Generation of human chondroprogenitor cells for cartilage restoration

用于软骨修复的人类软骨祖细胞的产生

• 批准号: 8304960
• 负责人: DENIS EVSEENKO
• 金额: $ 11.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304960
• 关键词: Address; Adult; Affect; Animal Model; Arthritis; Biology; Bioluminescence; Bone Marrow; Cardiovascular system; Cartilage; Cartilage injury; Cells; Chondrocytes; Chondrogenesis; Clinical Research; Clinical Research Curriculum Award; Data; Degenerative polyarthritis; Development; Dexamethasone; Dinoprostone; Embryo; Embryonic Development; Erinaceidae; Exogenous Factors; FGF2 gene; Funding; Gene Expression Profile; Generations; Goals; Grant; Health Sciences; Hospitals; Human; Hyaline Cartilage; Hypoxia; Image; In Vitro; Insulin-Like Growth Factor I; Joints; Luciferases; Mechanics; Mentors; Mesenchymal Stem Cells; Mesenchyme; Molecular Profiling; Morbidity - disease rate; Orthopedic Surgery procedures; Orthopedics; Outcome; Pluripotent Stem Cells; Population; Regenerative Medicine; Relative (related person); Reporting; Research; Research Personnel; Staging; Surface; Surface Antigens; Telomerase; Testing; Tissues; Training; Training Activity; Transforming Growth Factor beta; Tretinoin; United States; United States National Institutes of Health; Work; Writing; Xenograft Model; Xenograft procedure; articular cartilage; base; bone; career development; cartilage cell; cartilage regeneration; cartilage repair; design; early embryonic stage; improved; in vivo; induced pluripotent stem cell; innovation; knowledge base; lipid mediator; luminescence; meetings; mortality; novel; novel therapeutic intervention; osteogenic; progenitor; regenerative; repaired; restoration; skills; stem cell biology; stem cell differentiation

DESCRIPTION (provided by applicant): This application is designed to develop new therapeutic approaches for cartilage restoration, which in turn will reduce morbidity and mortality from degenerative joint disease. None of the current cartilage repair strategies has generated long lasting hyaline cartilage replacement tissue that meets functional demands placed upon this tissue in vivo. I hypothesize that human pluripotent stem cell (PSC) derived chondroprogenitor cells (ChPC) or the precursors of ChPC may have greater potential for use in regenerative medicine than adult articular chondrocytes and adult mesenchymal stem cells based on their chondrogenic commitment, lineage potential and proliferative ability. Further I propose that studies to identify and characterize the stages of human chondrogenesis are needed to insure successful generation and isolation of identical ChPC from PSC. Thus, the overall goal of the proposed study is to define the stages through which ChPC are generated from multipotent mesodermal ancestors, with the ultimate objective of producing ChPC with the highest potential for use in regenerative medicine. Our group has recently reported the earliest embryonic mesodermal progenitor (EMP) produced during human PSC differentiation. EMPs are ancestors of more lineage restricted mesenchymal progenitor cells (osteo- and chondrogenic), hematoendothelial and cardiovascular progenitors. I will use this novel EMP population to recapitulate early stages of embryonic mesenchyme generation, chondrogenesis and eventually, articular cartilage formation. I also carried out pilot immunophenotypical characterization of primary ChPC at early stages of human embryogenesis. In combination with in vitro studies of primary and induced PSC (iPSC)-derived ChPC populations, a xenograft animal model and in vivo bioluminescence imaging will be utilized in the following specific aims to study the potential of iPSC-derived ChPC for use in regenerative medicine. This application is submitted by Dr. Denis Evseenko, an investigator in the field of developmental and stem cell biology whose objective is to transition into an independent researcher. As part of his career development he will receive training in the new fields of cartilage biology and xenograft models of osteoarthritis. In addition this proposal outlines the course work through the NIH funded K30 program at UCLA and other training activities that will help Denis to increase his knowledge base and improve his grant writing skills and ability to execute translational clinical research. This application is strongly supported by the Orthopedic Research Hospital at UCLA. Dr John Adams who is a Vice Chair of Research Department of Orthopedic Surgery and Director of Orthopedic Hospital Research Center at UCLA will act as a primary mentor for this application. In summary, this application will serve not only to address immediate and long term scientific questions in the field of chondrogenesis, but also the career development of Dr Evseenko into a successful independent researcher.

描述（由申请人提供）：本申请旨在开发用于软骨恢复的新治疗方法，这反过来又将降低退行性关节疾病的发病率和死亡率。当前的软骨修复策略都没有产生持久的透明软骨置换组织，该组织满足了在体内对该组织的功能需求。我假设人类多能干细胞（PSC）衍生的软骨元素细胞（CHPC）或CHPC的前体可能比成人关节软骨细胞和成人间质干细胞具有更大的再生医学使用潜力，其基于其软骨蛋白的承诺，线层的潜力和增殖能力。此外，我建议需要研究和表征人软骨发生阶段的研究，以确保成功地产生和分离与PSC相同的CHPC。因此，拟议的研究的总体目标是定义从多能中胚层祖先产生CHPC的阶段，其最终目标是生产CHPC具有最高使用再生医学潜力的CHPC。我们的小组最近报道了人类PSC分化过程中最早的胚胎中胚层祖细胞（EMP）。 EMP是谱系限制性限制性间充质祖细胞（骨和软骨生成），血红素内皮和心血管祖细胞的祖先。我将使用这种新的EMP种群来概括胚胎间充质产生，软骨发生以及最终是关节软骨形成的早期阶段。我还在人类胚胎发生的早期阶段对原代CHPC进行了试点免疫表征。结合对原代和诱导PSC（IPSC）衍生的CHPC种群的体外研究，异种移植动物模型和体内生物发光成像将在以下具体目的中使用，以研究IPSC衍生的CHPC在再生药物中使用的潜在。该应用是由发育和干细胞生物学领域的研究者丹尼斯·埃文科（Denis Evseenko）提交的，其目的是过渡到独立的研究人员。作为他职业发展的一部分，他将在软骨生物学和骨关节炎的异种移植模型的新领域接受培训。此外，该提案还概述了UCLA的NIH资助K30计划和其他培训活动的课程工作，这将有助于丹尼斯提高其知识库并提高他的赠款写作能力和执行翻译临床研究的能力。该应用程序得到了UCLA骨科研究医院的强烈支持。约翰·亚当斯（John Adams）博士是骨科外科研究系副主席，UCLA骨科医院研究中心主任将担任此应用程序的主要导师。总而言之，该应用程序不仅可以解决软骨发生领域的直接和长期科学问题，而且还将解决Evseenko博士的职业发展，成为一名成功的独立研究人员。