem cell (iPSC) technology and iPSC-derived disease models have tremendously changed the paradigm of preclinical studies (Wu and

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Hochedlinger, 2011). For example, Genentech is now routinely using ESCs and iPSC-derived cardiomyocytes (Hou et al., 2013) as high-throughput models to assess cardiotoxicity for drugs

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in development as well as to investigate specific mechanistic cardiotoxicity findings during in vivo studies or in the clinic. It was also found that liver toxicity can be cured by disrupting the

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nitrosylation pathway so that nitric oxide could change proteins in the liver (Cox et al., 2014). They tested a nitrosylation enhancer currently investigated in clinical trials for other therapeutic purposes in stem cell-derived models of pathological conditions, such as Tylenol overdose, where it proved effective.

By gaining continuous expertise in the field, future applications could gradually shift from early stage drug discovery to the clinical space where iPSC technology based modeling approaches will be explored to study patient-specific drug effects and responses.

6.2. Future prospects for clinical application of stem cell therapy The rapid and steady progress of stem cell research in leading life-threatening and disability diseases, such as cardiovascular diseases, neurodegenerative disorders and liver

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ACCEPTED MANUSCRIPT diseases, is driving stem cell based therapy towards success in clinical application, in which the safety and scaling issues are still a major hurdle (Trainor et al., 2014). Although a stem cell

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therapy is an effective treatment for various diseases, it can cause several side effects referred to

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as "after effects", such as infection and graft-versus-host disease (Dobkin et al., 2006; Amariglio et al., 2009). The type and intensity of these side effects depend on the types of treatment and the

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person's overall health, and other personal and environmental factors. The health care providers

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should work with patients to prevent side effects through palliative and supportive care which would be an integral part of overall stem cell therapy (Lawrence, 2015). The pathological

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improvement should be carefully evaluated to ensure the efficacy of stem cell therapy, which requires a prolonged survival of engrafted cells and partly regulated by NO.

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When technical issues on cell survival and involved mechanisms are clearly addressed in detail, we can eventually benefit from what we have experienced for the success of NO-involved

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stem cell therapy in the future. For instance, advanced technologies have enhanced the current visual data so that it’s easier to better track and study the movement and multiplication of cells, and to identify the relationships between cells and their regulators including NO – the main obstacle to investigating the abnormal cell proliferation that causes cancer, and also to using stem cells in regenerative medicine (Jose et al., 2014, Rahmat et al., 2013). For this purpose, software was developed to analyze time-lapse images capturing live stem cell behaviors (Wait et al., 2014). This technology will allow scientists to search for mechanisms that control stem cell specialization and could lead to new research into causes of various diseases. Advanced technologies including electric chemical sensors also help scientists real-time monitor and quantitatively trace the production and movement of NO in stem cells much more accurately and simpler in recent years. Multiple microelectrode array (MMA) was previously

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ACCEPTED MANUSCRIPT utilized to study the impact of external factors, such as angiogenin, on stem cells or progenitor cells, and their interaction

with NO (Trouillon et al., 2011). Because cellular NO upon

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interacting with fluorescent probes formed diazo rings only when NO oxidation occurred

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(Ghebremariam et al., 2014), the distribution of NO in organelles of stem cell-derived ECs and induced pluripotent stem cells in response to pharmacological agents are readily quantified.

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Numerous advanced materials are introduced to meet current challenges in

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bioengineering. The hemin-functionalized graphene field-effect transistor has been emerged as an NO sensor to detect its sub-nanomolar level (Jiang et al., 2013). The semi-conductor based

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single layer sensor greatly enhances the sensitivity and selectivity to NO molecule signals, allowing precise monitoring under varying physiological conditions. In a sensing probe,

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graphene-hemin convents π–π interaction to electrical currents that allows for real-time monitoring and chronical recording the concentration of NO, providing a new era to

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synchronously associate stem cells metabolites reaction to NOS activity. These unparalleled technical advances in analyzing NO surrounding stem cells and time-lapse images of live stem cell behaviors render their easy and broad application and alleviate regulatory standardization challenges in the process towards successful stem cell therapies.

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ACCEPTED MANUSCRIPT Legend Figure 1. NO involvement in the regulation of stem cells. Figure 2. Secretion of neurotropic factors and therapeutic mechanisms.

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Figure 3. Novel NO delivery platforms for stem cells. Table 1. NO involved stem cell applications.

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Table 2. Novel NO delivery strategies

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Figure 1.

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Figure 2.

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Figure 3

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Neuronal stem

Nervous

cells (NSCs)

system

(EPCs) Bone marrowderived stem cells (BMSCs) Hematopoietic stem cells (HSCs) Muscle stem cells (MuSCs)

circulation

Endothelium regeneration Vascular permeability

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progenitor cells

Blood

Bone marrows

Tissue repair Multi-potent differentiation

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Endothelial

Neuron regeneration Neural mediator production

Red bone marrows, mesoderm

Human skeletal Muscle tissue

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adipose tissue

Mesoderm

differentiation

Skeletal muscle regeneration

NO Involvement

References

Suture wound (Laverdet et al., healing 2014, Lu et al., Inflammatory Calvarial defect 2014, repair processes modulation Reckhenrich et Articular cartilage al., 2014) repair Neural degenerative (Janeczek et al., Immune cell diseases 2013, Luo et al., suppression Stroke 2010, Sauer et Neurogenesis Neuron damage al., 2011, Wang regulation by nNOS repair et al., 2009) Homeostasis S-nitrosylation on maintenance maturation (Gomes et al., Neural vessel repair VEGF-R2 2013, Obi et al., Marrow P13K/Akt/mTOR 2012) mobilization activation Vehicle for gene NO assisted homing (Ali et al., 2012, therapy SNP preTong et al., Multi-potent tissue conditioning 2013) repair eNOS gene insertion Multiple myeloma NO autocrine (Dai et al., Replacement NO production 2006, Tiribuzi Chemotherapy nNOS regulation et al., 2013) Ischemic injury Macrophage Muscular dystrophy (Rigamonti et infiltration Cardiac muscle al., 2013) damage repair iNOS induction

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Human

Connective tissue repair Autocrine Paracrine

Applications

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Adipose-derived mesenchymal stem cells (ADSCs)

Therapeutic

Function

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Cells

Origin

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Type of Stem

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Table 1

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NO-donor preconditioning

NO emitting scaffolds NO releasing nanoparticles

Simple diffusion i.v. infusion PCP light irradiation PHD plasma Calveoli formation Local engulfment LED triggered release Multiple microelectrode array

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Graft host response to local implant Bone remodeling Renal ischemic injury Kidney damage Cytotoxicity

References

(Deezagi, 2012, Xing et al., 2013) (Berardi et al., 2011, Gorbe et al., 2014, Masoud et al., 2012)

Infection Wound healing

(Diring et al., 2013, Dobrynin et al., 2011)

eNOS deficiency Glioma development

(Duong et al., 2013, Nishikawa et al., 2009) (Romanowicz et al., 2013, Trouillon et al., 2011)

Tissue repair Multi-potent differentiation

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NO discharging devices

Medical device grafting

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(SNP)

Therapeutic Applications

Strategies

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NO-donors carriers

Delivery

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NO Source

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Table 2

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