Embryonic stem cell-derived osteoprogenitor cells for bone formation and repair

用于骨形成和修复的胚胎干细胞衍生的骨祖细胞

• 批准号: 7910347
• 负责人: Ross A Kopher
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-03 至 2011-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910347
• 关键词: Adult; American; Arthritis; Back Pain; Bone Development; Bone Diseases; Bone Injury; Bone Regeneration; Bone Tissue; CD34 gene; Cell Line; Cell Therapy; Cells; Craniosynostosis; Derivation procedure; Development; Developmental Therapeutics Program; Disease; Engineering; Experimental Models; Fracture; Genetic; Growth; Hematopoietic; Human; In Vitro; Joints; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; Mesoderm; Modeling; Musculoskeletal; Musculoskeletal Diseases; Osteoblasts; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Pain; Pathway interactions; Population; Proteins; RNA; Reporter; Reporting; Resources; Rodent; Signal Transduction; Source; Stem cells; Testing; Transcript; Translating; Trauma; Undifferentiated; United States; adult stem cell; base; bone; cell type; clinical practice; design; embryonic stem cell; human embryonic stem cell; implantation; in vitro Assay; in vivo; innovation; insight; meetings; novel; novel strategies; novel therapeutic intervention; osteoblast differentiation; osteogenic; osteoprogenitor cell; progenitor; promoter; public health relevance; regenerative therapy; repaired; scaffold; subcutaneous; therapeutic development; tissue regeneration; transcription factor

DESCRIPTION (provided by applicant): Novel therapeutic approaches to treat bone diseases remain a critical medical issue. Diseases such as osteoporosis, osteogenesis imperfecta and craniosynostosis, as well as traumatic bone injury have been treated utilizing cell-based approaches using adult mesenchymal or endothelial progenitor cells. However, results of these studies have been inconclusive, and currently no cell-based treatment utilizing adult progenitor cells has yet translated into routine clinical practice for bone repair. As an important and novel approach, this proposal will test the use of human embryonic stem cells (hESCs) to create an innovative model of bone development and repair. Additionally, these studies of hESC differentiation into osteogenic cells will shed new insights into basic cellular and genetic mechanisms that regulate human osteoblast differentiation. In turn, these studies will provide additional approaches to treat genetic and acquired disorders of bone formation, such as osteogenesis imperfecta and osteoporosis. Previous studies by our group demonstrate hESCs can be routinely supported to differentiate into multiple cellular lineages including hematopoietic and other mesodermal progenitor cells. Here we will test the central hypothesis that hESC-derived CD34+ cells serve as mesoderm progenitor cells with osteogenic potential. Testing this hypothesis will be advanced by developing hESC lines engineered to express fluorescent reporter molecules driven by the RUNX2 promoter to facilitate the identification of key signaling and developmental pathways that mediate the development of osteogenic cells. These cells will also enable subsequent analysis of agents that may be utilized to promote bone formation, as well as the testing of hESC- derived MSCs and more differentiated osteo-progenitor cells in a fracture repair model. This proposal will show that hESCs can efficiently differentiate into osteogenic cells in vitro and in vivo and that they can represent a novel resource for studies of bone repair and development. Public Health Relevance: It is estimated that more than 10 million Americans have osteoporosis, and that 5-10% of all fractures are complicated by delayed union or nonunion, thus indicating that diseases of bone formation represent a serious medical issue. While a variety of cell-based therapies have been tested for bone disorders, there are inherent limitations to the types of cells (principally adult mesenchymal or endothelial progenitor cells) that have been used in the existing experimental models. The derivation and characterization of human embryonic stem cells (hESCs) provides a unique and potentially highly significant advance in understanding the mechanisms pertaining to bone regeneration and the management of these conditions.

描述（由申请人提供）：治疗骨骼疾病的新型治疗方法仍然是一个关键的医学问题。诸如骨质疏松症、成骨不全和颅缝早闭以及创伤性骨损伤的疾病已经利用使用成体间充质或内皮祖细胞的基于细胞的方法来治疗。然而，这些研究的结果尚未得出结论，目前还没有利用成体祖细胞的基于细胞的治疗转化为骨修复的常规临床实践。作为一种重要而新颖的方法，该提案将测试使用人类胚胎干细胞（hESC）来创建骨发育和修复的创新模型。此外，这些hESC分化成骨细胞的研究将为调节人成骨细胞分化的基本细胞和遗传机制提供新的见解。反过来，这些研究将提供额外的方法来治疗骨形成的遗传和获得性疾病，如骨生成障碍和骨质疏松症。我们小组先前的研究表明，hESC可以常规地支持分化成多种细胞谱系，包括造血和其他中胚层祖细胞。在这里，我们将测试的核心假设，hESC衍生的CD 34+细胞作为中胚层祖细胞与成骨潜能。通过开发工程化的人胚胎干细胞系以表达由RUNX 2启动子驱动的荧光报告分子，以促进鉴定介导成骨细胞发育的关键信号传导和发育途径，将进一步验证这一假设。这些细胞还将使得能够随后分析可用于促进骨形成的试剂，以及在骨折修复模型中测试hESC衍生的MSC和更分化的骨祖细胞。这一提议将表明hESCs可以在体外和体内有效地分化为成骨细胞，并且它们可以代表骨修复和发育研究的新资源。 公共卫生相关性：据估计，超过1000万美国人患有骨质疏松症，并且所有骨折中的5-10%并发延迟愈合或不愈合，因此表明骨形成疾病代表严重的医学问题。虽然已经测试了各种基于细胞的疗法用于骨疾病，但在现有实验模型中使用的细胞类型（主要是成体间充质或内皮祖细胞）存在固有的局限性。人胚胎干细胞（hESC）的衍生和表征提供了一个独特的和潜在的非常重要的进展，了解有关骨再生和这些条件的管理机制。