人羊膜上皮细胞与胞外基质成分透明质酸联合干预1型糖尿病的协同效应机制

项目名称： 人羊膜上皮细胞与胞外基质成分透明质酸联合干预1型糖尿病的协同效应机制

项目编号： No.81460156

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖建辉

作者单位： 遵义医科大学

项目金额： 46万元

中文摘要： 人羊膜上皮细胞(hAECs)是细胞移植与再生医学领域最有潜力的干细胞资源，然而其在移植治疗1型糖尿病（T1DM）却未得到预想的结果。基于前期研究及文献报道，可能是移植策略和微环境影响了干细胞的迁移归巢与分化。胞外基质成分透明质酸(HA)是干细胞增殖分化先天调节子，也是减轻T1DM胰岛炎性反应与免疫应答的潜在因子，而hAECs具有分化胰岛β细胞与增强机体免疫耐受的潜力。为此提出hAECs联合HA移植治疗T1DM有协同效应，将有利于重建免疫平衡，修复与重塑胰岛组织，且FoxP3+信号通路发挥了积极作用。围绕这一假说，采用免疫印迹、RT-PCR、RNA干扰、基因敲除、PCR芯片等方法，拟在揭示HA促hAECs增殖的分子调控网络基础上，从分子、细胞及个体水平上阐明hAECs与HA治疗T1DM的协同效应及机制，为完善hAECs增殖分化的调控网络体系奠定基础，也为hAECs移植治疗T1DM提供新思路。

中文关键词： 人羊膜上皮细胞；透明质酸；1型糖尿病；增殖分化；FoxP3；信号通路

英文摘要： Human amniotic epithelial cells (hAECs) are recognized as a promising and noncontroversial source of stem cells for cell transplantation and regenerative medicine. Regretfully, previous studies showed that only a few hAECs could be observed in pancreas, and did not differentiate into insulin-producing cells (IPCs) in following hAECs transplantation into type 1 diabetes mellitus (T1DM) model. So no desirable outcomes were obtained in the past years. Based on our results and the related research progress on stem cell, we think carefully that these authors possibly underestimated the influences of transplantation strategy and microenvironment regulation of stem cell niche, and finally affected the migration, homing and differentiation of hAECs. As we known, extracellular matrix (ECM) is a major factor of stem cell microenvironment. Hyaluronan (HA), as a major component of extracelluar matrix, could also modulate the proliferation & differentiation of stem cell, and are looked as potential factor reducing the inflammatory reaction and immune response of insulitis in T1DM model. To hAECs, it can differentiate into IPCs, and enhance the immunotolerance of IPCs in T1DM model under a good microenvironment condition. Therefore, we presume that a combination therapty of hAECs and HA for T1DM rat may exert synergy to rebulid the immune balance, and restore or/and remodel the new IPCs system in T1DM rat, in which the FoxP3 signal pathway will play a vital role. To verify the hypothesis, a series of experimental techniques, such as immunoblotting, RT-PCR, RNAi, gene knock-out and PCR array, will be employed to investigate the molecular regulating networks of hAECS proliferation after HA treatment, and mainly observe the synergy effects of a combination therapty of hAECs and HA on T1DM rat and then elucidate their mechanisms of action at different levels ranged from molecule, cell to overall accordingly. These findings will replenish and enrich the regulatory network of proliferation & differentiation of hAECs in vivo/vitro, and provide a new therapeutic approach for T1DM by hAECs transplantation at the same time.

英文关键词： human amniotic epithelial cells;hyaluronan;type 1 diabetes;proliferation & differentiation;FoxP3 signal pathway