软骨调节素-I调控骨髓基质干细胞体内软骨形成

Due to poor regenerative capacity of cartilage in vivo, the repair of cartilage defects is always a great challenge in surgery therapy.The success of in vitro cartilage regeneration based on bone marrow stem cells(BMSCs) provides a promising approach for cartilage repair.However, the currently BMSC- engineered cartilage in vitro is unsatisfactory for clinical application due to ectopic ossification after subcutaneous implantation.It has been widely reported that endochondral ossification mainly results from angiogenesis and thus anti-angiogenesis becomes the major obstacle for clinical application of the BMSC-engineered cartilage. Chondromodulin-1(ChM-I), one of the anti-angiogenic factors during embryonic chondrogenesis, plays the most important role in maintaining the cartilage stability. But it remains unclear whether ChM-I could modulate the ectopic chondrogenesis in BMSC-based cartilage engineering. Our preliminary study has already showed that the ChM-I expression might be correlated with ectopic angiogenesis of BMSC-engineered cartilage. Based on the preliminary study, this research project will investigate the indispensability of ChM-I during BMSC-based cartilage engineering through the comparison of both in vitro construction and in vivo fate between the ChM-I knockout and widetype mice. Besides, this project includes the further exploration of the related mechanism about the impact of ChM-I on the ectopic chondrogenesis by employing the ChM-I overexpress mice. Furthermore, we will attempt to apply the ChM-I controlled release system in BMSC-based cartilage engineering, which might lay the foundation for the clinical application of cartilage engineering.

由于缺乏理想的软骨移植供体，耳、鼻、气管等非关节部位软骨缺损的修复一直是外科治疗的难题。骨髓基质干细胞(BMSC)体外三维软骨构建的成功，为解决这一难题提供了可能。然而，BMSC再生的软骨在非关节环境中很容易丧失软骨表型和功能，严重阻碍了其向临床应用的转化。究其原因主要与血管化有关，解决问题的关键是抑制血管化。软骨调节素1(ChM-I)是维持软骨表型稳定最重要的抗血管化因子，但ChM-I能否用于调控BMSC异位软骨形成的稳定性尚不清楚。本项目将以预实验证实的ChM-I表达水平与构建软骨体内异位稳定性的关联为依据，通过ChM-I基因敲除及过表达小鼠BMSC构建软骨的体内外系统研究，深入阐明ChM-I调控BMSC体外软骨形成及体内异位稳定性的重要作用与机制，并以此为基础，进一步探讨ChM-I缓释技术提高BMSC构建软骨体内异位稳定性的可行性，以期为基于干细胞的组织工程软骨临床应用奠定基础。

骨髓基质干细胞（BMSC）再生的软骨在非关节环境（异位环境）中容易发生终末骨化，这是干细胞难以用于修复耳、鼻、气管等非关节部位软骨缺损的重要原因。研究证实，血管化是导致干细胞再生软骨异位骨化的关键因素，而软骨调节素1（Chm-I）是维持软骨稳定表型最重要的抗血管化因子。本项目以Chm-I基因敲除小鼠为模型，证实了1）Chm-I基因敲除不影响天然软骨原位发育、软骨细胞体外特性、功能和再生软骨能力，也不影响BMSC体外增殖、分化能力；2）Chm-I基因敲除影响天然软骨和再生软骨的异位稳定性，也影响软骨细胞异位再生软骨能力；3）体外再生软骨的成熟程度能够正向影响其体内异位稳定性，但不能补偿Chm-I缺失造成的影响。上述研究为利用干细胞修复异位软骨缺损提供了理论参考，并且为应用组织再生体系研究基因功能提供了新的研究模型。