Facilitating cartilage regeneration by heterogeneous progenitor cells

目前软骨损伤的护理标准不能可靠地提供持续的临床改善，因此 人们对开发替代的生物修复/再生方法很感兴趣。 再生医学方法通常涉及招募或移植内源性 间充质祖细胞(MFC)移植到缺损处。在受控条件下，这些细胞具有 有可能沿着相关的肌肉骨骼谱系增殖、分化和再生受损的骨骼 组织基质。然而，关节内环境可能不利于软骨形成；具体地说， 损伤关节内的炎症会抑制组织再生。局部的关节炎症是由 白介素1和肿瘤坏死因子-a等细胞因子。尽管促炎性细胞因子在 在骨性关节炎的发病机制中起重要作用，但对它们如何影响软骨修复知之甚少。 涉及跨国公司的战略。塑造这个项目的中心假设是炎症继发于关节 创伤或随后的手术干预会抑制软骨内MFC的再生活性。 缺陷，因此限制了修复。在指导阶段，为以下对象开发了报告器构造工具集 监测人类MFC分化的状态，使用这些结构非侵入性地跟踪 免疫受损的大鼠软骨损伤模型中的炎症和软骨形成活性。vt.在.的基础上 过渡到项目的独立阶段，在指导阶段开发的工具将有所帮助 描述手术引起的关节创伤所致的促炎环境，确定 影响软骨形成和缺陷修复的因素。既有免疫能力也有无免疫能力 关节损伤的动物模型将被用来确定MFC修复/再生软骨的能力 不受已确定因素的影响。在这个项目期结束时，我们将更好地了解 关节环境--尤其是炎症信号--如何影响软骨的最终成功 使用异种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.