Abstract
BackgroundHuman induced pluripotent stem cells-derived mesenchymal stem cells (iPSC-MSCs) have been shown to be effective in Type 2 helper T cells (Th2)-dominant eosinophilic allergic airway inflammation. However, the role of iPSC-MSCs in Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation remains poorly studied. Therefore, this study was to explore the effects of iPSC-MSCs on an experimental mouse model of steroid-resistant neutrophilic airway inflammation and further determine the underlying mechanisms.MethodsA mouse model of neutrophilic airway inflammation was established using ovalbumin (OVA) and lipopolysaccharide (LPS). Human iPSC-MSCs were systemically administered, and the lungs or bronchoalveolar lavage fluids (BALF) were collected at 4 h and 48 h post-challenge. The pathology and inflammatory cell infiltration, the T helper cells, T helper cells-associated cytokines, nuclear transcription factors and possible signaling pathways were evaluated. Human CD4+ T cells were polarized to T helper cells and the effects of iPSC-MSCs on the differentiation of T helper cells were determined.ResultsWe successfully induced the mouse model of Th17 dominant neutrophilic airway inflammation. Human iPSC-MSCs but not dexamethasone significantly prevented the neutrophilic airway inflammation and decreased the levels of Th17 cells, IL-17A and p-STAT3. The mRNA levels of Gata3 and RORγt were also decreased with the treatment of iPSC-MSCs. We further confirmed the suppressive effects of iPSC-MSCs on the differentiation of human T helper cells.ConclusionsiPSC-MSCs showed therapeutic potentials in neutrophilic airway inflammation through the regulation on Th17 cells, suggesting that the iPSC-MSCs could be applied in the therapy for the asthma patients with steroid-resistant neutrophilic airway inflammation.
Highlights
Human induced pluripotent stem cells-derived mesenchymal stem cells have been shown to be effective in Type 2 helper T cells (Th2)-dominant eosinophilic allergic airway inflammation
We further identified that the level of p-STAT3 was significantly decreased after the administration of induced pluripotent stem cells (iPSCs)-mesenchymal stem cells (MSCs) (n = 6) but not DEX (n = 6) (Fig. 4b), suggesting that iPSC-MSCs may inhibit the differentiation of Type 17 helper T cells (Th17) cells in this model of neutrophilic airway inflammation via downregulating p-STAT3 level
In summary, our study showed that iPSC-MSCs were effective in steroid-insensitive neutrophilic airway inflammation
Summary
Human induced pluripotent stem cells-derived mesenchymal stem cells (iPSC-MSCs) have been shown to be effective in Type 2 helper T cells (Th2)-dominant eosinophilic allergic airway inflammation. The role of iPSC-MSCs in Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation remains poorly studied. This study was to explore the effects of iPSC-MSCs on an experimental mouse model of steroidresistant neutrophilic airway inflammation and further determine the underlying mechanisms. Asthma is characterized by heterogeneous upper airway inflammation in which different inflammatory cells are involved [1]. Based on the inflammatory cell profiles in induced sputum, neutrophilic asthma has been defined as a distinct phenotype from Type 2 helper T cells (Th2)-dominant eosinophilic asthma [2]. Previous studies have shown that the neutrophils present in the airway were highly associated with the severity of
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