Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids

The study of cardiac physiology and disease is hindered by physiological differences between humans and small-animal models. Here, we report the generation of multi-chambered vascularized human cardiac organoids under anisotropic stress, and their applicability to study electro-metabolic coupling in cardiac tissue. The organoids are derived from human induced pluripotent stem cells, and integrate sensors for the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. The microphysiological system allowed us to find that 1-Hz cardiac respiratory cycles are coupled with electrical activity rather than with mechanical activity, that calcium oscillations drive a mitochondrial respiration cycle, that the pharmaceutical or genetic inhibition of electro-mitochondrial coupling results in arrhythmogenic behaviour, and that the induction of arrythmia by the chemotherapeutic mitoxantrone can be partially reversed by the co-administration of metformin. Microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance the understanding of cardiac physiology.心脏生理学与疾病的研究常受限于人类与小型动物模型间的生理学差异。本研究报道了在各向异性应力条件下构建多腔室血管化人类心脏类器官的方法，以及该类器官在心脏组织电代谢耦合研究中的应用潜力。该类器官源自人类诱导多能干细胞（human induced pluripotent stem cells），集成了可同时测量氧摄取、细胞外场电位与心脏收缩的传感器，分辨率可达10赫兹以上。借助该微生理系统，本研究取得以下发现：1赫兹的心脏呼吸周期与电活动而非机械活动存在耦合；钙振荡驱动线粒体呼吸周期；电线粒体耦合的药物或遗传抑制会引发致心律失常行为；化疗药物米托蒽醌（mitoxantrone）诱导的心律失常可通过联合施用二甲双胍（metformin）得到部分逆转。此类心脏微生理系统或可进一步推动心脏节律的线粒体动力学研究，并加深人们对心脏生理学的认知。