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抗坏血酸诱导 MLC2v 蛋白表达并促进人诱导多能干细胞衍生的心肌细胞向心室样心肌细胞亚型分化。

Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes.

机构信息

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.

Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

出版信息

Theranostics. 2023 Jul 3;13(11):3872-3896. doi: 10.7150/thno.80801. eCollection 2023.

DOI:10.7150/thno.80801
PMID:37441603
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10334833/
Abstract

The potentially unlimited number of cardiomyocyte (CMs) derived from human induced pluripotent stem cells (hiPSCs) facilitates high throughput applications like cell transplantation for myocardial repair, disease modelling, and cardiotoxicity testing during drug development. Despite promising progress in these areas, a major disadvantage that limits the use of hiPSC derived CMs (hiPSC-CMs) is their immaturity. : Three hiPSC lines (PCBC-hiPSC, DP3-hiPSCs, and MLC2v-mEGFP hiPSC) were differentiated into CMs (PCBC-CMs, DP3-CMs, and MLC2v-CMs, respectively) with or without retinoic acid (RA). hiPSC-CMs were either maintained up to day 30 of contraction (D30C), or D60C, or purified using lactate acid and used for experiments. Purified hiPSC-CMs were cultured in basal maturation medium (BMM) or BMM supplemented with ascorbic acid (AA) for 14 days. The AA treated and non-treated hiPSC-CMs were characterized for sarcomeric proteins (MLC2v, TNNI3, and MYH7), ion channel proteins (Kir2.1, Nav1.5, Cav1.2, SERCA2a, and RyR), mitochondrial membrane potential, metabolomics, and action potential. Bobcat339, a selective and potent inhibitor of DNA demethylation, was used to determine whether AA promoted hiPSC-CM maturation through modulating DNA demethylation. AA significantly increased MLC2v expression in PCBC-CMs, DP3-CMs, MLC2v-CMs, and RA induced atrial-like PCBC-CMs. AA treatment significantly increased mitochondrial mass, membrane potential, and amino acid and fatty acid metabolism in PCBC-CMs. Patch clamp studies showed that AA treatment induced PCBC-CMs and DP3-CMs adaptation to a ventricular-like phenotype. Bobcat339 inhibited MLC2v protein expression in AA treated PCBC-CMs and DP3-CMs. DNA demethylation inhibition was also associated with reduced TET1 and TET2 protein expressions and reduced accumulation of the oxidative product, 5 hmC, in both PCBC-CMs and DP3-CMs, in the presence of AA. Ascorbic acid induced MLC2v protein expression and promoted ventricular-like CM subtype in hiPSC-CMs. The effect of AA on hiPSC-CM was attenuated with inhibition of TET1/TET2 mediated DNA demethylation.

摘要

从人类诱导多能干细胞（hiPSC）中获得的潜在无限数量的心肌细胞（CMs）促进了高通量应用，例如用于心肌修复的细胞移植、疾病建模和药物开发过程中的心脏毒性测试。尽管在这些领域取得了有希望的进展，但限制 hiPSC 衍生的 CMs（hiPSC-CMs）使用的一个主要缺点是它们的不成熟。：使用三种 hiPSC 系（PCBC-hiPSC、DP3-hiPSCs 和 MLC2v-mEGFP hiPSC）在有无视黄酸（RA）的情况下分化为 CMs（PCBC-CMs、DP3-CMs 和 MLC2v-CMs）。hiPSC-CMs 要么在收缩第 30 天（D30C）之前保持培养，要么在第 60 天（D60C）之前保持培养，要么使用乳酸进行纯化后用于实验。纯化的 hiPSC-CMs 在基础成熟培养基（BMM）或补充有抗坏血酸（AA）的 BMM 中培养 14 天。对经 AA 处理和未经处理的 hiPSC-CMs 进行肌节蛋白（MLC2v、TNNI3 和 MYH7）、离子通道蛋白（Kir2.1、Nav1.5、Cav1.2、SERCA2a 和 RyR）、线粒体膜电位、代谢组学和动作电位的特征分析。Bobcat339 是一种选择性和有效的 DNA 去甲基化抑制剂，用于确定 AA 是否通过调节 DNA 去甲基化来促进 hiPSC-CM 成熟。AA 显著增加了 PCBC-CMs、DP3-CMs、MLC2v-CMs 和 RA 诱导的心房样 PCBC-CMs 中 MLC2v 的表达。AA 处理显著增加了 PCBC-CMs 的线粒体质量、膜电位以及氨基酸和脂肪酸代谢。膜片钳研究表明，AA 处理诱导 PCBC-CMs 和 DP3-CMs 适应心室样表型。Bobcat339 抑制了 AA 处理的 PCBC-CMs 和 DP3-CMs 中 MLC2v 蛋白的表达。DNA 去甲基化抑制也与 TET1 和 TET2 蛋白表达的减少以及 AA 存在时 PCBC-CMs 和 DP3-CMs 中氧化产物 5 hmC 的积累减少有关。抗坏血酸诱导 MLC2v 蛋白表达并促进 hiPSC-CMs 中的心室样 CM 亚型。AA 对 hiPSC-CM 的影响在 TET1/TET2 介导的 DNA 去甲基化抑制时减弱。

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