Association of Human iPSC Gene Signatures and X Chromosome Dosage with Two Distinct Cardiac Differentiation Trajectories
Association of Human iPSC Gene Signatures and X Chromosome Dosage with Two Distinct Cardiac Differentiation Trajectories
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DOI：
10.1016/j.stemcr.2019.09.011
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发表时间：
2019-11-12
影响因子：
5.9
通讯作者：
Frazer, Kelly A.
中科院分区：
文献类型：
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作者：
D'Antonio-Chronowska, Agnieszka;Donovan, Margaret K. R.;Frazer, Kelly A.
尽管了解非遗传因素（克隆和传代）引起的诱导多能干细胞（iPSC）系的变异性如何影响其分化结果非常重要，但尚未进行能够解决这一问题的大规模研究。在这里，我们分化了191个iPSC系以产生iPSC衍生的心血管祖细胞（iPSC-CVPC）。我们观察到iPSC-CVPC样品中的细胞异质性，这是由于两种细胞类型的分数不同：心肌细胞（CM）和心外膜衍生细胞（EPDC）。比较CM-命运和EPDC-命运的iPSC的转录组，我们发现91个特征基因和X染色体剂量差异与这两种不同的心脏发育轨迹相关。在一组独立的39个分化为CM的iPSC中，我们证实了性别和转录差异影响心脏命运结果。我们的研究为iPSC转录和X染色体基因剂量差异如何影响其对分化刺激的反应以及心脏细胞命运提供了新的见解。
Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate.