Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China.
Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
Stem Cell Res Ther. 2018 May 24;9(1):147. doi: 10.1186/s13287-018-0897-y.
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. 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.
A 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.
We 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.
iPSC-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.
人诱导多能干细胞衍生的间充质干细胞（iPSC-MSCs）已被证明在 2 型辅助 T 细胞（Th2）占优势的嗜酸性粒细胞过敏性气道炎症中有效。然而，iPSC-MSCs 在 1 型 7 辅助 T 细胞（Th17）占优势的中性粒细胞性气道炎症中的作用仍研究甚少。因此，本研究旨在探讨 iPSC-MSCs 对实验性耐激素中性粒细胞性气道炎症小鼠模型的影响，并进一步确定其潜在机制。
使用卵清蛋白（OVA）和脂多糖（LPS）建立中性粒细胞性气道炎症小鼠模型。系统给予人 iPSC-MSCs，在攻毒后 4 小时和 48 小时收集肺或支气管肺泡灌洗液（BALF）。评估病理学和炎症细胞浸润、T 辅助细胞、T 辅助细胞相关细胞因子、核转录因子和可能的信号通路。将人 CD4 T 细胞极化为 T 辅助细胞，并确定 iPSC-MSCs 对 T 辅助细胞分化的影响。
我们成功诱导了 Th17 占优势的中性粒细胞性气道炎症小鼠模型。人 iPSC-MSCs 而非地塞米松可显著预防中性粒细胞性气道炎症，并降低 Th17 细胞、IL-17A 和 p-STAT3 的水平。iPSC-MSCs 治疗还降低了 Gata3 和 RORγt 的 mRNA 水平。我们进一步证实了 iPSC-MSCs 对人 T 辅助细胞分化的抑制作用。
iPSC-MSCs 通过调节 Th17 细胞显示出在中性粒细胞性气道炎症中的治疗潜力，表明 iPSC-MSCs 可应用于治疗对激素抵抗的中性粒细胞性气道炎症的哮喘患者。
