OSTEOGENIC AND IMMUNOMODULATORY PROPERTIES OF DECIDUOUS TOOTH STEM CELLS

乳牙干细胞的成骨和免疫调节特性

• 批准号: 9036998
• 负责人: SONGTAO SHI
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036998
• 关键词: Affect; Anatomy; Animal Model; Autologous; Bone Regeneration; Calvaria; Cell Count; Cells; Cephalic; Characteristics; Clinical; Data; Defect; Family suidae; Health; Immune; Immune System Diseases; Immune response; Immunotherapy; In Vitro; Infusion procedures; Lead; Link; MAPK3 gene; Mediating; Mesenchymal; Mesenchymal Stem Cells; Miniature Swine; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Natural regeneration; Neural Crest; Osteogenesis; Outcome; Pathway interactions; Pharmacological Treatment; Property; Regulation; Regulatory T-Lymphocyte; Research; Resources; Role; Signal Transduction; Site; Stem cells; T-Lymphocyte; Telomerase; Testing; Th1 Cells; Tooth structure; Tumor Necrosis Factor Ligand Superfamily Member 6; base; bone; craniofacial repair; deciduous tooth; human stem cells; immunoregulation; implantation; improved; in vivo; mouse model; novel; novel therapeutic intervention; orofacial; osteogenic; regenerative; regenerative therapy; repaired; skeletal; stem; stem cell population; tissue regeneration; transcription factor

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.

描述（申请人提供）：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）可用于修复动物模型中的颅骨缺损，但通常用于修复口面部骨缺损的中轴骨和附肢骨的自体移植物往往会导致不利的结果。使用从口面部供体部位获得的移植物来桥接口面部缺陷通常比从非口面部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会影响移植物的整合。人脱落乳牙（SHED）干细胞具有MSC特征，并表现出极高的增殖能力，表明培养扩增少量SHED可以为临床使用提供足够数量的细胞。因此，SHED 将是修复神经嵴相关口面部骨缺损的合适的干细胞资源。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调节。因此，我们的假设是，通过了解端粒酶调节成骨分化和 SHED 免疫调节的机制，可以显着改善基于 SHED 的组织再生。在此应用中，我们将描述端粒酶活性激活改善 SHED 介导的骨再生以修复颅骨缺损的机制。基于端粒酶控制 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。意义：这些研究很可能导致：1）揭示端粒酶相关途径控制 SHED 成骨和免疫调节的新分子机制； 2) 开发新的治疗策略，通过调节受体 T 细胞来突破改善颅骨再生的关键障碍。