Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, 30332, United States.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, 30332, United States; School of Chemistry and Biochemistry, School of Chemical and Biological Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, United States.
Biomaterials. 2022 Apr;283:121421. doi: 10.1016/j.biomaterials.2022.121421. Epub 2022 Feb 18.
Autologous cardiac cell therapy is a promising treatment for combating the right ventricular heart failure (RVHF) that can occur in patients with congenital heart disease (CHD). However, autologous cell therapies suffer from low cell retention following injection and patient-to-patient variability in cell quality. Here, we demonstrate how computational methods can be used to identify mechanisms of cardiac-derived c-Kit cell (CPC) reparative capacity and how biomaterials can be designed to improve cardiac patch performance by engaging these mechanisms. Computational modeling revealed the integrin subunit α (ITGAV) as an important mediator of repair in CPCs with inherently low reparative capacity (CPCs). We could engage ITGAV on the cell surface and improve reparative capacity by culturing CPCs on electrospun polycaprolactone (PCL) patches coated with fibronectin (PCL + FN). We tested CPCs from 4 different donors and found that only CPCs with high ITGAV expression (patient 956) had improved anti-fibrotic and pro-angiogenic paracrine secretion on PCL + FN patches. Further, knockdown of ITGAV via siRNA led to loss of this improved paracrine secretion in patient 956 on PCL + FN patches. When implanted in rat model of RVHF, only PCL + FN + 956 patches were able to improve RV function, while PCL +956 patches did not. In total, we demonstrate how cardiac patches can be designed in a patient-specific manner to improve in vitro and in vivo outcomes.
自体心脏细胞疗法是治疗先天性心脏病（CHD）患者发生的右心室心力衰竭（RVHF）的一种有前途的方法。然而，自体细胞疗法在注射后细胞保留率低，且患者间细胞质量存在差异。在这里，我们展示了如何使用计算方法来确定心脏源性 c-Kit 细胞（CPC）修复能力的机制，以及如何设计生物材料通过利用这些机制来改善心脏补片的性能。计算模型揭示了整合素亚基 α（ITGAV）是固有修复能力低的 CPC 修复的重要介质。我们可以通过在涂有纤维连接蛋白（PCL + FN）的静电纺聚己内酯（PCL）补片上培养 CPC 来在细胞表面上结合 ITGAV，从而提高修复能力。我们测试了来自 4 个不同供体的 CPC，并发现只有具有高 ITGAV 表达的 CPC（患者 956）在 PCL + FN 补片上具有改善的抗纤维化和促血管生成旁分泌分泌。此外，通过 siRNA 敲低 ITGAV 会导致患者 956 在 PCL + FN 补片上这种改善的旁分泌分泌丧失。当植入 RVHF 大鼠模型中时，只有 PCL + FN + 956 补片才能改善 RV 功能，而 PCL + 956 补片则不能。总的来说，我们展示了如何以患者特异性的方式设计心脏补片，以改善体外和体内结果。
