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

BackgroundHuman induced pluripotent stem cells (iPSCs) possess remarkable self-renewal capacity and the potential to differentiate into novel cell types, such as mesenchymal stem cells (MSCs). iPSC-MSCs have been shown to enhance tissue regeneration and attenuate tissue ischaemia; however, their contribution to the immune regulation of Th2-skewed allergic rhinitis (AR) and asthma remains unclear.ObjectiveThis study compared the immunomodulatory effects of iPSC-MSCs and bone marrow-derived MSCs (BM-MSCs) on lymphocyte proliferation, T-cell phenotypes and cytokine production in peripheral blood mononuclear cells (PBMCs) in patients with AR, and investigated the possible molecular mechanisms underlying the immunomodulatory properties of iPSC-MSCs.MethodsIn co-cultures of PBMCs with iPSC-MSCs or BM-MSCs, lymphocyte proliferation was evaluated using 3H-thymidine (3H-TdR) uptake, carboxyfluorescein diacetate, succinimidyl ester (CFDA-SE) assays; the regulatory T-cell (Treg) phenotype was determined by flow cytometry, and cytokine levels were measured using an enzyme-linked immunosorbent assay. The immunomodulatory properties of both MSCs were further evaluated using NS398 and transwell experiments.ResultsSimilar to BM-MSCs, we determined that iPSC-MSCs significantly inhibit lymphocyte proliferation and promote Treg response in PBMCs (P < 0.05). Accordingly, the cytokine milieu (IFN-γ, IL-4, IL-5, IL-10 and IL-13) in the supernatants of PBMCs changed significantly (P < 0.05). The immunomodulatory properties of iPSC-MSCs and BM-MSCs were associated with prostaglandin E2 (PGE2) production and cell–cell contact.ConclusionsThese data demonstrate that iPSC-MSCs are capable of modulating T-cell phenotypes towards Th2 suppression through inducing Treg expansion, suggesting that iPSC-MSCs can be used as an alternative candidate to adult MSCs to treat allergic airway diseases.

BackgroundMesenchymal stem cells (MSCs) have potent immunomodulatory effects on multiple immune cells and have great potential in treating immune disorders. Induced pluripotent stem cells (iPSCs) serve as an unlimited and noninvasive source of MSCs, and iPSC-MSCs have been reported to have more advantages and exhibit immunomodulation on T lymphocytes and natural killer cells. However, the effects of iPSC-MSCs on dendritic cells (DCs) are unclear. The aim of this study is to investigate the effects of iPSC-MSCs on the differentiation, maturation, and function of DCs.MethodsHuman monocyte-derived DCs were induced and cultured in the presence or absence of iPSC-MSCs. Flow cytometry was used to analyze the phenotype and functions of DCs, and enzyme-linked immunosorbent assay (ELISA) was used to study cytokine production.ResultsIn this study, we successfully induced MSCs from different clones of human iPSCs. iPSC-MSCs exhibited a higher proliferation rate with less cell senescence than BM-MSCs. iPSC-MSCs inhibited the differentiation of human monocyte-derived DCs by both producing interleukin (IL)-10 and direct cell contact. Furthermore, iPSC-MSCs did not affect immature DCs to become mature DCs, but modulated their functional properties by increasing their phagocytic ability and inhibiting their ability to stimulate proliferation of lymphocytes. More importantly, iPSC-MSCs induced the generation of IL-10-producing regulatory DCs in the process of maturation, which was mostly mediated by a cell-cell contact mechanism.ConclusionsOur results indicate an important role for iPSC-MSCs in the modulation of DC differentiation and function, supporting the clinical application of iPSC-MSCs in DC-mediated immune diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0499-0) contains supplementary material, which is available to authorized users.

Local IL-25 plays a crucial role in promoting Th2-biased inflammatory profiles in NP and may serve as a promising therapeutic target in CRSwNP patients.

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-c (IFN-c), 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-c 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-c-induced HLA-II expression and iPSCMSCs have a stronger immune privilege after transplantation. It may attribute to a better therapeutic efficacy in allogeneic transplantation. STEM CELLS 2015;33:3452-3467 SIGNIFICANCE STATEMENTAllogenic transplantation of MSCs derived from bone marrow has been used clinically in graft versus host disease, multiple sclerosis, diabetes or ulcerative colitis, Crohn's disease and the other diseases. Here we identified that human MSCs derived from human-induced pluripotent stem cells (iPSCs) exhibited poor immunogenicity after IFN-c stimulation in vitro and exerted more cell retention, less inflammation and better efficacy in a model of limb ischemia in immune humanized mice compared to BM-MSCs. It suggests that these cells may have more potential clinical implications with a lower risk of rejection and a better therapeutic efficacy in allogenic transplantation.

Background Eosinophilic inflammation is a major phenotype associated with poorly controlled disease in nasal polyp patients. The difference between systemic and local eosinophilia in relation to disease control is poorly understood. Objective To explore whether blood and polyp tissue eosinophil numbers are independent risk factors for poor disease control in patients with nasal polyp. Methods By using the electronic medical records database and manual evaluation, 183 nasal polyp patients who had undergone endoscopic sinus surgery at least one year prior to the study with complete data of tissue specimens, baseline blood routine test, nasal endoscopy and sinus computed tomography, were identified and recruited to assess disease control based on the criteria of a European position paper on rhinosinusitis and nasal polyps 2012 (EPOS 2012). Multiple logistic regression model was used to determine the association between blood and tissue eosinophil numbers and risk of poor disease control by adjusting for demographics and comorbidities. Results We broke down the cohort into 4 groups according to blood (0.3 ​× ​10 9 /L) and tissue (10%) eosinophils. The patients without eosinophilic inflammation represented the largest group (41.5%). The group with concordant blood and tissue eosinophilia represented the second largest (31.2%), and the patients with isolated tissue (15.3%) or blood (12.0%) eosinophilia were relatively rare. Multiple logistic regression models found blood eosinophil count and tissue eosinophil percentage were independently associated with increased risk for poor disease control after adjustments for covariates related to poor treatment outcome. Furthermore, subjects with concordant blood and tissue eosinophilia had a higher risk for poor disease control than those with isolated blood or tissue eosinophilia. Conclusion Concordant blood and tissue eosinophilia relates to a higher likelihood of poor disease control than isolated blood or tissue eosinophilia after adjustment of potential confounders in nasal polyp patients.

Objectives/Hypothesis The European Position Paper on Rhinosinusitis and Nasal Polyps proposes an assessment of clinical control of chronic rhinosinusitis (CRS). However, there are limited data about the percentage of postoperative control, and no prediction models for uncontrolled CRS have been reported. The aim of the study was to develop prediction models for postoperative uncontrolled CRS. Study Design Retrospective case series. Methods Patients (n = 136) who had undergone endoscopic sinus surgery at least 1 year prior to the study were recruited to assess the clinical control. Risk factors were determined by logistic models and presented as odds ratio (OR) with a 95% confidence interval. Receiver operating characteristics curves were constructed to set the cutoff points and create predictive models. Results Approximately 47.8% of patients had controlled, 22.1% partially controlled, and 30.1% uncontrolled CRS. Univariate regression models revealed the risk factors for uncontrolled CRS: tissue eosinophilia, blood eosinophilia, high computed tomography (CT) score, bilateral disease, asthma, and allergic rhinitis. Multiple regression models found tissue eosinophil ratio >0.206 (OR: 12.96, P = .001) or blood eosinophil ratio >0.025 (OR: 4.56, P = .003), Lund‐Mackay (LM) score ≥ 15 (OR: 15.50, P < .001) and CT ethmoid (E) score ≥ maxillary (M) score (OR: 3.51, P = .037) were independent risk factors. We generated a pathological model (tissue eosinophil ratio and LM score) and a clinical model (blood eosinophil ratio, LM score and E ≥ M score) to categorize CRS into mild, moderate, and severe. Conclusions This research provides simplified and efficient prediction models for uncontrolled CRS. It may help otolaryngologists to predict the prognosis before surgery in daily practice. Level of Evidence 2b Laryngoscope, 128:2673–2680, 2018

EESS for patients with CRSwNP and with asthma may help to improve the subjective olfaction and endoscopic appearance.