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Residential environments are known to contribute to asthma.To examine the joint impacts of exposures to residential indoor and outdoor air pollutants and housing risk factors on adult asthma-related health outcomes.We analyzed1-year of data from 53 participants from 41 homes in the pre-intervention period of the Breathe Easy Project prior to ventilation and filtration retrofits. Health outcomes included surveys of asthma control, health-related quality of life, stress, and healthcare utilizations. Environmental assessments included quarterly measurements of indoor and outdoor pollutants (e.g., HCHO, CO, COCross-sectional analyses using mixed-effects models indicated that lower annual average asthma control test (ACT) scores were associated (p 0.05) with higher indoor NOFindings suggest that residential risk factors, including indoor air pollution (especially NOThis study highlights the importance of residential indoor air quality and environmental risk factors for asthma control, health-related quality of life, and emergency department visits for asthma. Two timescales of mixed models suggest that exposure to indoor NO

Background Niemann-Pick disease, type C (NPC) is a childhood-onset, lethal, neurodegenerative disorder caused by autosomal recessive mutations in the genes NPC1 or NPC2 and characterized by impaired cholesterol homeostasis, a lipid essential for cellular function. Cellular cholesterol levels are tightly regulated, and mutations in either NPC1 or NPC2 lead to deficient transport and accumulation of unesterified cholesterol in the late endosome/lysosome compartment, and progressive neurodegeneration in affected individuals. Previous cell-based studies to understand the NPC cellular pathophysiology and screen for therapeutic agents have mainly used patient fibroblasts. However, these do not allow modeling the neurodegenerative aspect of NPC disease, highlighting the need for an in vitro system that permits understanding the cellular mechanisms underlying neuronal loss and identifying appropriate therapies. This study reports the development of a novel human iPSC-derived, inducible neuronal model of Niemann-Pick disease, type C1 (NPC1). Results We generated a null i3Neuron (inducible × integrated × isogenic) (NPC1−/− i3Neuron) iPSC-derived neuron model of NPC1. The NPC1−/− and the corresponding isogenic NPC1+/+ i3Neuron cell lines were used to efficiently generate homogenous, synchronized neurons that can be used in high-throughput screens. NPC1−/− i3Neurons recapitulate cardinal cellular NPC1 pathological features including perinuclear endolysosomal storage of unesterified cholesterol, accumulation of GM2 and GM3 gangliosides, mitochondrial dysfunction, and impaired axonal lysosomal transport. Cholesterol storage, mitochondrial dysfunction, and axonal trafficking defects can be ameliorated by treatment with 2-hydroxypropyl-β-cyclodextrin, a drug that has shown efficacy in NPC1 preclinical models and in a phase 1/2a trial. Conclusion Our data demonstrate the utility of this new cell line in high-throughput drug/chemical screens to identify potential therapeutic agents. The NPC1−/− i3Neuron line will also be a valuable tool for the NPC1 research community to explore the pathological mechanisms contributing to neuronal degeneration. Graphical abstract

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that present immunosuppressive effects in experimental and clinical trials targeting various rare diseases including inflammatory bowel disease (IBD). In addition, recent studies have reported tryptophanyl-tRNA synthetase (WRS) possesses uncanonical roles such as angiostatic and anti-inflammatory effects. However, little is known about the function of WRS in MSC-based therapy. In this study, we investigated if a novel factor, WRS, secreted from MSCs has a role in amelioration of IBD symptoms and determined a specific mechanism underlying MSC therapy. Experimental colitis was induced by administration of 3% DSS solution to 8-week-old mice and human umbilical cord blood-derived MSCs (hUCB-MSCs) were injected intraperitoneally. Secretion of WRS from hUCB-MSCs and direct effect of WRS on isolated CD4＋ T cells was determined via in vitro experiments and hUCB-MSCs showed significant therapeutic rescue against experimental colitis. Importantly, WRS level in serum of colitis induced mice decreased and recovered by administration of MSCs. Through in vitro examination, WRS expression of hUCB-MSCs increased when cells were treated with interferon-γ (IFN-γ). WRS was evaluated and revealed to have a role in inhibiting activated T cells by inducing apoptosis. In summary, IFN-γ- mediated secretion of WRS from MSCs has a role in suppressive effect on excessive inflammation and disease progression of IBD and brings new highlights in the immunomodulatory potency of hUCB-MSCs. [BMB Reports 2019; 52(5): 318-323]

Social requirements are needed for living in an aging society and individual longevity. Among them, improved health and medical cares, appropriate for an aging society are strongly demanded. Human cord blood-derived plasma (hUCP) has recently emerged for its unique anti-aging effects. In this study, we investigated brain rejuvenation, particularly olfactory function, that could be achieved by a systemic administration of young blood and its underlying mechanisms. Older than 24-month-old mice were used as an aged group and administered with intravenous injection of hUCP repetitively, eight times. Anti-aging effect of hUCP on olfactory function was evaluated by buried food finding test. To investigate the mode of action of hUCP, brain, serum and spleen of mice were collected for further ex vivo analyses. Systemic injection of hUCP improved aging-associated olfactory deficits, reducing time for finding food. In the brain, although an infiltration of activated microglia and its expression of cathepsin S remarkably decreased, significant changes of proinflammatory factors were not detected. Conversely, peripheral immune balance distinctly switched from predominance of Type 1 helper T (Th1) cells to alternative regulatory T cells (Tregs). These findings indicate that systemic administration of hUCP attenuates age-related neuroinflammation and subsequent olfactory dysfunction by modulating peripheral immune balance toward Treg cells, suggesting another therapeutic function and mechanism of hUCP administration. [BMB Reports 2019; 52(4): 259-264].

Although human mesenchymal stem cells (hMSCs) hold considerable promise as an alternative therapeutic reagent for allergic disorders including atopic dermatitis (AD), the strategy for enhancing hMSC-based therapy remains challenging. We sought to investigate whether preconditioning with mast cell (MC) granules could enhance the therapeutic efficiency of human umbilical cord blood-derived MSCs (hUCB-MSCs) against AD. Methods: AD was experimentally induced in NC/Nga mice by repeated applications of 4% sodium dodecyl sulfate (SDS) and dermatophagoides farinae (Df) extract, and preconditioned hUCB-MSCs were subcutaneously injected. The therapeutic effect was determined by gross examination and additional ex vivo experiments performed using blood and skin samples to determine the resolution of allergic inflammation. To explore the underlying mechanisms, several co-culture assays with primary isolated immune cells and wound closure assays were conducted. Results: Pretreatment of MC granules enhanced the therapeutic effects of hUCB-MSCs by attenuating the symptoms of AD in an experimental animal model. MC granule-primed cells suppressed the activation of major disease-inducing cells, MCs and B lymphocytes more efficiently than naïve cells both in vitro and in vivo. Histamine-mediated upregulation of the COX-2 signaling pathway was shown to play a crucial role in suppression of the allergic immune response by MC-pretreated hUCB-MSCs. Moreover, MC pretreatment improved the wound healing ability of hUCB-MSCs. Conclusions: Our findings indicate that pre-exposure to MC granules improved the therapeutic effect of hUCB-MSCs on experimental AD by resolving the allergic immune reaction and accelerating the tissue regeneration process more efficiently than naïve cells, suggesting a potential enhancement strategy for stem cell-based therapy.

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann–Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients., Inherited metabolic disease: Restoring motor function by reducing cholesterol An acid secreted by stem cells can reduce the excess cholesterol caused by a genetic metabolic disorder. Niemann–Pick type C disease is a rare, inherited condition that causes defective muscular development and progressive neurological degeneration. A key disease mechanism is the excessive accumulation of cholesterol within cells. Kyung-Sun Kang at Seoul National University, South Korea, and co-workers have demonstrated that a metabolite molecule called 14,15-epoxyeicosatrienoic acid (14,15-EET) derived from stem cells from human umbilical cord blood significantly reduced cholesterol in Neimann-Pick Type C mouse models and human cell samples. The team administered the stem cell therapy non-invasively via the nose, and observed significant improvements in motor function in the mice. Experiments in both animals and cells showed that the treatment resulted in reduced cholesterol levels and the correction of defective signalling within cells.

Identification of the immunomodulatory and regenerative properties of mesenchymal stem cells (MSCs) have made them an attractive alternative therapeutic option for diseases with no effective treatment options. Numerous clinical trials have followed; however, issues such as infusional toxicity and cellular rejection have been reported. To address these problems associated with cell-based therapy, MSC exosome therapy was developed and has shown promising clinical outcomes. MSC exosomes are nanosized vesicles secreted from MSCs and represent a non-cellular therapeutic agent. MSC exosomes retain therapeutic features of the cells from which they originated including genetic material, lipids, and proteins. Similar to MSCs, exosomes can induce cell differentiation, immunoregulation, angiogenesis, and tumor suppression. MSC exosomes have therefore been employed in several experimental models and clinical studies. Here, we review the therapeutic potential of MSC-derived exosomes and summarize currently ongoing clinical trials according to disease type. In addition, we propose several functional enhancement strategies for the effective clinical application of MSC exosome therapy.

While the neuropathological characteristics of Niemann-Pick disease type C (NPC) result in a fatal diagnosis, the development of clinically available therapeutic agent remains a challenge. Here we propose graphene quantum dots (GQDs) as a potential candidate for the impaired functions in NPC in vivo. In addition to the previous findings that GQDs exhibit negligible long-term toxicity and are capable of penetrating the blood-brain barrier, GQD treatment reduces the aggregation of cholesterol in the lysosome through expressed physical interactions. GQDs also promote autophagy and restore defective autophagic flux, which, in turn, decreases the atypical accumulation of autophagic vacuoles. More importantly, the injection of GQDs inhibits the loss of Purkinje cells in the cerebellum while also demonstrating reduced activation of microglia. The ability of GQDs to alleviate impaired functions in NPC proves the promise and potential of the use of GQDs toward resolving NPC and other related disorders.

Background Niemann-Pick disease type C (NPC) is caused by the mutation of NPC genes, which leads to the abnormal accumulation of unesterified cholesterol and glycolipids in lysosomes. This autosomal recessive disease is characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. Recently, the application of induced neural stem cells (iNSCs), converted from fibroblasts using specific transcription factors, to repair degenerated lesions has been considered a novel therapy. Objectives The therapeutic effects on NPC by human iNSCs generated by our research group have not yet been studied in vivo; in this study, we investigate those effects. Methods We used an NPC mouse model to efficiently evaluate the therapeutic effect of iNSCs, because neurodegeneration progress is rapid in NPC. In addition, application of human iNSCs from NPC patient-derived fibroblasts in an NPC model in vivo can give insight into the clinical usefulness of iNSC treatment. The iNSCs, generated from NPC patient-derived fibroblasts using the SOX2 and HMGA2 reprogramming factors, were transplanted by intracerebral injection into NPC mice. Results Transplantation of iNSCs showed positive results in survival and body weight change in vivo. Additionally, iNSC-treated mice showed improved learning and memory in behavior test results. Furthermore, through magnetic resonance imaging and histopathological assessments, we observed delayed neurodegeneration in NPC mouse brains. Conclusions iNSCs converted from patient-derived fibroblasts can become another choice of treatment for neurodegenerative diseases such as NPC.

In this paper, we introduce a new map merging method based on least squares method (LSM) in cluster-based multidimensional scaling (MDS) localization systems. Most map merging algorithms used in cluster-based MDS localization systems cannot avoid the accumulation of errors in the map merging process in common. Unfortunately, these errors accumulated in the map merging process lead to a decrease in the performance of position estimation of the whole nodes in a network. Through the proposed merging algorithm based on LSM, the errors accumulated in the map merging process can be avoided. The proposed algorithm can be applied not only to the MDS-based localization system but also to other coordinate-based localization systems. The proposed map merging algorithm shows better performance of position estimation accuracy than the simple merging method used in many cluster-based MDS localization systems in all simulations which are not considering map weight factors. As an example of the highest improvement, a simulation result shows 29% improvement in position estimation accuracy after using each corresponding merging method.

Graphene quantum dots attenuate intestinal inflammation by modulating immune homeostasis., While graphene and its derivatives have been suggested as a potential nanomedicine in several biomimetic models, their specific roles in immunological disorders still remain elusive. Graphene quantum dots (GQDs) may be suitable for treating intestinal bowel diseases (IBDs) because of their low toxicity in vivo and ease of clearance. Here, GQDs are intraperitoneally injected to dextran sulfate sodium (DSS)–induced chronic and acute colitis model, and its efficacy has been confirmed. In particular, GQDs effectively prevent tissue degeneration and ameliorate intestinal inflammation by inhibiting TH1/TH17 polarization. Moreover, GQDs switch the polarization of macrophages from classically activated M1 to M2 and enhance intestinal infiltration of regulatory T cells (Tregs). Therefore, GQDs effectively attenuate excessive inflammation by regulating immune cells, indicating that they can be used as promising alternative therapeutic agents for the treatment of autoimmune disorders, including IBDs.

Defects in the nuclear lamina occur during physiological aging and as a result of premature aging disorders. Aging is also accompanied by an increase in transcription of genes encoding cytokines and chemokines, a phenomenon known as the senescence-associated secretory phenotype (SASP). Progerin and prelamin A trigger premature senescence and loss of function of human mesenchymal stem cells (hMSCs), but little is known about how defects in nuclear lamin A regulate SASP. Here, we show that both progerin overexpression and ZMPSTE24 depletion induce paracrine senescence, especially through the expression of monocyte chemoattractant protein-1 (MCP-1), in hMSCs. Importantly, we identified that GATA4 is a mediator regulating MCP-1 expression in response to prelamin A or progerin in hMSCs. Co-immunoprecipitation revealed that GATA4 expression is maintained due to impaired p62-mediated degradation in progerin-expressing hMSCs. Furthermore, depletion of GATA4 abrogated SASP-dependent senescence through suppression of NF-ĸB and MCP-1 in hMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin A proteins trigger paracrine senescence through a GATA4-dependent pathway in hMSCs. This molecular link between defective lamin A and GATA4 can provide insights into physiological aging and pathological aging disorders., Aging: Clues in nuclear proteins Abnormal versions of proteins that support the structure and function of the membrane of the cell nucleus are implicated in premature aging disorders, and also in normal aging. Researchers in South Korea led by Kyung-Sun Kang at Seoul National University investigated the protein network known as the nuclear lamina. They studied a specific type of human stem cell that gives rise to bone, cartilage, muscle and fat. They found that altering the levels of proteins produced by specific key genes promotes cell aging, and the alterations led to abnormalities in the proteins of the nuclear lamina. The researchers suggest that their work provides new insights into the molecular and cellular causes of premature and normal aging. Understanding the molecular triggers of aging could lead to treatments to delay both its normal and disease-linked forms.

Recent advances have shown the direct reprogramming of mouse and human fibroblasts into induced neural stem cells (iNSCs) without passing through an intermediate pluripotent state. Thus, direct reprogramming strategy possibly provides a safe and homogeneous cellular platform. However, the applications of iNSCs for regenerative medicine are limited by the restricted availability of cell sources. Human umbilical cord blood (hUCB) cells hold great potential in that immunotyped hUCB units can be immediately obtained from public banks. Moreover, hUCB samples do not require invasive procedures during collection or an extensive culture period prior to reprogramming. We recently reported that somatic cells can be directly converted into iNSCs with high efficiency and a short turnaround time. Here, we describe the detailed method for the generation of iNSCs derived from hUCB (hUCB iNSCs) using the lineage-specific transcription factors SOX2 and HMGA2. The protocol for deriving iNSC-like colonies takes 1~2 weeks and establishment of homogenous hUCB iNSCs takes additional 2 weeks. Established hUCB iNSCs are clonally expandable and multipotent producing neurons and glia. Our study provides an accessible method for generating hUCB iNSCs, contributing development of in vitro neuropathological model systems.

A stem cell tracking system is in high demand for the determination of cell destinations and for the validation of cell therapeutic efficacy in regenerative transplantation. To date, near-infrared (NIR) imaging technology has received considerable attention in cell behavior monitoring, owing to its patient compatibility, easy accessibility and cost effectiveness. Conventionally, in vivo cell tracking has been visualized by direct in-cell staining with NIR, where it may be achieved by complicated genetic engineering. Such genetic amendment techniques have suffered from serious challenges, which can destroy a cell's metabolism and can accidentally incur unexpected carcinoma. Herein we demonstrate a novel cell nano-modulation method for noninvasive stem cell monitoring. It is simply achieved by conjugating stem cells with lipid-supported, NIR-tagged, polymeric nanoparticles. These engineered cells, which are designated as NIR-labeled light-emitting stem cells (LESCs), maintain their biochemical functionality (i.e., differentiation, quantum efficacy, etc.) even after conjugation. LESCs were used for in situ stem cell monitoring at inoculation sites. It is speculated that the LESC technique could provide a new preparative methodology for in vivo cell tracking in advanced diagnostic medicine, where cell behavior is a critical issue.

// Tae-Hoon Shin 1, 2, * , Byung-Chul Lee 1, 2, * , Soon Won Choi 1, 2 , Ji-Hee Shin 1, 2 , Insung Kang 1, 2 , Jin Young Lee 1, 2 , Jae-Jun Kim 1, 2 , Hong-Ki Lee 3 , Jae-Eon Jung 3 , Yong-Woon Choi 3 , Sung-Hoon Lee 3 , Jin-Sang Yoon 3 , Jin-Sub Choi 3 , Chi-Seung Lee 4, 5 , Yoojin Seo 1, 4, 5 , Hyung-Sik Kim 1, 4, 5 , Kyung-Sun Kang 1, 2 1 Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea 2 Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, South Korea 3 Biotechnology Institute, EHL-BIO Co., Ltd., Uiwang 16006, South Korea 4 School of Medicine, Pusan National University, Busan 49241, South Korea 5 Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea * These authors contributed equally to this work Correspondence to: Kyung-Sun Kang, email: kangpub@snu.ac.kr Hyung-Sik Kim, email: hskimcell@pusan.ac.kr Keywords: mesenchymal stem cells, atopic dermatitis, B cell maturation, mast cell degranulation, distribution Received: June 06, 2016 Accepted: November 12, 2016 Published: November 19, 2016 ABSTRACT Mesenchymal stem cell (MSC) has been applied for the therapy of allergic disorders due to its beneficial immunomodulatory abilities. However, the underlying mechanisms for therapeutic efficacy are reported to be diverse according to the source of cell isolation or the route of administration. We sought to investigate the safety and the efficacy of human adipose tissue-derived MSCs (hAT-MSCs) in mouse atopic dermatitis (AD) model and to determine the distribution of cells after intravenous administration. Murine AD model was established by multiple treatment of Dermatophagoides farinae . AD mice were intravenously infused with hAT-MSCs and monitored for clinical symptoms. The administration of hAT-MSCs reduced the gross and histological signatures of AD, as well as serum IgE level. hAT-MSCs were mostly detected in lung and heart of mice within 3 days after administration and were hardly detectable at 2 weeks. All of mice administered with hAT-MSCs survived until sacrifice and did not demonstrate any adverse events. Co-culture experiments revealed that hAT-MSCs significantly inhibited the proliferation and the maturation of B lymphocytes via cyclooxygenase (COX)-2 signaling. Moreover, mast cell (MC) degranulation was suppressed by hAT-MSC. In conclusion, the intravenous infusion of hAT-MSCs can alleviate AD through the regulation of B cell function.