OSTEOGENIC AND IMMUNOMODULATORY PROPERTIES OF DECIDUOUS TOOTH STEM CELLS

描述（申请人提供）：目前颅面骨缺损的修复需求很大。尽管最近的研究表明，间充质干乳牙（MSC）可以在动物模型中用于修复颅骨缺损，但通常用于修复口面骨缺损的轴骨和尾骨的自体移植物往往导致不良的结果。从供口部位获得的移植物桥接口面缺损通常比从非口面部位获得的移植物更成功，这表明解剖骨骼部位的特异性差异影响移植物的整合。人脱落乳牙干细胞（Human Exfoliated dec乳牙，SHED）具有间充质干细胞的特性，且具有极高的增殖能力，提示少量培养的脱落乳牙干细胞可以为临床提供足够数量的细胞。因此，SHED将是修复神经嵴相关的口面骨缺损的一种合适的可获得的干细胞资源。我们的初步数据表明，SHED的再生和免疫调节特性受端粒酶活性的调节。因此，我们的假设是，了解端粒酶调节SHED成骨分化和免疫调节的机制，可以显著提高基于shedd的组织再生。在这个应用中，我们将描述端粒酶活性激活改善shed介导的骨再生修复颅骨缺损的机制。基于我们关于端粒酶控制SHED免疫调节功能的新发现，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shedd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shedd的治疗提供分子基础。意义：这些研究将很有可能导致：1)揭示端粒酶相关通路调控SHED成骨和免疫调节的新分子机制；2)开发新的治疗策略，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.