IGFBP5在牙周膜干细胞介导组织再生中的作用及分子机制研究

Insulin-like growth factor binding protein (IGFBP) is a family of six highly conserved proteins which mainly involved in regulating biological activity of insulin-like growth factors(IGF). Our group previous study revealed IGFBP5 highly express in odontogenic mesenchymal stem cells, IGFBP5 is regulated by BCL6 co-repressor (BCOR), which is a possibly down-stream factor of BCOR in mediating multi-potent differentiation of mesenchymal stem cells. These results indicate that IGFBP5 may play a vital role in regeneration of tooth and its supporting tissues. But the detail function and its underlying mechanism have not yet been defined.To test this possibility, we design lost/gain function of IGFBP5 in mesenchymal stem cells derived from health or inflamed periodontal ligaments (PDLSC) to investigate whether IGFBP5 involves in regulating its differentiate, anti-inflammatory and immunomodulatory properties in vitro, and to observe periodontal tissue regeneration in an animal model of periodontitis in miniature pigs in vivo. After that, base on the study of IGFBP5 function, the mechanism by which BCOR in regulating Igfbp5 gene transcription (in its promoter domain) and down-regulating factors of IGFBP5 will be explored by micro-array, ChIP/reChIP and bioinformatics analysis.This proposal may provide a novel principle in elucidating the mechanism of odontogenic MSC mediated tissue regeneration and scientific evidences in future clinical application of periodontal ligament stem cells in periodontal regeneration.

如何促进间充质干细胞介导的牙及支持组织再生是目前口腔再生与转化医学研究的热点。本课题组前期研究发现，IGFBP5在牙源性间充质干细胞中高表达并调节其定向分化，可能是BCOR调节间充质干细胞的功能的下游关键靶基因，提示IGFBP5在牙齿及其支持组织再生中潜在的重要作用，但功能与机制尚不清楚。本课题拟通过获得性及丧失性功能研究揭示IGFBP5在牙周膜干细胞中的作用，并在大型动物小型猪建立实验性牙周炎动物模型，研究IGFBP5对牙周组织炎症反应、免疫调节和组织再生的影响。在IGFBP5功能研究的基础上，利用基因芯片及生物信息学分析发现其调控的关键下游基因，并揭示BCOR调节IGFBP5基因的表观遗传学机制，进而调控牙周膜干细胞参与组织再生的分子机制。该研究有望进一步阐明牙周膜干细胞定向分化、炎症及免疫调节和组织再生的分子机制，为增强牙周膜干细胞介导的组织再生的研究临床应用提供科学依据。

如何促进间充质干细胞介导的牙及支持组织再生是目前口腔再生与转化医学研究的热点。本课题组前期研究发现，IGFBP5在牙源性间充质干细胞中高表达并调节其定向分化，提示IGFBP5在牙齿及其支持组织再生中潜在的重要作用。本研究采用获得性及丧失性功能研究揭示IGFBP5具有促进牙周膜干细胞成骨向分化，抑制炎症免疫反应的作用。建立小型猪建立实验性牙周炎动物模型，发现移植过表达IGFBP5的脐带间充质干细胞有促进牙周组织再生，缓解炎症的作用。在IGFBP5功能研究的基础上，利用基因芯片及生物信息学分析和染色质免疫共沉淀等技术发现，KDM6B去IGFBP5转录起始区H3K27三甲基化促进PDLSCs中IGFBP5基因转录。是调节IGFBP5基因的表观遗传学机制。进一步研究发现IGFBP5通过MEK, ERK1/2, JNK信号通路促进WJCMSCs和PDLSCs成骨向分化。该研究进一步阐明牙周膜干细胞定向分化、炎症及免疫调节和组织再生的分子机制，为牙周膜干细胞介导的组织再生的研究临床应用提供科学依据。