Cartilage Repair with Synovial Joint Precursors

描述（由申请人提供）： 关节软骨覆盖关节表面，在正常活动时吸收和传递机械力。鉴于其较差的愈合能力和软骨疾病（包括骨关节炎）的高发病率，对基于细胞的修复策略存在日益增长的迫切需求。我们的团队在创建3D合成微环境方面取得了相当大的进展，在该微环境中，细胞可以存款软骨细胞外基质（ECM）并成熟为功能性工程软骨。这些研究采用了与基于软骨ECM（透明质酸（HA））的水凝胶偶联的成人骨髓来源的间充质干细胞（MSC）。尽管我们在这一领域取得了进展，但这些构建体的临床使用仍然存在一些障碍。这些包括发现MSC不能产生与天然特性匹配的工程化组织，不能完全采用软骨细胞表型，并且此外对体内不需要的表型转变敏感（即，进展为骨样表型）。然而，我们团队最近的研究已经确定了一组新的祖细胞，它们负责胚胎中的滑膜关节形成，与形成骨的祖细胞不同，并作为祖细胞库在关节软骨中持续存在。我们假设这些滑膜关节形成祖细胞具有上级和独特的生成软骨的能力，并且可以用于工程化和再生具有天然关节相关性质的软骨。为了验证这一假设，我们将开发用于细胞分离和扩增的新方法，将在3D培养中评估该细胞群体（相对于MSC）的分化和稳定性，并将在大型动物缺损模型中泰特它们在体内形成功能性软骨的转化功效。在本申请中，我们通过两个目的探索滑膜关节祖细胞的转化潜力。如果成功，这项工作将开发一种独特的滑膜祖细胞来源，并验证这种细胞类型在长期转化研究中的功效。这项工作有可能通过改善软骨修复手术后的患者结局来改变临床实践

DESCRIPTION (provided by applicant): ABSTRACT Cartilage covers the joint surface and absorbs and transmits mechanical forces during normal activity. Given its poor healing capacity and the high incidence of cartilage disease including osteoarthritis, there exists a growing and urgent demand for cell-based repair strategies. Our group has made considerable progress in the creation of 3D synthetic microenvironments in which cells can deposit cartilage extracellular matrix (ECM) and mature into functional engineered cartilage. These studies have employed adult bone marrow derived mesenchymal stem cells (MSCs) coupled with hydrogels based on cartilage ECM (hyaluronic acid (HA)). Despite our progress in this area, several impediments remain in the clinical use of these constructs. These include the finding that MSCs fail to produce engineered tissues that match native properties, fail to fully adopt the chondrocyte phenotype, and are furthermore susceptible to unwanted phenotypic transitions in vivo (i.e., progress to a bone-like phenotype). However, recent studies by our team have identified a novel cohort of progenitor cells that are responsible for synovial joint formation in the embryo, are distinct from progenitors that form bone, and persist within articular cartilage as a progenitor pool. We hypothesize that these synovial joint- forming progenitor cells have a superior and unique capacity to generate cartilage and can be used to engineer and regenerate cartilage with native joint-associated properties. To test this hypothesis, we will develop new methods for cell isolation and expansion, will evaluate differentiation and stability of this cell population (relative to MSCs) in 3D culture, and will tet their translational efficacy in forming functional cartilage in vivo in a large animal defect model In this application, we explore the translational potential of synovial joint progenitor cells throgh two Aims. If successful, this work will develop a unique synovial progenitor cell source and validate the efficacy of this cell type in long-term translational studies. This work has the potential to alter clinical practice by improving patient outcomes after cartilage repair surgeries