Qing-Ling Fu

Human Pluripotent Stem Cell‐Derived Mesenchymal Stem Cells Prevent Allergic Airway Inflammation in Mice

We previously found that mesenchymal stem cells (MSCs) derived from human‐induced pluripotent stem cells (iPSCs) exerted immunomodulatory effects on Th2‐mediated allergic rhinitis in vitro. However, their contribution to the asthma and allergic rhinitis in animal models remains unclear. In this study, we developed a mouse model of ovalbumin (OVA)‐induced allergic inflammation in both the upper and lower airways and evaluated the effects of the systemic administration of human iPSC‐MSCs and bone marrow‐derived MSCs (BM‐MSCs) on allergic inflammation. Our results showed that treatments with both the iPSC‐MSCs and BM‐MSCs before the challenge phase protected the animals from the majority of allergy‐specific pathological changes. This protection included an inhibition of inflammatory cell infiltration and mucus production in the lung, a reduction in eosinophil infiltration in the nose, and a decrease in inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids. In addition, treatment with iPSC‐MSCs or BM‐MSCs before the challenge phase resulted in reduced serum levels of Th2 immunoglobulins (e.g., IgE) and decreased levels of Th2 cytokines including interleukin (IL)‐4, IL‐5, or IL‐13 in the bronchoalveolar and/or nasal lavage fluids. Similar therapeutic effects were observed when the animals were pretreated with human iPSC‐MSCs before the sensitization phase. These data suggest that iPSC‐MSCs may be used as an alternative strategy to adult MSCs in the treatment of asthma and allergic rhinitis. STEM CELLS 2012;30:2692–2699

Epidemiology of chronic rhinosinusitis: results from a cross-sectional survey in seven Chinese cities

Chronic sinusitis (CRS) is a common otorhinolaryngologic disease that is frequently encountered in everyday practice, but there is a lack of precise data regarding the prevalence of CRS in developing countries. We performed a national investigation in China to determine the prevalence and associated factors of CRS.

Combined effect of brain-derived neurotrophic factor and LINGO-1 fusion protein on long-term survival of retinal ganglion cells in chronic glaucoma

Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. There are no effective neuroprotectants to treat this disorder. Brain-derived neurotrophic factor (BDNF) is well known to transiently delay RGC death in ocular hypertensive eyes. The CNS-specific leucine-rich repeat protein LINGO-1 contributes to the negative regulation to some trophic pathways. We thereby examined whether BDNF combined with LINGO-1 antagonists can promote long-term RGC survival after ocular hypertension. In this study, intraocular pressure was elevated in adult rats using an argon laser to photocoagulate the episcleral and limbal veins. BDNF alone shows slight neuroprotection to RGCs after a long-term progress of 4 weeks following the induction of ocular hypertension. However, combination of BDNF and LINGO-1-Fc prevents RGC death in the same condition. We further identified that (1) LINGO-1 was co-expressed with BDNF receptor, TrkB in the RGCs, and (2) BDNF combined with LINGO-1-Fc activated more TrkB in the injured retina compared to BDNF alone. These results indicate that the combination of BDNF with LINGO-1 antagonist can provide long-term protection for RGCs in a chronic ocular hypertension model. TrkB may be the predominant mediator of this neuroprotection.

Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM). Compared with BM-MSCs-CdM, NRCMs treated with iPSC-MSCs-CdM exhibit significantly less ROS and cell apoptosis in a dose-dependent manner. Transplantation of BM-MSCs-CdM or iPSC-MSCs-CdM into mice with AIC remarkably attenuated left ventricular (LV) dysfunction and dilatation. Compared with BM-MSCs-CdM, iPSC-MSCs-CdM treatment showed better alleviation of heart failure, less cardiomyocyte apoptosis and fibrosis. Analysis of common and distinct cytokines revealed that macrophage migration inhibitory factor (MIF) and growth differentiation factor-15 (GDF-15) were uniquely overpresented in iPSC-MSC-CdM. Immunodepletion of MIF and GDF-15 in iPSC-MSCs-CdM dramatically decreased cardioprotection. Injection of GDF-15/MIF cytokines could partially reverse Dox-induced heart dysfunction. We suggest that the potent paracrine effects of iPSC-MSCs provide novel “cell-free” therapeutic cardioprotection against AIC, and that MIF and GDF-15 in iPSC-MSCs-CdM are critical for these enhanced cardioprotective effects.

LINGO-1 negatively regulates TrkB phosphorylation after ocular hypertension.

The antagonism of LINGO‐1, a CNS‐specific negative regulator of neuronal survival, was shown to promote short‐term survival of retinal ganglion cell (RGC) in an ocular hypertension model. LINGO‐1 antagonists, combined with brain‐derived neurotrophic factor (BDNF), can increase the length of neuron survival through an unclear molecular mechanism. To determine the relationship between LINGO‐1 and BDNF/TrkB receptor in neuronal protection, we show here that LINGO‐1 forms a receptor complex with TrkB and negatively regulates its activation in the retina after ocular hypertension injury. LINGO‐1 antagonist antibody 1A7 or soluble LINGO‐1 (LINGO‐1‐Fc) treatment upregulates phospho‐TrkB phosphorylation and leads to RGC survival after high intraocular pressure injury. This neuronal protective effect was blocked by anti‐BDNF antibody. LINGO‐1 antagonism therefore promotes RGC survival by regulating the BDNF and TrkB signaling pathway after ocular hypertension.

Insensitivity of Human iPS Cells-Derived Mesenchymal Stem Cells to Interferon-γ-induced HLA Expression Potentiates Repair Efficiency of Hind Limb Ischemia in Immune Humanized NOD Scid Gamma Mice.

Adult mesenchymal stem cells (MSCs) are immunoprivileged cells due to the low expression of major histocompatibility complex (MHC) II molecules. However, the expression of MHC molecules in human‐induced pluripotent stem cells (iPSCs)‐derived MSCs has not been investigated. Here, we examined the expression of human leukocyte antigen (HLA) in human MSCs derived from iPSCs, fetuses, and adult bone marrow (BM) after stimulation with interferon‐γ (IFN‐γ), compared their repair efficacy, cell retention, inflammation, and HLA II expression in immune humanized NOD Scid gamma (NSG) mice of hind limb ischemia. In the absence of IFN‐γ stimulation, HLA‐II was expressed only in BM‐MSCs after 7 days. Two and seven days after stimulation, high levels of HLA‐II were observed in BM‐MSCs, intermediate levels were found in fetal‐MSCs, and very low levels in iPSC‐MSCs. The levels of p‐STAT1, interferon regulatory factor 1, and class II transactivator exhibited similar phenomena. Moreover, p‐STAT1 antagonist significantly reversed the high expression of HLA‐II in BM‐MSCs. Compared to adult BM‐MSCs, transplanting iPSC‐MSCs into hu‐PBMNC NSG mice revealed markedly more survival iPSC‐MSCs, less inflammatory cell accumulations, and better recovery of hind limb ischemia. The expression of HLA‐II in MSCs in the ischemia limbs was detected in BM‐MSCs group but not in iPSC‐MSCs group at 7 and 21 days after transplantation. Our results demonstrate that, compared to adult MSCs, human iPSC‐MSCs are insensitive to proinflammatory IFN‐γ‐induced HLA‐II expression and iPSC‐MSCs have a stronger immune privilege after transplantation. It may attribute to a better therapeutic efficacy in allogeneic transplantation. Stem Cells 2015;33:3452–3467

Biological characteristics of CD133+ cells in nasopharyngeal carcinoma

Cancer stem cells are regarded as the cause of tumour formation and recurrence in nasopharyngeal carcinoma (NPC). However, ideal surface markers for stem cells in NPC remain unidentified. In the present study, we investigated the expression of CD133, Nanog and Sox2 in the nasopharyngeal carcinoma cell line CNE2 and primarily cultured NPC cells using immunofluorescence or flow cytometry. A cell population with a CD133+ phenotype was enriched using magnetic-activated cell sorting technology. We demonstrated that CD133+ cells exhibited a strong potential for self-renewal, proliferation and differentiation and a greater potential for in vivo tumour formation in nude mice compared to CD133− cells, although the percentage of CD133+ cells was small. However, the specific marker antigens Nanog and Sox2 were simultaneously expressed in normal cancer stem cells. Our results showed that CD133 can serve as a specific surface marker for nasopharyngeal cancer stem cells.

A bacterial extract of OM-85 Broncho-Vaxom prevents allergic rhinitis in mice.

Background According to the hygiene hypothesis, bacterial infections during early life contribute to a reduced incidence of asthma in animals. However, the effects of microbial products at a safe dose and within a rational time course on the prevention of allergic rhinitis (AR) have been inconclusive. This study investigated the immunomodulatory effects of oral administration of a bacterial extract, OM-85 Broncho-Vaxom (BV), with a low dose and general time course, which is currently used for respiratory infections in humans, on AR inflammation in mice. Methods We developed a mouse model of ovalbumin (OVA)-induced AR allergic inflammation in the nose mucosa of mice. Low doses of OM-85 BV were orally administered for 3 months (long term) before sensitization. We evaluated nasal symptoms, pathology in the nose, inflammatory cells, and the levels of T helper 1 (Th1)/Th2 cytokines in the nasal lavage fluids, and the serum levels of specific IgE and IgG1. We also observed enhanced effects of OM-85BV with 1 month (short term) of treatment. Results We found that long-term pretreatment with OM-85 BV protected the mice from the majority of allergy-specific symptoms; specifically, OM-85 BV suppressed nasal symptoms, inhibited eosinophil infiltration in the nose, inhibited inflammatory infiltrates and the Th2 response by reducing cytokines (IL-4, IL-5, or IL-13) in the nasal lavage fluids, and reduced IgE and IgG1 levels. Furthermore, short-term treatment with OM-85 BV decreased the levels of Th2 cytokines and IgE. Conclusion Taken together, our data suggested that OM-85 BV is a low-cost alternative candidate to prevent AR with simple oral administration.

Influence of Self-Reported Chronic Rhinosinusitis on Health-Related Quality of Life: A Population-Based Survey

Chronic rhinosinusitis (CRS) is a frequently occurring chronic respiratory disease. There is evidence that effective treatment of CRS can improve patients’ quality of life, but the data regarding the extent to which CRS impairs patients’ quality of life (QoL) is sparse. This study aimed to evaluate the effect of self-reported CRS on health-related QoL and to determine whether the influence was associated with gender, age and socio-economic status. A four-stage random sampling method was used to select the participants from the general population in Guangzhou, China. All participants were interviewed face-to-face at their homes using a standardized questionnaire. The health-related QoL of each participant was assessed using the SF-36 Health Survey. The scores of the SF-36 after adjusting for gender, age, socioeconomic conditions, smoking and some important comorbid conditions were compared between the CRS group and the non-CRS group using analysis of covariance. A multiple linear regression model with interaction terms was established to determine whether CRS affected QoL to the same degree across the different subpopulations. Among a total of 1,411 participants aged at least 15 years, 118 persons (8.4%) had self-reported CRS. Subjects with CRS had an increased prevalence of allergic rhinitis, chronic obstructive pulmonary disease and gout than subjects without CRS. The CRS group had lower scores in all eight domains and the physical and mental component summary than those without CRS (P<0.05), and the greatest differences were in role emotional function (RE), general health (GH) and role physical function (RP). The impairments of the CRS participants in RE and RP were greater among the females than the males. Moreover, physical domains were affected to greater degrees among the elderly and those with high-level education. In conclusion, CRS is a common chronic disorder. Persons with self-reported CRS perceived themselves as having impaired QoL in both the physical and mental domains. These findings shed new light on the health burden of CRS and should be taken into account by clinicians involved in the care of CRS patients.

Evaluation of Long-Term Clarithromycin Treatment in Adult Chinese Patients with Chronic Rhinosinusitis without Nasal Polyps

Objective: To evaluate the efficacy of long-term clarithromycin (CAM) treatment in adult Chinese patients suffering from chronic rhinosinusitis without nasal polyps (CRSnNP). Methods: Thirty-three CRSnNP patients were enrolled and subjected to CAM treatment for 12 weeks (250 mg daily). The total nasal symptom scores (TNSS), nasal resistance and inflammatory mediators including interleukin (IL)-8 and myeloperoxidase (MPO) were evaluated at weeks 0 and 12. Quality of life (QoL) was assessed in all patients by using the Sinonasal Outcome Test 20 and Short Form 36 questionnaires. Results: CAM treatment significantly improved TNSS, nasal resistance and QoL, and it inhibited IL-8 and MPO production in CRSnNP patients (p < 0.05). CAM treatment was more effective for IL-8high CRSnNP patients than for IL-8low CRSnNP patients (p < 0.05). Conclusion: Long-term, low-dose CAM treatment is effective and safe for the treatment of CRSnNP in Chinese patients.