从小鼠多能干细胞生成高质量心脏起搏器细胞的新范例。

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zheyi Lin, Bowen Lin, Chengwen Hang, Renhong Lu, Hui Xiong, Junyang Liu, Siyu Wang, Zheng Gong, Mingshuai Zhang, Desheng Li, Guojian Fang, Jie Ding, Xuling Su, Huixin Guo, Dan Shi, Duanyang Xie, Yi Liu, Dandan Liang, Jian Yang, Yi-Han Chen
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引用次数: 0

摘要

心脏生物起搏(BP)是缓性心律失常干预的未来发展方向之一。目前,用于心脏生物起搏的心脏起搏器细胞(PCs)主要来自多能干细胞(PSCs)。然而,如何从多能干细胞制备高质量的心脏起搏器细胞仍是一项挑战。在这里,我们通过采用双PC标记物和模拟PC的发育路线,开发了一种心脏PC分化策略。首先,我们选择了Shox2和Hcn4这两个PC标记物,建立了Shox2:EGFP; Hcn4:mCherry小鼠PSC报告基因系。然后,我们设计了FSK方法,该方法能提高具有典型PC特征的SHOX2+; HCN4+细胞的产量,比类胚体(EB)和单层M10方法分别高出12倍和42倍。此外,通过单细胞RNA测序(scRNA-seq)绘制的体外心脏多核细胞分化轨迹与体内多核细胞发育相似,ZFP503被证实是心脏多核细胞分化的关键调控因子。这些来源于造血干细胞的心脏多核细胞有望推动心脏BP技术的进步,有助于了解多核细胞的(病)生理学,并有利于多核细胞相关疾病的药物研发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells.

A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells.

Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2+; HCN4+ cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.

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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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