OSTEOGENIC MECHANISMS OF SHED

棚的成骨机制

• 批准号: 7390379
• 负责人: SONGTAO SHI
• 金额: $ 28.21万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390379
• 关键词: Adipocytes; Autologous; Autologous Transplantation; BMP2 gene; Bone Marrow; Bone Regeneration; Cell Count; Cell Therapy; Cell physiology; Characteristics; Condition; Cultured Cells; Defect; Development; Elements; Fibroblast Growth Factor 2; Gene Expression Profile; Genetic; Growth Factor; Hematopoietic; Human; Immunocompromised Host; In Vitro; Lead; Longevity; Maintenance; Marrow; Mediating; Mesenchymal Stem Cells; Mesoderm; Miniature Swine; Molecular; Molecular Analysis; Mus; Neural Crest Cell; Neurons; Nude Mice; Odontoblasts; One-Step dentin bonding system; Organ; Osteogenesis; Outcome; Parietal; Parietal bone structure; Population; Process; Property; Recovery; Research Personnel; Resources; Retroviridae; Serum; Signal Pathway; Small Interfering RNA; Stem cell transplant; Stem cells; Structure; Surface; Technology; Telomerase; Therapeutic; Tooth structure; Transfection; Translating; Transplantation; Trauma; Virus; base; bone; bone morphogenetic protein 2; cell type; clinical application; craniofacial repair; deciduous tooth; fluorescence activated cell sorter device; genetic manipulation; human TERT protein; human stem cells; improved; in vivo; long bone; novel; orofacial; pre-clinical; programs; repaired; size; tissue regeneration; trait; tumor

DESCRIPTION (provided by applicant): The objective of this application is to understand osteogenic mechanisms of stem cells from human exfoliated deciduous teeth (SHED) as a basis for the development of therapeutic technologies for repairing orofacial bone defects. Autologous grafts from long bones that are commonly used to repair orofacial bone defects often result in unfavorable outcomes, which may be due, in part, to the fact that orofacial and long bones originate from neural crest cells and mesoderm, respectively, and orofacial mesenchymal stem cells show a distinctive differentiation trait from long bone mesenchymal stem cells. Previously, we showed that SHED are capable of differentiating into odontoblasts, adipocytes, and neural cells. However, one of the most distinct characteristics of SHED is their strong osteogenic capacity when transplanted into immunocompromised mice. Our preliminary studies demonstrated that SHED could be utilized to repair critical-size parietal defects in mice, offering an attractive stem cell resource for orofacial bone regeneration. Interestingly, our preliminary studies showed also that SHED has a gene expression profile distinct from that of bone marrow mesenchymal stem cells (BMMSCs), which correspond to the fact that SHED-generated bone structure lacks associated bone marrow elements, as seen in BMMSC transplants. Our hypothesis is that SHED, derived from neural crest cells, possesses a unique osteogenic trait and may be an optimal stem cell resource for repairing orofacial bone defects. In this application, we will examine whether a sub-population of SHED purified according to their surface molecules show superior differentiation and tissue regeneration capacities. We will characterize the distinctive osteogenic trait of SHED, such as how BMP-2 and bFGF regulate SHED-mediated osteogenesis. On the basis of our novel findings on the maintenance of BMMSCs function by telomerase, we examine how to use growth factors to activate telomerase activity in SHED for improving their tissue regeneration capacity. Finally, we develop optimal conditions to expand minipig SHED and utilize them for autologous transplantation to repair parietal defects, which is a necessary pre-clinical step to examine any efficacy and potential challenges before conducting a human SHED trial. Collectively, novel findings from our proposed studies will provide a molecular basis for understanding SHED-mediated bone formation and have important impacts in orofacial bone regeneration.

描述（由申请人提供）：本申请的目的是了解人脱落乳牙（SHED）干细胞的成骨机制，作为开发修复口面部骨缺陷的治疗技术的基础。通常用于修复口面部骨缺损的长骨自体移植物往往会导致不良后果，部分原因可能是口面部和长骨分别起源于神经嵴细胞和中胚层，而口面部间充质干细胞细胞表现出与长骨间充质干细胞独特的分化特征。此前，我们证明 SHED 能够分化为成牙本质细胞、脂肪细胞和神经细胞。然而，SHED 最显着的特征之一是移植到免疫功能低下的小鼠体内时具有很强的成骨能力。我们的初步研究表明，SHED 可用于修复小鼠临界尺寸的顶骨缺损，为口面部骨再生提供有吸引力的干细胞资源。有趣的是，我们的初步研究还表明，SHED 具有与骨髓间充质干细胞 (BMMSC) 不同的基因表达谱，这对应于 SHED 生成的骨结构缺乏相关骨髓元素的事实，如 BMMSC 移植中所见。我们的假设是，源自神经嵴细胞的 SHED 具有独特的成骨特性，可能是修复口面部骨缺损的最佳干细胞资源。在此应用中，我们将检查根据其表面分子纯化的 SHED 亚群是否表现出卓越的分化和组织再生能力。我们将描述 SHED 独特的成骨特征，例如 BMP-2 和 bFGF 如何调节 SHED 介导的成骨。基于端粒酶维持BMMSCs功能的新发现，我们研究如何利用生长因子激活SHED中的端粒酶活性，以提高其组织再生能力。最后，我们开发了扩大小型猪 SHED 的最佳条件，并利用它们进行自体移植来修复顶壁缺陷，这是在进行人类 SHED 试验之前检查任何功效和潜在挑战的必要临床前步骤。总的来说，我们提出的研究的新发现将为理解 SHED 介导的骨形成提供分子基础，并对口面部骨再生产生重要影响。