胚胎干细胞肝向分化的力学-生物学耦合规律及其分子机制研究

The coupling of biochemical and mechanical signals determine embryonic stem cells (ESCs) differentiation. It remains unknown, however, how the mechanical factors (especially the characterized mechanical microenvironment of hepatic sinusoids) regulate the directed differentiation of ESCs to hepatocytes. This project attempts to address the scientific issue how mechanical environment modulates the differentiation from ESCs to hepatocyte. The specific aim is to quantify the impact and rule of substrate stiffness and topology on ESCs differentiation. A novel approach that coordinates the stiffness-topology coupling assay, the mechanically-controllable ESCs culture and differentiation system, cell adhesion dynamics and real-time dynamic observation technology is developed. Dynamics and molecular mechanisms of how substrate stiffness and topology affect the ESCs differentiation are studied to further the understandings of mechano-biological coupling of ESCs differentiation. The results enlighten new idea and methods in clinical liver disease treatment.

生物化学和力学环境的协同作用是影响干细胞分化的关键因素，然而力学因素（尤其是基于肝血窦特殊力学微环境）调控胚胎干细胞的肝向分化知之甚少。本项目以力学微环境调控胚胎干细胞肝向分化为科学问题，以基底硬度和拓扑结构等力学因素影响胚胎干细胞分化的规律及动力学为有限目标，拟建立耦合基底硬度和拓扑结构效应的新方法及力学可控的胚胎干细胞培养和分化新体系，结合细胞黏附动力学、实时动态观测技术研究基底硬度和拓扑结构对胚胎干细胞分化的影响规律及其分子调控机制，深化对胚胎干细胞分化力学-生物学耦合规律认识的同时为临床肝病治疗提供新的思路和方法。

生物化学和力学环境的协同作用是影响干细胞分化的关键因素，然而力学因素（尤其是基于肝血窦特殊力学微环境）调控胚胎干细胞的肝向分化知之甚少。本项目以力学微环境调控胚胎干细胞肝向分化为科学问题，以基底硬度和拓扑结构等力学因素影响胚胎干细胞分化的规律及动力学为目标，开展以下研究：1）不同硬度或/和拓扑结构基底的制备及检测；建立不同硬度或/和拓扑结构基底表面胚胎干细胞的黏附、生长及肝向分化方法。2）基底硬度及拓扑结构对胚胎干细胞黏附、生长及肝向分化独立或耦合影响规律研究。3）基底硬度及拓扑结构对胚胎干细胞肝向分化影响的重要分子机制研究。4）在真实空间微重力条件下干细胞的肝向分化及其分子机制方面进行了拓展研究。项目顺利完成预定目标，发表标注项目编号的SCI论文4篇，EI论文1篇，其他论文1篇，正在整理3篇；授权发明专利1项；参编著作章节2章；协助指导毕业博士生2名。