材料微环境对细胞直接重编程的影响及作用机制

The direct lineage reprogramming, i.e., the direct induction of functional cell types without passing through an intermediate pluripotent stage, has become an important new strategy and direction for the development of cellular reprogramming techniques. The process, however, still faces the main challenges to improve both the induction efficiency and the functional maturation of the converted cells. The matrix itself, a critical microenvironment for the cells, has demonstrated a critical modulation effect on stem cell differentiation into a specific lineage and on transcription. This project aims to make a piloting study on how the material microenvironment affects the direct lineage reprogramming. First, we systematically compare the effect of matrixes on the direct reprogramming of fibroblasts into different functional cells, such as neural cells, cardiomyocytes, chondrocytes, and osteobalsts. In particular, we study how the physical and chemical microenvironments of the matrixes affect the direct lineage reprogramming process and its underlying mechanisms, through modulating the chemical and physical properties of the matrixes. This study aims to elucidate the key factors and molecular mechanisms for the direct induction of the specific functional cell types, and to improve the induction efficiency and biological functions of the converted cells. This project might provide an insight for our understanding on the molecular mechanism of the cellular reprogramming, and provide a new strategy for improving the direct cellular reprogramming, which have important implications in both fundamental science and clinical potential of cellular reprogramming.

细胞直接重编程，即将体细胞直接诱导转化为特定功能细胞，有望降低致癌风险，成为重编程技术的一个最新发展方向和趋势。但这种技术面临转化效率相对低下及诱导转化的功能细胞的扩增能力受到严重限制的挑战。基质材料本身，作为一个关键的细胞微环境，可直接调控干细胞分化命运及显著影响细胞转录。本课题将对材料微环境对直接重编程的影响及作用机制进行前期探索性的研究,比较不同基质材料对体细胞向神经、心肌、骨和软骨细胞重编程的影响，明确基质材料与特定转录因子调控直接重编程之间有无协同作用。进一步通过对材料化学及物理性质的调控深入研究材料物理及化学微环境对直接重编程进程的影响及分子机制，及诱导转化为特定功能细胞的关键因素，以通过材料的选择及优化设计提高转化功能细胞的增殖等生物学功能及转化效率。本研究将增进我们对直接重编程进程中分子机制的了解，为改善直接重编程提供一个有效的新途径，具有良好的科学意义及临床应用前景。

细胞直接重编程，即将体细胞直接诱导转化为特定功能细胞，有望降低致癌风险，成为重编程技术的一个最新发展方向和趋势。但这种技术面临转化效率相对低下及诱导转化的功能细胞的扩增能力受到严重限制的挑战。基质材料本身，作为一个关键的细胞微环境，可直接调控干细胞分化命运及显著影响细胞转录。我们采用胶原-PAM水凝胶模拟骨细胞生态位的微环境特征，深入研究材料物理及化学微环境对直接重编程进程的影响及分子机制，及诱导转化为特定功能细胞的关键因素，以通过材料的选择及优化设计提高转化功能细胞的增殖等生物学功能及转化效率。结果表明，在水凝胶底物上培养的细胞在第2天增强了成骨转录因子的表达，并提高了部分成骨样细胞的产量。机制分析表明水凝胶通过骨架传导力学信号，继而影响细胞核转录因子的表达。本研究将增进我们对直接重编程进程中分子机制的了解，为改善直接重编程提供一个有效的新途径，具有良好的科学意义及临床应用前景。