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揭示 GSK3β 抑制剂 CHIR99021 诱导人多能干细胞心脏分化效率不一致性的机制

Unraveling the Inconsistencies of Cardiac Differentiation Efficiency Induced by the GSK3β Inhibitor CHIR99021 in Human Pluripotent Stem Cells.

机构信息

Bioprocessing Technology Institute, 20 Biopolis Way, Centros #06-01, Singapore 138668, Singapore.

Bioprocessing Technology Institute, 20 Biopolis Way, Centros #06-01, Singapore 138668, Singapore.

出版信息

Stem Cell Reports. 2018 Jun 5;10(6):1851-1866. doi: 10.1016/j.stemcr.2018.03.023. Epub 2018 Apr 26.

DOI:10.1016/j.stemcr.2018.03.023
PMID:29706502
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5989659/
Abstract

Cardiac differentiation efficiency is hampered by inconsistencies and low reproducibility. We analyzed the differentiation process of multiple human pluripotent stem cell (hPSC) lines in response to dynamic GSK3β inhibition under varying cell culture conditions. hPSCs showed strong differences in cell-cycle profiles with varying culture confluency. hPSCs with a higher percentage of cells in the G1 phase of the cell cycle exhibited cell death and required lower doses of GSK3β inhibitors to induce cardiac differentiation. GSK3β inhibition initiated cell-cycle progression via cyclin D1 and modulated both Wnt signaling and the transcription factor (TCF) levels, resulting in accelerated or delayed mesoderm differentiation. The TCF levels were key regulators during hPSC differentiation with CHIR99021. Our results explain how differences in hPSC lines and culture conditions impact cell death and cardiac differentiation. By analyzing the cell cycle, we were able to select for highly cardiogenic hPSC lines and increase the experimental reproducibility by predicting differentiation outcomes.

摘要

心脏分化效率受到不一致性和低重现性的阻碍。我们分析了多种人类多能干细胞（hPSC）系在不同细胞培养条件下对动态 GSK3β 抑制的分化过程。hPSC 在细胞培养汇合度不同时显示出细胞周期谱的强烈差异。具有更高 G1 期细胞百分比的 hPSC 表现出细胞死亡，并需要较低剂量的 GSK3β 抑制剂来诱导心脏分化。GSK3β 抑制通过细胞周期蛋白 D1 启动细胞周期进程，并调节 Wnt 信号和转录因子（TCF）水平，从而加速或延迟中胚层分化。TCF 水平是 CHIR99021 诱导 hPSC 分化过程中的关键调节剂。我们的结果解释了 hPSC 系和培养条件的差异如何影响细胞死亡和心脏分化。通过分析细胞周期，我们能够选择具有高心脏生成能力的 hPSC 系，并通过预测分化结果来提高实验重现性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/f55e6c2c0404/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/4ffca01b2c3b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/129658bf8d86/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/a3ae4126efbb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/0c7ffe36af91/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/985b97aa6942/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/1e78a8c90e7f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/f55e6c2c0404/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/4ffca01b2c3b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/129658bf8d86/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/a3ae4126efbb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/0c7ffe36af91/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/985b97aa6942/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/1e78a8c90e7f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1499/5989659/f55e6c2c0404/gr7.jpg

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