Cartilage Repair with Synovial Joint Precursors

描述(由申请人提供)： 摘要软骨覆盖关节表面，在正常活动中吸收和传递机械力。鉴于其较差的愈合能力和包括骨关节炎在内的软骨疾病的高发病率，对基于细胞的修复策略的需求日益增长和迫切。我们的团队在创造3D合成微环境方面取得了长足的进展，在这个微环境中，细胞可以沉积软骨细胞外基质(ECM)并成熟为功能工程软骨。这些研究使用了成人骨髓间充质干细胞(MSCs)和基于软骨ECM(透明质酸(HA))的水凝胶。尽管我们在这一领域取得了进展，但在这些结构的临床应用中仍然存在一些障碍。这些发现包括：MSCs未能产生与天然特性匹配的工程化组织，未能完全采用软骨细胞的表型，而且更容易在体内发生不必要的表型转变(即进展为骨样表型)。然而，我们团队最近的研究发现了一组新的前体细胞，它们负责胚胎中滑膜关节的形成，与形成骨的前体细胞不同，并作为祖细胞池持续存在于关节软骨中。我们推测，这些滑膜关节形成的祖细胞具有优越而独特的软骨生成能力，可以用于工程和再生具有天然关节相关特性的软骨。为了验证这一假设，我们将开发新的细胞分离和扩增方法，评估该细胞群(相对于MSCs)在3D培养中的分化和稳定性，并在大型动物缺损性模型中测试其在体内形成功能性软骨的翻译效率。在这一应用中，我们从两个方面探索滑膜关节前体细胞的翻译潜力。如果成功，这项工作将开发出一种独特的滑膜祖细胞来源，并在长期的翻译研究中验证这种细胞类型的有效性。这项工作有可能通过改善软骨修复手术后患者的预后来改变临床实践。

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