仿生心肌纤维化体外模型用于基于力生物学的纤维化发生/扩张机制研究及药物筛选

Cardiac fibrosis occurs mainly due to poor prognosis after myocardial infarction which results in heart failure. However, mechanism of cardiac fibrosis initiation from local obstruction and expansion to large area infarction is still not clear. Meanwhile, there is no clinically effective drug specific for cardiac fibrosis treatment and targeted therapies. Here we will target myofibroblasts (abbreviated MF), which are believed to be the 'culprit' of cardiac fibrosis process, to establish novel biomimetic in vitro pathological model through integration of microfabrication and tissue engineering technologies. We will systematically explore the mechanisms of MF activation in 3D collagen matrix and matrix remodeling as well as fibrosis expansion. Our hypothesis that 'collagen fiber could mediate the cardiac fibrosis expansion through mechanotransduction' is proposed for the first time which will be applied to validate our new theory that the matrix remodeling and stiffness increase is not only the outcome of fibrosis but also the one of the main factors leading to fibrosis expansion. At the same time, we plan to apply this microscale cardiac fibrosis model for high-throughput screening of 1028 FDA-approved drugs to discover potential compounds with inhibitory effect for cardiac fibrosis expansion. The efficacy of the screened compounds will be verified in animal models of cardiac fibrosis. This study will facilitate pathogenesis understanding of cardiac fibrosis during malignant cardiac remodeling and provide new methods and concepts for drug development for prevention and treatment of cardiac fibrosis.

心肌纤维化是心梗发生后因不良预后所导致心衰的主要原因。然而由局部梗阻到大面积梗死过程中心肌纤维化发生和扩张的机制尚不明确，临床上也尚无治疗心肌纤维化的特效药物和针对性治疗方案。本研究计划将围绕心肌纤维化中的“罪魁祸首”肌成纤维细胞（简称MF）通过结合微加工和组织工程技术构建新型体外仿生病理模型；从力生物学的独特视角，系统探究MF在3D胶原基质中的活化过程、其对基质的重塑以及导致纤维化扩张的相关机制。首次提出胶原纤维可通过机械力传导介导心肌纤维化扩张的假设，以验证基质重塑和硬度增强不仅是纤维化的结果，同时是导致纤维化扩张的重要因素这一创新理论。同时将应用此心肌纤维化模型对FDA批准的1028种常见药物进行高通量筛选，以发现潜在对心肌纤维化有抑制效果的化合物，并在心肌纤维化动物模型中验证疗效。本研究有助于理解恶性心脏重塑中心肌纤维化的病理过程，并为开发治疗心肌纤维化相关药物提供新的方法和思路。

项目进行的四年中，依照项目计划的各个方向有序进行，顺利完成了项目计划，在理论和应用层面均取得了较好的成果。其中心肌纤维化体外模型构建、抗纤维化药物测试和胶原纤维介导的旁张力理论的相关工作发表在美国科学院院刊（PNAS）和ACS Biomater。筛选出的具有抗纤维化的两个小分子药物分别完成了两项中国发明专利申请受理。 3D微环境体外模型调控方式发表在自然通讯(Nature Communications)。 相关的体外仿生病理模型构建方法和药物测试手段应用于肿瘤体外模型构建和药敏检测领域发表两篇生物材料（Biomaterials）。