IL-1-JNK/MAPK通路对成体干细胞再生晶状体的调控机制

The approach of in situ lens regeneration using endogenous stem cells demonstrates a novel treatment strategy for cataracts. However, the dysfunction of lens epithelial stem cells (LECs) and abnormality of microenvironment will lead to insufficient lens regeneration or secondary lens opacity. Interleukin 1（IL-1）is a key inflammatory mediator. It contributes to local inflammatory microenvironment and could influence on the biological process including stem cell proliferation and migration by stimulating JNK (member of MAPK protein families) pathways. Our preliminary research found that IL-1-JNK/MAPK pathway molecules were up-regulated in LECs and were significantly correlated with quality of regenerated lens. We therefore hypothesis that IL-1-JNK/MAPK pathways may effect on the quality of regenerated lens by regulating the stemness of LECs. In this project, we plan to establish three experimental models: in vitro human primary LECs, transgenic mice with IL-lα over-expressed specially in lens, and rabbits with regenerated lens after minimally invasive lens surgical approach. By using these three experimental models, we plan to evaluate the influence of IL-1-JNK/MAPK on the stemness of LECs (proliferation and apoptosis) and the quality of regenerated lens (transparency and thickness). Further molecular mechanism will also be explored then. We aim to demonstrate the influence of inflammatory microenvironment on in situ lens regeneration. We hope the results of this project could help maintain the stability of LECs stemness and improve the quality of regenerative lens to achieve better long-term visual function.

利用内源性成体干细胞原位再生晶体状的实现为治疗白内障提供了新思路。但晶状体上皮干细胞功能及囊袋微环境改变可致再生晶状体透明性及厚度异常。白细胞介素1（IL-1）是机体重要炎症介质，可激活MAPK激酶家族成员JNK，调节局部炎症微环境，影响干细胞增殖、迁移等多种生物过程。前期研究发现，IL-1-JNK/MAPK通路分子在晶状体上皮干细胞中高表达，且与再生晶状体性状显著相关。因此推测IL-1-JNK/MAPK通路可能调控晶状体成体干细胞功能和组织再生。本项目拟通过构建体外人晶状体上皮干细胞原代培养、内源性IL-lα转基因鼠、兔超微创晶状体再生手术三种实验模型，探究IL-1-JNK/MAPK通路对晶状体上干细胞功能（增殖、凋亡）和再生晶状体性状（透明性、厚度）的影响及其分子机制，阐明炎症微环境在晶状体原位再生中的调控机制，为维持晶状体上皮干细胞功能稳定，提升原位再生晶状体的远期功能奠定基础。

利用内源性成体干细胞原位再生晶体状的实现为治疗白内障提供了新思路。但晶状体上皮干细胞功能及囊袋微环境改变可致再生晶状体透明性及厚度异常。通过调节局部炎症微环境，可影响干细胞增殖、迁移等多种生物过程。前期研究发现，眼内炎症微环境相关通路分子在晶状体上皮干细胞中高表达，且与再生晶状体性状显著相关。因此推测炎症微环境可能调控晶状体成体干细胞功能和组织再生。本项目执行期内发现婴幼儿晶状体免疫微环境随年龄动态变化特征，且得到婴幼儿晶状体炎症微环境与白内障术后晶状体再生反应相关性，进一步通过体外细胞分子实验证实巨噬细胞参与的炎症微环境在损伤后修复晶状体上皮干细胞的生物行为有重要影响。本项目开展为后续进一步研究研究炎症通路对晶状体成体干细胞干性（更新及分化能力）和再生晶状体性状（再生晶状体组织厚度及透明性）的影响及分子机制，以及动物实验验证，完善再生技术奠定了理论基础。