Meniscus Regeneration by Endogenous Stem/Progenitor Cells

内源干/祖细胞的半月板再生

• 批准号: 9145633
• 负责人: LISA A FORTIER
• 金额: $ 94.46万
• 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/9145633
• 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; 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）：半月板是股骨远端和楔形的半节和楔形的纤维软骨结构， 膝关节。半月板在关节一致性，减震和应力传播中扮演着必不可少的角色。半月板伤害不会自发治愈。在临床上，在美国，每年有超过一百万的患者进行半月板切除术。从尸体移植的同种异体移植是切除的半月板的主要临床替代品，但患有供体短缺，病原体传播，免疫注射和组织不对。半月板切除术，有或没有同种异体移植移植，充其量可以减轻疼痛，但大大增加了骨关节炎的发生率。到2020年，总共有6700万美国人将遭受亲身关节炎。毫不奇怪，膝盖弯面条的再生是骨科医学中有抱负的目标，但遇到了多个障碍。目前没有针对半月板伤害的再生疗法。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，即纤维软骨细胞的起源和谱系衍生物的了解很少。我们的初步数据表明，1）纤维软骨细胞是通过逐步诱导源自成年茎/祖细胞的，具有两个重组人的生长因子，这些因子既需要且足以在体外和体内诱导纤维软骨细胞。 2）这两个生长因子的时空释放在解剖学上正确的生物符号中诱导的多相纤维纤维组织的从头形成，在临床前模型中替代了在体内部分切除的膝盖弯面条。将宿主内源性细胞募集到解剖上正确的微孔支架中，并主要在外部区域产生I型胶原蛋白，在内部区域内的II型胶原蛋白，并在再生孟虫组织中间区的I型和II型胶原蛋白中混合。该提案的总体目标是优化募集宿主内源细胞的策略，并在我们现有的拟曲板弯板再生模型中分化为纤维软骨细胞，而无需细胞移植。我们的总体假设是，特定生物活性提示的时空传递调节内源性细胞（包括茎/祖细胞）的内源性细胞的募集和纤维显基分化，朝着半月板再生。在椎间盘，肌腱 - 骨连接和颞下颌关节中，没有用于纤维球缺损的再生疗法。计划的研究将确定纤维软骨细胞的群体对弯月面的再生至关重要，并且可能对其他纤维球杆菌结构的再生有影响。计划的细胞募集策略可能适用于其他组织的再生。