Perelman School of Medicine, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Boulevard, 11-101, Philadelphia, PA, 19104, USA.
Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
J Cardiovasc Transl Res. 2023 Aug;16(4):828-841. doi: 10.1007/s12265-022-10348-4. Epub 2023 Mar 6.
Engineered cardiac microtissues were fabricated using pluripotent stem cells with a hypertrophic cardiomyopathy associated c. 2827 C>T; p.R943x truncation variant in myosin binding protein C (MYBPC3). Microtissues were mounted on iron-incorporated cantilevers, allowing manipulations of cantilever stiffness using magnets, enabling examination of how in vitro afterload affects contractility. MYPBC3 microtissues developed augmented force, work, and power when cultured with increased in vitro afterload when compared with isogenic controls in which the MYBPC3 mutation had been corrected (MYPBC3(ed)), but weaker contractility when cultured with lower in vitro afterload. After initial tissue maturation, MYPBC3 CMTs exhibited increased force, work, and power in response to both acute and sustained increases of in vitro afterload. Together, these studies demonstrate that extrinsic biomechanical challenges potentiate genetically-driven intrinsic increases in contractility that may contribute to clinical disease progression in patients with HCM due to hypercontractile MYBPC3 variants.
使用与肥厚型心肌病相关的突变型肌球蛋白结合蛋白 C (MYBPC3) c.2827 C>T; p.R943x 截断变体的多能干细胞，构建了工程化的心脏微组织。将微组织安装在铁掺入的悬梁上，使用磁铁操纵悬梁的刚度，从而可以检查体外后负荷如何影响收缩性。与 MYBPC3 突变已被纠正的同基因对照相比（MYPBC3(ed)），在体外后负荷增加时培养的 MYPBC3 微组织表现出增强的力、功和功率，但在体外后负荷较低时培养的收缩性较弱。在组织初始成熟后，MYPBC3 CMT 对体外后负荷的急性和持续增加均表现出增强的力、功和功率。这些研究表明，外在生物力学挑战增强了遗传驱动的内在收缩性增加，这可能导致肥厚型心肌病患者由于肌球蛋白结合蛋白 C 变体的高收缩性而导致临床疾病进展。
