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修改的mRNA基因编辑揭示了人类诱导多能干细胞衍生的心肌细胞中基于sarcomere的基因表达调节

Yuqing Huang¹, Yueyang Zhang², Ze Wang²

¹Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

International immunopharmacology

|October 18, 2024

概括

化学修饰的mRNA (modRNA) 能够在人类多能干细胞衍生心肌细胞 (hPSC-CMs) 中进行高效的基因组编辑. 这种方法精确地准了sarcomere基因,揭示了它们在心脏功能和基因调节中的关键作用.

科学领域:

心血管生物学心血管生物学
干细胞生物学干细胞生物学
分子遗传学分子遗传学

背景情况:

遗传性心肌病是源于sarcomere基因的突变.
使用人类多能干细胞 (hPSC) 建模这些疾病,通常需要在分化之前进行基因组编辑.
在早期分化过程中区分突变效应与终端心肌细胞功能仍然是一个挑战.

研究的目的:

在hPSC衍生心肌细胞 (hPSC-CMs) 中开发一种高效,特定阶段的基因组编辑方法.
调查萨尔科默尔基因突变对心肌细胞结构,功能和基因表达的影响.
利用RNA技术在心脏分化过程中进行精确的基因改造.

主要方法:

使用化学修饰的mRNA (modRNA) 和合成的单导向RNA进行CRISPR/Cas9基因组编辑.
在hPSC-CMs.中对TNNT2基因 (心脏中多素T) 的向突变发生.
评估了 sarcomere 结构,收缩功能,氧化酸化基因表达和心脏应激标志物 (NPPA,NPPB).

主要成果:

在hPSC-CM中成功对TNNT2进行基于modRNA的CRISPR/Cas9编辑.
诱导了瘤细胞的分解和受损的收缩功能.
观察到氧化酸化基因的下调和NPPA和NPPB心脏压力标志物的上调.

结论:

瘤体在hPSC-CMs.中调节基因表达方面发挥着关键作用.
基于RNA的基因组编辑是hPSC分化过程中特定阶段的基因修饰的强大工具.
这项技术有助于精确建模遗传性心肌病变和心脏病变的发生.

关键词:

基因编辑CRISPR/Cas9基因编辑心脏中的热素T T.心肌病是一种心肌病.人类诱导的多能干细胞衍生的心肌细胞.经过修改的mRNA.

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