Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes.
Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes.
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DOI：
10.1038/s41598-021-83398-4
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发表时间：
2021-02-24
影响因子：
4.6
通讯作者：
Tung L
中科院分区：
文献类型：
--
作者：
Kostecki GM;Shi Y;Chen CS;Reich DH;Entcheva E;Tung L
心肌成纤维细胞和肌细胞之间的相互作用可能会减慢传导速度并在纤维化过程中产生自发搏动，从而增加危及生命的心律失常的机会。虽然共培养研究表明肌成纤维细胞可以在体外影响心肌细胞电生理学，但合胞体中肌成纤维细胞-肌细胞电导的程度尚不清楚。在这项新生大鼠研究中，用视紫红质通道蛋白 2 转导心脏肌成纤维细胞，使肌成纤维细胞电流急剧选择性增加，并将其铺在心肌细胞顶部。光学测绘显示，当共培养物中，传导速度（− 27 ± 6%，p < 10–3）、上冲频率（− 13 ± 4%，p = 0.002）和动作电位持续时间（− 14 ± 7%，p = 0.004）显着降低。应用 0.017 mW/mm2 光，6/7 个样本出现局灶性自发搏动，并且在 0.057 mW/mm2 光下循环长度缩短（− 36 ± 18%，p = 0.002）。实验的计算机模拟再现了实验结果，并表明实验中使用的光水平产生了与内源性肌成纤维细胞电流相似的过量电流。将模型与实验数据进行拟合，预测肌成纤维细胞和心肌细胞之间 3-D 界面的组织级电导为 ~ 5 nS/心肌细胞，并显示了肌成纤维细胞-肌细胞电导的增加、肌成纤维细胞/肌细胞电容比的增加以及纤维化过程中肌成纤维细胞电流的增加如何协同作用，从而产生促心律失常的传导和自发性搏动增加。
Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the extent of myofibroblast-myocyte electrical conductance in a syncytium is unknown. In this neonatal rat study, cardiac myofibroblasts were transduced with Channelrhodopsin-2, which allowed acute and selective increase of myofibroblast current, and plated on top of cardiomyocytes. Optical mapping revealed significantly decreased conduction velocity (− 27 ± 6%, p < 10–3), upstroke rate (− 13 ± 4%, p = 0.002), and action potential duration (− 14 ± 7%, p = 0.004) in co-cultures when 0.017 mW/mm2 light was applied, as well as focal spontaneous beating in 6/7 samples and a decreased cycle length (− 36 ± 18%, p = 0.002) at 0.057 mW/mm2 light. In silico modeling of the experiments reproduced the experimental findings and suggested the light levels used in experiments produced excess current similar in magnitude to endogenous myofibroblast current. Fitting the model to experimental data predicted a tissue-level electrical conductance across the 3-D interface between myofibroblasts and cardiomyocytes of ~ 5 nS/cardiomyocyte, and showed how increased myofibroblast-myocyte conductance, increased myofibroblast/myocyte capacitance ratio, and increased myofibroblast current, which occur in fibrosis, can work in tandem to produce pro-arrhythmic increases in conduction and spontaneous beating.
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影响因子：
4.6
作者：
Piek A;de Boer RA;Silljé HH
通讯作者：
Silljé HH
影响因子：
10.8
作者：
Askar, Said F. A.;Ramkisoensing, Arti A.;Pijnappels, Daniel A.
通讯作者：
Pijnappels, Daniel A.
影响因子：
4
作者：
De Simone, Stefano Andrea;Moyle, Sarah;Rohr, Stephan
通讯作者：
Rohr, Stephan
影响因子：
14
作者：
Blazeski A;Kostecki GM;Tung L
通讯作者：
Tung L
DOI：
10.1152/ajpheart.00148.2020
发表时间：
2020-11-01
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
--
作者：
Li W;Han JL;Entcheva E
通讯作者：
Entcheva E