Rupert Cassady E, Kim Tae Yun, Choi Bum-Rak, Coulombe Kareen L K
Center for Biomedical Engineering, School of Engineering and Division of Biology and Medicine, Brown University, Providence, RI, USA.
Cardiovascular Research Center, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Stem Cells Int. 2020 Jul 16;2020:9363809. doi: 10.1155/2020/9363809. eCollection 2020.
Cardiac tissue engineering using hiPSC-derived cardiomyocytes is a promising avenue for cardiovascular regeneration, pharmaceutical drug development, cardiotoxicity evaluation, and disease modeling. Limitations to these applications still exist due in part to the need for more robust structural support, organization, and electromechanical function of engineered cardiac tissues. It is well accepted that heterotypic cellular interactions impact the phenotype of cardiomyocytes. The current study evaluates the functional effects of coculturing adult human cardiac fibroblasts (hCFs) in 3D engineered tissues on excitation and contraction with the goal of recapitulating healthy, nonarrhythmogenic myocardium in vitro. A small population (5% of total cell number) of hCFs in tissues improves tissue formation, material properties, and contractile function. However, two perturbations to the hCF population create disease-like phenotypes in engineered cardiac tissues. First, increasing the percentage of hCFs to 15% resulted in tissues with increased ectopic activity and spontaneous excitation rate. Second, hCFs undergo myofibroblast activation in traditional two-dimensional culture, and this altered phenotype ablated the functional benefits of hCFs when incorporated into engineered cardiac tissues. Taken together, the results of this study demonstrate that human cardiac fibroblast number and activation state modulate electromechanical function of hiPSC-cardiomyocytes and that a low percentage of quiescent hCFs are a valuable cell source to advance a healthy electromechanical response of engineered cardiac tissue for regenerative medicine applications.
利用人诱导多能干细胞衍生的心肌细胞进行心脏组织工程，是心血管再生、药物研发、心脏毒性评估和疾病建模的一个有前景的途径。这些应用仍存在局限性，部分原因是工程化心脏组织需要更强大的结构支持、组织和机电功能。异型细胞相互作用会影响心肌细胞的表型，这一点已得到广泛认可。本研究评估了在三维工程组织中共培养成人心脏成纤维细胞（hCFs）对兴奋和收缩的功能影响，目的是在体外重现健康、无致心律失常的心肌。组织中少量的hCFs（占总细胞数的5%）可改善组织形成、材料特性和收缩功能。然而，对hCF群体的两种干扰会在工程化心脏组织中产生疾病样表型。首先，将hCFs的百分比增加到15%会导致组织的异位活动和自发兴奋率增加。其次，hCFs在传统二维培养中会发生肌成纤维细胞活化，当将这种改变的表型纳入工程化心脏组织时，会消除hCFs的功能益处。综上所述，本研究结果表明，人心脏成纤维细胞的数量和活化状态可调节人诱导多能干细胞衍生心肌细胞的机电功能，并且低百分比的静止hCFs是促进工程化心脏组织健康机电反应以用于再生医学应用的宝贵细胞来源。
