iPSC-MSCs通过树突状细胞调控鼻息肉Th2型炎症及机制探讨

We have reported induced pluripotent stem cell-derived mesenchymal stem cell (iPSC-MSC) was able to suppress allergic airway inflammation and modulate the differentiation and function of dendritic cell (DC). Recent studies demonstrated that eosinophilic nasal polyps (Eos-NP) is characterised by T-helper type 2 inflammation which is similar to allergic inflammation, and DC plays an important role in the pathogenesis of Eos-NP. However, the effect of iPSC-MSC on nasal polyps remains unknown. Our preliminary findings showed iPSC-MSC is able to decrease T-helper type 2 cytokines. Thus, we hypothesize iPSC-MSC could modulate T-helper type 2 inflammation in nasal polyps via dendritic cells. In the present study, we plan to separate Eos-NP cells to co-culture with iPSC-MSC, analyze the immunomodulatory effect of iPSC-MSC on the T-helper type 2 inflammation in Eos-NP; to purify DC from Eos-NP to co-culture with iPSC-MSC, examine the role of DC in the immunomodulatory effect of iPSC-MSC on T-helper type 2 inflammation in Eos-NP; to employ Transwell system, neutralizing antibody or antagonist to further investigate the molecular mechanisms of the immunomodulatory effect of iPSC-MSC. This study will provide a bran-new stem cell-based therapy for the treatment of Eos-NP and provide good theoretical foundation for the new treatment strategy targeting DC.

我们报道了多能干细胞来源的间充质干细胞（iPSC-MSC）可抑制气道变应性炎症，且其可调控树突状细胞（DC）的分化及功能。最新研究发现嗜酸粒细胞性鼻息肉（Eos-NP）亦属类似于变应性炎症的Th2型炎症，且DC在其发病中具有重要作用，但iPSC-MSC对鼻息肉的作用未见报道。我们前期证实iPSC-MSC可下调Eos-NP中的Th2型细胞因子，由此我们假设iPSC-MSC可通过DC调控鼻息肉Th2型炎症。本研究拟应用体外共培养，分离Eos-NP细胞而验证iPSC-MSC对Eos-NP中Th2型炎症的调节作用；分离Eos-NP中的DC而确定iPSC-MSC可通过DC抑制Eos-NP的Th2型炎症；进一步应用Transwell、中和性抗体/阻断剂等揭示其中的分子机制，这将为目前Eos-NP 的防治提供以干细胞为基础的全新方案，也为以DC为新靶点的治疗方案提供有力的理论依据，具有深远的应用前景。

诱导性多潜能干细胞来源的间充质干细胞（iPSC-MSCs）是一种新型来源的MSCs。我们先前报道了iPSC-MSCs 能有效抑制小鼠气道的Th2 型炎症，并且发现树突状细胞（DCs）介导了iPSC-MSCs对小鼠气道变应性炎症的免疫调节作用。在本项目的资助下，我们进一步探讨了iPSC-MSCs 对Eos-NP的Th2 型炎症和DCs的免疫调节作用和机制。实验结果发现iPSC-MSCs在体外能显著下调Eos-NP中IL-4和IL-5的表达水平，提示iPSC-MSCs在体外可抑制Eos-NP的Th2型炎症反应。进一步我们通过建立人单核细胞诱导的DCs和iPSC-MSCs共培养体系的实验发现iPSC-MSCs能够通过分泌IL-10在体外显著抑制CD14+单核细胞分化为不成熟DCs（iDCs）。但是，iPSC-MSCs不影响LPS诱导的DCs成熟，而是将其诱导为一种具有高表达IL-10的具有免疫性DCs；介导这一部分iPSC-MSCs作用的机制主要是通过细胞-细胞接触来实现的。这些实验结果表明iPSC-MSCs对最强大的抗原提呈细胞DCs具有免疫调节作用，鉴于DCs在免疫性疾病发病中的重要作用，本研究结果也提示iPSC-MSCs或可应用于DCs介导的其它免疫性疾病的免疫治疗。此外，通过建立体外和体内实验模型，我们还发现糖皮质激素地塞米松不会对iPSC-MSCs的免疫调节功能产生显著影响，提示iPSC-MSCs在进行临床应用时可与糖皮质激素同时应用。