Meniscus Regeneration by Endogenous Stem/Progenitor Cells

内源干/祖细胞的半月板再生

• 批准号: 8697945
• 负责人: LISA A FORTIER
• 金额: $ 101.24万
• 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/8697945
• 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; 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; public health relevance; 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(申请人提供)：半月板是位于股骨远端和胫骨平台之间的半月形楔形纤维软骨结构。 膝关节。半月板在关节接合、减震和应力传递中起着不可或缺的作用。半月板损伤不会自发愈合。临床上，美国每年有100多万患者接受半月板切除术。同种异体身体半月板移植是临床上主要的半月板切除替代物，但存在供体短缺、病原体传播、免疫排斥和组织错配等问题。半月板切除，无论有没有同种异体移植，充其量是减轻疼痛，但显著增加以后生活中骨关节炎的发生率。到2020年，总共将有6700万美国人罹患关节炎。毫不奇怪，膝关节半月板的再生是骨科医学中一个有抱负的目标，但遇到了多重障碍。目前还没有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了解不足，半月板细胞被称为纤维软骨细胞，其起源和谱系起源尚不清楚。我们的初步数据表明，1)在体外和体内诱导纤维软骨细胞所必需的和充分的两种重组人生长因子的逐步诱导下，纤维软骨细胞从成体干/祖细胞分化而来；2)在临床前模型中，这两种生长因子的时空释放诱导了多相纤维软骨组织在解剖学上正确的生物支架中重新形成，以取代体内部分切除的膝关节半月板。宿主内源性细胞被招募到解剖正确的微孔支架中，并在再生半月板组织的外区主要产生I型胶原，在内区产生II型胶原，在中间区产生I型和II型混合胶原。这项建议的总体目标是在我们现有的临床前半月板再生模型中优化宿主内源性细胞的招募和分化为纤维软骨细胞的策略，而不是细胞移植。我们的主要假设是，特定生物活性信号的时空传递调节了内源性细胞(包括干细胞/祖细胞)向半月板再生的募集和纤维软骨分化。对于间盘、肌腱-骨交界处和颞下颌关节的纤维软骨缺损，尚无再生疗法。计划中的研究将确定对半月板再生至关重要的纤维软骨细胞群，并可能对其他纤维软骨结构的再生产生影响。计划中的细胞募集策略可能适用于其他组织的再生。