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）：本申请旨在开发软骨修复的新治疗方法，从而降低退行性关节疾病的发病率和死亡率。目前的软骨修复策略都没有产生能够满足体内对该组织的功能需求的持久的透明软骨替代组织。我假设人类多能干细胞 (PSC) 衍生的软骨祖细胞 (ChPC) 或 ChPC 的前体细胞可能比成人关节软骨细胞和成人间充质干细胞在再生医学中具有更大的潜力，基于其软骨形成承诺、谱系潜力和增殖能力。此外，我建议需要进行研究来识别和表征人类软骨形成的各个阶段，以确保从 PSC 中成功生成和分离相同的 ChPC。因此，本研究的总体目标是确定从多能中胚层祖先产生 ChPC 的阶段，最终目标是产生在再生医学中具有最高应用潜力的 ChPC。我们课题组最近报道了人类 PSC 分化过程中产生的最早的胚胎中胚层祖细胞 (EMP)。 EMP 是更多谱系限制的间充质祖细胞（成骨和软骨祖细胞）、血液内皮和心血管祖细胞的祖先。我将使用这个新的 EMP 群体来概括胚胎间质生成、软骨形成以及最终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初级 ChPC 进行了试点免疫表型表征。结合原代和诱导 PSC (iPSC) 衍生 ChPC 群体的体外研究，异种移植动物模型和体内生物发光成像将用于以下具体目标，以研究 iPSC 衍生 ChPC 在再生医学中的应用潜力。该申请由 Denis Evseenko 博士提交，他是发育和干细胞生物学领域的研究人员，其目标是转型为独立研究人员。作为职业发展的一部分，他将接受软骨生物学和骨关节炎异种移植模型新领域的培训。此外，该提案还概述了 NIH 资助的 UCLA 的 K30 项目的课程工作以及其他培训活动，这些活动将帮助 Denis 增加知识基础、提高资助写作技巧和执行转化临床研究的能力。该申请得到了加州大学洛杉矶分校骨科研究医院的大力支持。加州大学洛杉矶分校骨科外科研究部副主席兼骨科医院研究中心主任 John Adams 博士将担任该申请的主要导师。总之，该应用程序不仅有助于解决软骨形成领域的当前和长期科学问题，而且有助于 Evseenko 博士的职业发展成为一名成功的独立研究员。