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过表达 HCN4 增强人多能干细胞源性心肌细胞的起搏功能。

Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes.

机构信息

Department of Cardiovascular Medicine, Okayama University Hospital, Okayama, Japan.

Department of Cardiovascular Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, 700-8558, Kita-ku, Okayama, Japan.

出版信息

Stem Cell Res Ther. 2022 Apr 1;13(1):141. doi: 10.1186/s13287-022-02818-y.

DOI:10.1186/s13287-022-02818-y
PMID:35365232
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8973792/
Abstract

BACKGROUND

The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells.

METHODS

Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared.

RESULTS

HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and β adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs.

CONCLUSIONS

Overexpression of HCN4 showed enhancement of I current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker.

摘要

背景

随着人口老龄化和心脏病患者数量的增加，患有缓心律失常和心脏起搏器患者的数量也在增加。一些植入心脏起搏器的患者会出现起搏器感染和电磁干扰引起的不便等问题。我们已经报道过，在鼠胚胎干细胞衍生的心肌细胞中过表达产生起搏电流的 HCN 通道可增强体外和体内的起搏功能。本研究旨在确定在人诱导多能干细胞衍生的心肌细胞（iPSC-CMs）中过表达 HCN4 是否可以增强细胞的起搏功能。

方法

通过核转染将人 HCN4 转导至人诱导多能干细胞的 AAVS1 基因座，并生成 HCN4 过表达的 iPSC-CMs。比较 HCN4 过表达和非过表达的 iPSC-CMs 的基因表达谱、自发收缩频率和体外起搏能力。

结果

HCN4 过表达的 iPSC-CMs 比非过表达的 iPSC-CMs 具有更高的自发收缩频率。它们对 HCN 通道阻滞剂和β肾上腺素刺激有反应。与亲本 iPSC 系衍生的心肌细胞相比，HCN4 过表达的 iPSC-CMs 的起搏率也更高。

结论

HCN4 的过表达增强了 iPSC-CMs 中的 I 电流、自发放电和起搏功能。这些数据表明，这种转基因细胞系可用作心脏起搏器。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/3bd3c9710331/13287_2022_2818_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/b1e096c5b97d/13287_2022_2818_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/4f2955499681/13287_2022_2818_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/b3ed34fa53a2/13287_2022_2818_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/be9bebabe451/13287_2022_2818_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/cf4509fff29f/13287_2022_2818_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/3bd3c9710331/13287_2022_2818_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/b1e096c5b97d/13287_2022_2818_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/4f2955499681/13287_2022_2818_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/b3ed34fa53a2/13287_2022_2818_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/be9bebabe451/13287_2022_2818_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/cf4509fff29f/13287_2022_2818_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a27/8973792/3bd3c9710331/13287_2022_2818_Fig6_HTML.jpg

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