Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload
Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload
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DOI：
10.1038/s41551-018-0280-4
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发表时间：
2018-12-01
影响因子：
28.1
通讯作者：
Healy, Kevin E.
中科院分区：
文献类型：
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作者：
Ma, Zhen;Huebsch, Nathaniel;Healy, Kevin E.
体外心脏组织模型、人诱导多能干细胞（hiPSC）和基因组编辑工具的整合允许增强生理表型的询问和疾病病理的再现。在此，使用由丝状三维基质组成的心脏组织模型，所述丝状三维基质填充有源自健康野生型（WT）hiPSC的心肌细胞，（WT hiPSC-CM）或肌节蛋白心肌肌球蛋白结合蛋白C缺陷的同基因hiPSC（MYBPC 3（-/-）hiPSC-CM），我们表明WT微组织适应机械环境，具有与基质刚度相称的增加的收缩力，而MYBPC 3（-/-）微组织表现出与基质硬度无关的受损的力发展动力学，并且仅当在具有高纤维硬度的基质上生长时才表现出收缩力不足。在机械过载下，MYBPC 3（-/-）微组织具有更高程度的钙瞬时异常，并表现出钙动力学的加速衰减以及钙脱敏，当对较硬的纤维收缩时加速。我们的研究结果表明，MYBPC 3缺陷和环境压力的存在协同导致心脏组织收缩缺陷。
The integration of in vitro cardiac tissue models, human induced pluripotent stem cells (hiPSCs) and genome-editing tools allows for the enhanced interrogation of physiological phenotypes and recapitulation of disease pathologies. Here, using a cardiac tissue model consisting of filamentous three-dimensional matrices populated with cardiomyocytes derived from healthy wild-type (WT) hiPSCs (WT hiPSC-CMs) or isogenic hiPSCs deficient in the sarcomere protein cardiac myosin-binding protein C (MYBPC3(-/-) hiPSC-CMs), we show that the WT microtissues adapted to the mechanical environment with increased contraction force commensurate to matrix stiffness, whereas the MYBPC3(-/-)microtissues exhibited impaired force development kinetics regardless of matrix stiffness and deficient contraction force only when grown on matrices with high fibre stiffness. Under mechanical overload, the MYBPC3(-/-) microtissues had a higher degree of calcium transient abnormalities, and exhibited an accelerated decay of calcium dynamics as well as calcium desensitization, which accelerated when contracting against stiffer fibres. Our findings suggest that MYBPC3 deficiency and the presence of environmental stresses synergistically lead to contractile deficits in cardiac tissues.