非共价键调控水凝胶性能维持MSCs的干性及其在心肌梗死治疗中的应用

Maintaining the stemness and paracrine effects of mesenchymal stem cells (MSCs) are essential for the treatment of myocardial infarction. Although a large number of literatures have devoted on regulating the differentiation of stem cells through biomaterial properties, there are few conclusions on how to maintain the stemness of stem cells. In vivo, MSCs maintain their stemness by dynamically regulating the extracellular matrix and communicating with the surrounding cells. With respect to the challenging scientific issue that is how to maintain the stemness of MSCs and improve the curative effects of myocardial infarction, an injectable hydrogel system with dynamic mechanical properties and controllable biodegradation, which possesses the similar properties with extracellular matrix, is proposed with the incorporation of non-covalent interactions and matrix metalloproteinases sensitive peptides. This project would markedly broaden the new approaches to construct biomimetic hydrogel systems, and explore the internal mechanisms on regulating the stemness and paracrine effects of MSCs by dynamic mechanical properties and biodegradation behavior of a hydrogel. The electrical signal propagation could be improved in the infarcted myocardium by injection the hydrogels incorporating conductive polymers, and material factors underling the curative effects of myocardial infarction by MSCs would be figured out. The stem cells/injectable hydrogel system favoring the therapy of myocardial infarction would be developed by this project, which would provide theoretical basis and biomaterial reservoir for stem cell therapy of myocardial infarction in the future clinical applications.

间充质干细胞(MSCs)的干性维持及旁分泌效应对其心梗治疗效果是至关重要的。虽然大量研究实现了通过材料性能调控干细胞分化，但对生物材料性能如何影响干细胞干性的报道较少，也未形成定论。在生物体内，MSCs通过动态调控其细胞外基质及感受干细胞之间相互作用实现其干性维持。针对如何维持MSCs干性及改善其心梗疗效的科学问题，本项目拟通过引入非共价键和基质金属蛋白酶敏感肽段仿生构建具有动态力学性能及降解可控的可注射水凝胶体系，拓展仿生构建功能化可注射水凝胶新途径，阐明水凝胶动态力学性能及降解行为调控MSCs干性及旁分泌效应的内在机制；通过引入导电聚合物改善心梗区电信号传导，明确MSCs在心梗区实现其功能的材料学影响因素，开发具有良好治疗效果的干细胞/可注射水凝胶体系，为临床上干细胞心梗治疗提供理论基础和材料储备。

虽然通过手术介入治疗能疏通堵塞的血管，但再灌注会给损伤心肌组织带来新的应激伤害，无法改变受损心肌组织的预后。再生医学策略为恢复受损心脏功能及诱导心肌再生开辟了新的途径。本项目完成以下三个方面的系列创新性研究成果：(1) 针对移植干细胞在心梗区存活率低，治疗效果有待提高的瓶颈问题，创建了水凝胶、干细胞/外泌体复合体系，显著提高心肌损伤治疗效果；(2) 针对心梗病灶区病变微环境及血运不足的病理特征，本项目构建了多种载药可注射水凝胶系统，明确设计体系对受损心肌的治疗性作用；(3) 拓展了生物相容性良好的超支化聚合物合成制备技术，发展了非公价键弱相互作用力增强型多功能生物贴片，并探索其生物医学应用。本项目基于上述研究内容，在执行期间围绕心肌组织修复及再生相关研究内容发表基金标注SCI论文14篇，申请中国发明专利9项（授权5项），项目负责人获得2019年度第九届中国组织工程与再生医学优秀青年研究奖，项目负责人会议邀请报告6次，培养硕士研究生9人，博士研究生3人。本项目拓宽了生物材料构建途径、探索了生物材料/干细胞结合策略重建心肌功能的新方法，为组织损伤治疗提供材料学及技术储备。