Decellularized Matrix and Cartilage Regeneration

项目摘要 关节软骨修复仍然是一个挑战，因为缺乏血液供应和伴随 创伤后发炎。尽管自体软骨细胞移植(ACT)是一种选择， 细胞来源的限制阻碍了这种方法在临床上的广泛应用。最近，有越来越多的人 有证据表明，成体干细胞是很有希望的细胞来源，特别是来自 滑膜(SDSCs)，由于其较高的软骨形成潜力和较低的肥厚。细小的活组织检查 关节镜检查只能提供有限数量的自体干细胞用于组织再生，因此细胞的体外扩增 不幸的是，塑料烧瓶上的常规膨胀会导致细胞衰老和 增殖分化能力。我们最近的报告表明，脱细胞的细胞外基质 SDSCs沉积的DECM可促进扩增干细胞的增殖和成软骨潜能。在……里面 这一建议，我们的中心假设是，由SDSCs沉积的DECM可以提供更好的组织特异性 基质微环境对人成体SDSCs软骨再生和再生的影响 缺陷修复。为了实现这一假设，我们想要确定SDSCs存放的dECM是否提供了 与脂肪基质相比，用于成人SDSC年轻化的基质微环境更优越 干细胞(ADSCs)、尿源性干细胞(UDSCs)或真皮成纤维细胞(DFS)(目标1)。我们也 计划通过确定负责以下方面的特定矩阵组件(S)来探索潜在的年轻化机制 关键整合素受体(S)激活对兔成软骨能力的恢复作用 扩大可持续发展服务中心(目标2)。最后，将使用翻译动物模型来评估SDSC/dECM修复 战略(目标3)。我们的目标是确定这种新型细胞扩增系统在提供 大量高质量的SDSCs用于软骨缺损的治疗。这一目标与我们的 长期目标是确定改善骨关节炎患者软骨缺陷修复的策略 使用自体干细胞。我们预期的发现的主要影响将是显著的，不仅是在 促进基于干细胞的新一代软骨工程方法的开发和 再生，而且还提供了关于干细胞之间相互作用的基本新知识 和基质微环境以及干细胞再生的潜在机制 周围的干细胞基质。我们的DECM方法也可能为开发其他 组织再生接近成功。

Project Summary Articular cartilage repair remains a challenge because of the lack of blood supply and accompanying posttraumatic inflammation. Despite the fact that autologous chondrocyte transplantation (ACT) is an option, cell source limitations retard the broad application of this approach clinically. Recently, there is increasing evidence indicating that adult stem cells are promising cell sources, particularly for stem cells derived from synovium (SDSCs), owing to its higher chondrogenic potential and lower hypertrophy. A small biopsy through arthroscopy can only provide a limited number of SDSCs for tissue regeneration, thus in vitro cell expansion is necessary; unfortunately, conventional expansion on plastic flasks causes cell senescence and loss of proliferation and differentiation capacity. Our recent reports indicated that decellularized extracellular matrix (dECM) deposited by SDSCs could enhance expanded stem cells' proliferation and chondrogenic potential. In this proposal, our central hypothesis is that dECM deposited by SDSCs can provide a superior tissue-specific matrix microenvironment for the optimal rejuvenation of human adult SDSCs in cartilage regeneration and defect repair. To achieve this hypothesis, we want to determine whether dECM deposited by SDSCs provides a superior matrix microenvironment for human adult SDSC rejuvenation compared to matrices from adipose- derived stem cells (ADSCs), urine-derived stem cells (UDSCs), or dermal fibroblasts (DFs) (Aim 1). We also plan to explore potential rejuvenation mechanisms by identifying specific matrix component(s) responsible for the rejuvenation of chondrogenic capacity via triggering the activation of critical integrin receptor(s) in expanded SDSCs (Aim 2). Lastly, a translational animal model will be used to evaluate SDSC/dECM repair strategies (Aim 3). Our objective is to determine the efficacy of this novel cell expansion system in providing a high quantity of high-quality SDSCs for the treatment of cartilage defects. This objective is consistent with our long-term goal which is to identify strategies for improved repair of cartilage defects in osteoarthritic patients using autologous stem cells. The primary impact of our expected findings would be significant not only in advancing the development of new generations of stem cell-based approaches for cartilage engineering and regeneration, but also in providing fundamental new knowledge regarding the interaction between stem cell and matrix microenvironment as well as potential mechanisms underlying stem cell rejuvenation by the surrounding stem cell matrix. Our dECM approach may also provide an excellent model for developing other tissue regeneration approaches.