Meniscus Regeneration by Endogenous Stem/Progenitor Cells

内源干/祖细胞的半月板再生

• 批准号: 8838048
• 负责人: LISA A FORTIER
• 金额: $ 98.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838048
• 关键词: Adult; Allografting; American; Animal Model; Arthritis; Biomedical Engineering; Bone Marrow; Cadaver; Cell Culture Techniques; Cell Differentiation process; Cell Separation; Cell Transplantation; Cells; Clinical; Collagen; Collagen Type I; Collagen Type II; Cues; Data; Defect; Degenerative polyarthritis; Derivation procedure; Distal; Femur; Fibrocartilages; Flow Cytometry; Goals; Growth Factor; Healed; Health; Histology; Human; Immunohistochemistry; In Vitro; Incidence; Incubated; Injury; Intervertebral disc structure; Joints; Knee; Knee joint; Knowledge; Leg Bones; Life; Magnetic Resonance; Mechanics; Medicine; Meniscus structure of joint; Mesenchymal; Mesenchymal Stem Cells; Natural regeneration; Orthopedics; Pain; Patients; Phenotype; Play; Population; Pre-Clinical Model; Property; Proteins; Recombinants; Recruitment Activity; Research Project Grants; Resected; Resort; Rheumatoid Arthritis; Risk; Role; Sampling; Shapes; Sheep; Shock; Source; Stem cells; Stress; Structure; Surface; Synovial Membrane; Temporomandibular Joint; Tendon structure; Testing; Thigh structure; Time; Tissues; Transforming Growth Factors; Transplantation; Trauma; United States; absorption; bone; computerized; connective tissue growth factor; efficacy testing; healing; in vivo; meetings; pathogen; regenerative therapy; response; scaffold; spatiotemporal; stem; tibia; transmission process

DESCRIPTION (provided by applicant): The meniscus is a semi-lunar and wedge-shaped fibrocartilaginous structure between the distal femoral condyle and the proximal tibial plateaus in the knee joint. Meniscus plays indispensable roles in joint congruence, shock absorption, and stress transmission. Meniscus injuries do not heal spontaneously. Clinically, over one million patients undergo meniscectomy each year in the United States. Allograft transplantation from cadavers is the primary clinical substitute of resected meniscus, but suffers from donor shortage, pathogen transmission, immunorejection and tissue mis-match. Meniscectomy, with or without allograft transplantation, alleviates pain at best, but significantly increases the incidence of osteoarthritis later in life. By 2020, a total of 67 million Americans will suffer fro arthritis. Not surprisingly, regeneration of knee meniscus is an aspiring goal in orthopedic medicine, but has encountered multiple barriers. No regenerative therapies exist for meniscus injuries at this time. One of the critical barriers of meniscus regeneration is our insufficient knowledge of meniscus cells, known as fibrochondrocytes whose origin and lineage derivation are poorly understood. Our preliminary data demonstrate that 1) fibrochondrocytes were derived from adult stem/progenitor cells by step-wise induction with two recombinant human growth factors that are both necessary and sufficient for induction of fibrochondrocytes in vitro and in vivo; 2) spatiotemporal release of these two growth factors induced de novo formation of multiphase fibrocartilage tissues in anatomically correct bioscaffolds that replaced partially resected knee meniscus in vivo in a preclinical model. Host endogenous cells were recruited into anatomically correct, microporous scaffolds and produced primarily type I collagen in the outer region, type II collagen in the inner region and blended type I and II collagens in the intermediate zone of the regenerated meniscus tissues. The overall objectives of this proposal are to optimize strategies for the recruitment of host endogenous cells and differentiation into fibrochondrocytes in our existing pre-clinical model of meniscus regeneration, without cell transplantation. Our overarching hypothesis is that spatiotemporal delivery of specific bioactive cues regulates the recruitment and fibrochondrogenic differentiation of endogenous cells, including stem/progenitor cells, towards meniscus regeneration. No regenerative therapies exist for fibrocartilage defects in intervertebral disks, tendon-bone junction and the temporomandibular joint. The planned studies will identify fibrochondrocyte populations that are pivotal for meniscus regeneration, and may have implications for the regeneration of other fibrocartilage structures. The planned cell recruitment strategies may be applicable in the regeneration of other tissues.

描述（由申请人提供）：半月板是股骨远端髁和胫骨近端平台之间的半月形楔形纤维软骨结构， 膝关节。半月板在关节贴合、减震、应力传递等方面起着不可或缺的作用。半月板损伤不会自行愈合。临床上，在美国每年有超过一百万的患者接受直肠癌切除术。同种异体尸体半月板移植是临床上主要的半月板替代物，但存在供体短缺、病原体传播、免疫排斥和组织配型不匹配等问题。半月板切除术，伴或不伴同种异体移植，最多减轻疼痛，但会显著增加日后骨关节炎的发病率。到2020年，共有6700万美国人将患有关节炎。毫不奇怪，膝关节半月板的再生是骨科医学的一个有抱负的目标，但遇到了多重障碍。目前还没有针对半月板损伤的再生疗法。半月板再生的关键障碍之一是我们对半月板细胞的认识不足，半月板细胞被称为纤维软骨细胞，其起源和谱系来源知之甚少。我们的初步数据表明：1）纤维软骨细胞是通过两种重组人生长因子逐步诱导成人干/祖细胞而产生的，这两种生长因子对于体外和体内诱导纤维软骨细胞都是必要且足够的;（二）这两种生长因子的时空释放诱导在解剖学上正确的生物支架中重新形成多相纤维软骨组织，在临床前模型中的体内。宿主内源性细胞被招募到解剖学上正确的微孔支架中，并主要在外部区域产生I型胶原，在内部区域产生II型胶原，并在再生半月板组织的中间区产生混合的I型和II型胶原。该提案的总体目标是优化策略，在我们现有的半月板再生临床前模型中，无需细胞移植，即可招募宿主内源性细胞并分化为纤维软骨细胞。我们的首要假设是，时空传递特定的生物活性线索调节的招聘和纤维软骨分化的内源性细胞，包括干/祖细胞，对半月板再生。对于椎间盘、肌腱-骨连接和颞下颌关节中的纤维软骨缺损，没有再生疗法。计划中的研究将确定纤维软骨细胞群是半月板再生的关键，并可能对其他纤维软骨结构的再生产生影响。计划的细胞募集策略可能适用于其他组织的再生。