OSTEOGENIC AND IMMUNOMODULATORY PROPERTIES OF DECIDUOUS TOOTH STEM CELLS

描述（申请人提供）：颅面骨缺损的修复需求量很大。尽管近年来的研究表明，间充质干乳牙（MSC）可用于修复动物模型的颅骨缺损，自体移植的轴骨和无骨通常用于修复口面骨缺损往往会导致不利的结果。桥接口面缺损的移植物从口面供体部位获得的通常是更成功的比那些从非口面部位，这表明解剖骨骼部位的具体差异影响移植整合。人脱落乳牙干细胞（SHED）具有MSC特性，增殖能力极强，提示少量SHED培养扩增即可获得足够数量的细胞用于临床。因此，SHED将是修复神经嵴相关的口面骨缺损的合适的可获得的干细胞资源。我们的初步数据表明，再生和免疫调节特性的SHED调节端粒酶活性。因此，我们的假设是，通过了解端粒酶调控SHED成骨分化和免疫调节的机制，可以显着改善基于SHED的组织再生。在本申请中，我们将描述端粒酶活性的激活改善SHED介导的骨再生修复颅骨缺损的机制。基于我们的新发现，即端粒酶调控SHED的免疫调节功能，我们将研究端粒酶如何控制SHED介导的免疫调节。最后，我们将把受体免疫调节与基于SHED的组织再生联系起来。总的来说，我们提出的研究的新发现将为理解基于SHED的疗法提供分子基础。重要性：这些研究将最有可能导致：1）揭示端粒酶相关途径控制SHED的成骨和免疫调节的新分子机制; 2）开发新的治疗策略，以突破通过调节受体T细胞来改善颅骨骨再生的关键障碍。

DESCRIPTION (provided by applicant): There is a great demand thefor the repair of craniofacial bone defects. Despite the recent studies suggest that mesenchymal stem deciduous teeth (MSC) could be used to repair cranial defects in animal models, autologous grafts from axial and appendicular bones commonly used to repair orofacial bone defects often result in an unfavorable outcome. Bridging orofacial defects with grafts obtained from an orofacial donor site are usually more successful than those from non-orofacial sites, indicating that anatomic skeletal site-specific differences affect graft integration. Stem cells from Human Exfoliated Deciduous teeth (SHED) possess MSC characteristics and show extremely high proliferation capacity, suggesting that culture expanded small number of SHED can provide sufficient number of cells for clinical use. Therefore, SHED would be an appropriate accessible stem cell resource for repairing neural crest-related orofacial bone defects. Our preliminary data showed that regenerative and immunomodulatory properties of SHED are regulated by telomerase activity. Therefore, our hypothesis is that SHED-based tissue regeneration can be significantly improved with understanding mechanism by which telomerase regulates osteogenic differentiation and immunomodulation of SHED. In this application, we will characterize the mechanism by which activation of telomerase activity improves SHED-mediated bone regeneration for repairing calvarial defects. On the basis of our novel findings that telomerase governs immunomodulatory function of SHED, we will examine how telomerase controls SHED-mediated immune regulation. Finally, we will link recipient immunoregulation to SHED-based tissue regeneration. Collectively, novel findings from our proposed studies will provide a molecular basis for understanding SHED-based therapies. Significance: These studies will most likely lead to: 1) unveiling novel molecular mechanisms by which telomerase associated pathways govern osteogenesis and immunomodulation of SHED; and 2) developing new therapeutic strategies to break through the critical barrier for improving calvarial bone regeneration via regulation of recipient T cells.