表观调控活性支架促进肌腱分化的效应和机制研究

Tendon injuries occur frequently during sports and other rigorous physical activities. Due to their limited vascularity, innervation and cellular content, natural healing of tendon tissue is extremely inefficient. For the he lack of knowledge about the regulation mechanism of the tendon differentiation and maturation , tendon stem cells lose the phenotype when cultured in vitro and the regeneration potential for treating the tendon injuries. .Our previous study the divergent differentiation pathways of stem cells, including tendon stem cells(TSPCs) and mesenchymal stem cells (MSCs) and neo-tissue formation trigged by aligned and randomly-oriented fibrous scaffolds, both in vitro and in vivo. The aligned group was observed to form more mature tendon-like tissue in the Achilles tendon injury model. In contrast, the randomly-oriented group exhibited much chondrogenesis and subsequent bone tissue formation through ossification.(Biomaterials, 2010, 2015). Our preliminary experiment showed that the epigenetics regulation, including histone acylation, is involved in the materials induced tenogenesis. We also found that the loss of the phenotype of the TSPC is at least partially caused by HDAC induced de-acylation of the Histone. In this study, we hypothesis that the composite tendon scaffold with the combination of epigenetics regulation small molecular and aligned nano-fibers could promote tendon differentiation and regeneration. .This program based on our pilot studies about histone acylation on tendon stem cells function , interaction between stem cell and biomaterials, aimed to develop a biomimetic scaffold for tendon differentiation and tissue engineering. Firstly, we will determine the effects of epigenetics regulation small molecular inhibitors on maintaining the tendon stem cells phenotype in vitro. Then how does the small molecular inhibitor regulate the tendon stem cells differentiation will be clarified, Secondly, we develop a new practical tendon scaffold that synergistic incorporation of the small molecular inhibitor and aligned nanofibers. We try to explore the synergetic effect of the structure niche and epigenetics regulation on the tendon stem cells. Then, in vivo experiment will be performed to evaluate the utility and efficacy of bioscaffold. In conclusion, this study focus on investigating ideal bio-functional scaffold, which provides an instructive microenvironment and epigenetics regulation for tendon stem cell differentiation to teno-lineage. The exploring the mechanism of epigenetics regulation on tendon stem cell commitment will lead to the development of desirable engineered tendons.

肌腱分化成熟调控知识缺乏导致肌腱干细胞体外培养时表型丢失和肌腱损伤的再生治疗效果不满意。前期研究发现平行纳米纤维决定肌腱干细胞的分化，并在体内决定了干细胞向肌腱成熟的方向（Biomaterials 2010,2015），预实验发现该作用与组蛋白乙酰化等表观调控基因改变有关，且肌腱干细胞体外培养表型丢失及腱系分化与组蛋白乙酰化的表观调控关系密切。因此我们假说小分子复合平行纳米纤维的表观调控活性支架可促进肌腱分化和再生。本课题拟在此基础上结合现有的干细胞生物学、材料工程学和组织工程学手段，筛选表观调控小分子协同平行材料对肌腱干细胞的表型维持与腱系分化作用及机制，并构建复合HDAC小分子抑制剂的平行纳米肌腱支架，评估微环境协同组蛋白表观调控在肌腱干细胞的分化及体内再生的功效性。预期本研究将进一步阐明肌腱干细胞表型维持与腱系分化的分子机制，并为肌腱组织诱导性的功能支架的设计提供实验基础和全新的思路

肌腱分化成熟调控知识缺乏导致肌腱干细胞体外培养时表型丢失和肌腱损伤的再生治疗效果不满意。前期研究发现平行纳米纤维决定肌腱干细胞的分化，并在体内决定了干细胞向肌腱成熟的方向（Biomaterials 2010,2015），预实验发现该作用与组蛋白乙酰化等表观调控基因改变有关，且肌腱干细胞体外培养表型丢失及腱系分化与组蛋白乙酰化的表观调控关系密切。因此我们假说小分子复合平行纳米纤维的表观调控活性支架可促进肌腱分化和再生。本课题拟在此基础上结合现有的干细胞生物学、材料工程学和组织工程学手段，筛选表观调控小分子协同平行材料对肌腱干细胞的表型维持与腱系分化作用及机制，并构建复合HDAC小分子抑制剂的平行纳米肌腱支架，评估微环境协同组蛋白表观调控在肌腱干细胞的分化及体内再生的功效性。预期本研究将进一步阐明肌腱干细胞表型维持与腱系分化的分子机制，并为肌腱组织诱导性的功能支架的设计提供实验基础和全新的思路。