Bone Marrow Stromal Cells in Oral and Craniofacial Tissue Regeneration

描述(申请人提供)：骨再生是非常重要的，特别是在口腔和颅面部区域。创伤，包括口腔和颌面部肿瘤的手术切除，会导致骨骼损伤和损伤。先天性疾病可能带有严重的组织缺陷，干扰正常功能，通常会毁容。这些疾病的最终治疗目标是组织再生到正常或疾病前的状态。我们的长期目标是确定参与牙齿和颅面组织再生的细胞和分子机制，并进一步开发用于骨骼再生和组织工程的产品。这项应用的目的是确定成体干细胞在组织再生中的来源和潜力，并阐明关键的成骨转录因子OSX在骨形成细胞和牙本质形成细胞分化中的作用。需要测试的中心假设是，骨髓来源的细胞能够再生口腔颅面组织，而OSX刺激正常的骨合成代谢行为级联。其理论基础是有证据表明，将骨髓来源的未分化间充质干细胞转化为成熟的、具有功能的成骨和成牙本质母细胞是骨和牙本质形成以及再生的关键步骤。目的1：探讨骨髓基质细胞(BMSCs)在口腔颌面再生术中的分化潜能和组织发生。利用基于细胞的方法，基因标记的BMSCs将被引入口腔、牙科和颅面创伤，并将首次记录活动物中细胞的分化、迁移以及随后的骨和牙本质形成。目的：在体内研究OSX在骨再生和组织工程中促进骨髓间充质干细胞分化的作用及其机制。利用基因治疗策略，OSX将专门针对骨髓和/或局部组织来源的细胞，并将首次在一种新的转基因模型中确定OSX促进细胞分化、促进成骨和牙本质形成的效果。在活体动物身上的这些研究结果将有助于确定新的细胞来源，这是组织工程最重要的元素和最强大的引擎。这些研究还将为使用基因治疗方法对骨和牙齿组织的形成提供新的和重要的见解，这肯定会使口腔和颅面部有组织缺陷、损伤和损伤的患者受益。

DESCRIPTION (provided by applicant): Bone regeneration is of enormous importance, particularly in the oral and craniofacial region. Trauma, including surgical removal of tumors in the oral and maxillofacial region, causes bone damage and injury. Congenital disorders may carry severe tissue defects that interfere with normal function and are often disfiguring. The ultimate therapeutic goal for these diseases is regeneration of the tissues to a normal or pre-disease state. Our long-range goal is to determine the cellular and molecular mechanisms involved in the regeneration of dental and craniofacial tissues and to further the development of products for skeletal regeneration and tissue engineering. The objectives of this application are to determine the source and potential of adult stem cells in tissue regeneration and to elucidate the roles of osterix (Osx), a critical osteogenic transcription factor, in the differentiation of bone- and dentin-forming cells. The central hypotheses to be tested are that marrow-derived cells are capable of regenerating oral craniofacial tissues and Osx stimulates the normal cascade of bone anabolic behavior. The rationale is based on the evidence that the conversion of marrow-derived non-differentiated mesenchymal stem cells into mature and functional osteo- and odonto-blasts is a crucial step in bone and dentin formation, as well as in regeneration. Aim 1: To determine the differentiation potential and histogenesis of bone marrow stromal cells (BMSCs) in oral craniofacial regeneration. Using a cell-based approach, the genetically labeled BMSCs will be introduced into oral, dental and craniofacial wounds and, for the first time, the cell differentiation, migration, and subsequent bone and dentin formation in a live animal will be documented. Aim 2: To determine, in vivo, the effects and mechanisms of Osx in promoting BMSC differentiation in bone regeneration and tissue engineering. Using a gene-therapy strategy, Osx will specifically target the bone- marrow and/or local-tissue derived cells, and for the first time, the effects of Osx promoting cell differentiation and enhancing osteogenesis and dentinogenesis will be determined in a novel transgenic model. Results derived from these studies in live animals will help identify new sources of cells, which are the most important element and most powerful engine for tissue engineering. These investigations will also provide novel and important insights into bone and tooth tissue formation using a gene-therapy approach, which will certainly benefit the patients who have tissue defects, damages and injuries in mouth as well as craniofacial regions.