Facilitating cartilage regeneration by heterogeneous progenitor cells

目前的软骨损伤护理标准无法可靠地提供持续的临床改善，因此 人们对开发用于修复/再生的替代性生物方法非常感兴趣。 再生医学方法通常涉及募集或移植内源性 将间充质祖细胞（MFC）移植到缺损部位。在受控条件下，这些细胞具有 增殖、沿着相关肌肉骨骼谱系分化和受损再生的潜力 组织基质然而，关节内环境可能不利于软骨形成;具体而言， 受伤关节内的炎症可抑制组织再生。关节炎症是由局部 细胞因子如白细胞介素-1和肿瘤坏死因子-α。虽然促炎细胞因子在炎症反应中起着重要作用， 骨关节炎的发病机制中的重要作用，很少有人知道他们如何影响软骨修复 涉及MFC的战略。形成这个项目的中心假设是，继发于关节炎的炎症 创伤或随后的手术干预可抑制软骨内MFC的再生活性 缺陷，从而限制修复。在指导阶段，开发了一套报告结构工具， 监测人MFC分化的状态，使用这些构建体来非侵入性地追踪 在软骨损伤的免疫受损大鼠模型中的炎性和软骨形成活性。后 过渡到项目的独立阶段，在指导阶段开发的工具将有助于 表征关节损伤引起的促炎环境， 影响软骨形成和缺损修复的因素。既有免疫功能正常的，也有免疫功能不全的 关节损伤的动物模型将用于确定MFC修复/再生软骨的能力， 保护被识别的因素。在本项目期结束时，我们将更好地了解 关节环境-特别是炎症信号-如何影响软骨的最终成功 使用异质祖细胞群体的再生策略。

Current standards of care for cartilage injuries cannot reliably provide sustained clinical improvement, so there is much interest in the development of alternative, biological approaches towards repair/regeneration. Regenerative medicine approaches typically involve the recruitment or transplantation of endogenous mesenchymal progenitor cells (MFCs) to the defect site. Under controlled conditions, these cells have the potential to proliferate, differentiate along the relevant musculoskeletal lineage and regenerate damaged tissue matrix. However, the intra-articular environment can be hostile to chondrogenesis; specifically, inflammation within the injured joint can inhibit tissue regeneration. Joint inflammation is mediated locally by cytokines such as interleukin-1 and tumor necrosis factor-a. Although proinflammatory cytokines play an important role in the pathogenesis of osteoarthritis, little is known about how they affect cartilage repair strategies involving MFCs. The central hypothesis shaping this project is that inflammation secondary to joint trauma or subsequent surgical intervention can inhibit the regenerative activity of MFCs within the cartilage defect, thus limiting repair. During the mentored phase, a toolset of reporter constructs were developed for monitoring the state of human MFC differentiation, using these constructs to non-invasively track inflammatory and chondrogenic activity within an immunocompromised rat model of cartilage injury. Upon transition to the independent phase of the project, tools developed during the mentored phase will help characterize the proinflammatory environment resulting from surgically-induced joint trauma, identifying factors that impair chondrogenesis and defect repair. Both immunologically-competent and -incompetent animal models of joint injury will be used to determine the ability of MFCs to repair/regenerate cartilage when protected from the identified factors. At the end of this project period, we will have a better understanding of how the joint environment - particularly inflammatory signaling - impacts the ultimate success of cartilage regeneration strategies using heterogeneous progenitor cell populations.