Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states
Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states
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DOI：
10.1038/ncomms6605
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发表时间：
2014-12-01
影响因子：
16.6
通讯作者：
Bhatia, Mickie
中科院分区：
文献类型：
--
作者：
Lee, Jong-Hee;Lee, Jung Bok;Bhatia, Mickie
人类诱导的多能干细胞（hiPSC）为再生医学提供了宝贵的来源，但受到熟练的谱系特异性分化的限制。在这里，我们揭示了来源于人成纤维细胞（Fibs）与人脐带血（CB）的hiPSC表现出不可区分的多能性，但具有偏向分化的倾向。与胚层特化相关的基因在Fib-or CB-derived iPSC中是相同的，而谱系特异性标记在hiPSC的分化诱导后出现，其与起源细胞相关。分化倾向是以牺牲其他谱系为代价的，并且不能用替代细胞命运的刺激来克服。尽管谱系特异性基因座的不完全DNA甲基化和不同的组蛋白修饰与谱系特异性转录组引发相关，但将hiPSC转变为多能性的幼稚状态去除了iPSC记忆的转录组。在重新进入致敏状态时，转录组记忆恢复，表明人类特异性现象，由此谱系门控发育潜能不会被永久消除，而是可以通过多能状态调节。
Human-induced pluripotent stem cells (hiPSCs) provide an invaluable source for regenerative medicine, but are limited by proficient lineage-specific differentiation. Here we reveal that hiPSCs derived from human fibroblasts (Fibs) versus human cord blood (CB) exhibit indistinguishable pluripotency, but harbour biased propensities for differentiation. Genes associated with germ layer specification were identical in Fib-or CB-derived iPSCs, whereas lineage-specific marks emerge upon differentiation induction of hiPSCs that were correlated to the cell of origin. Differentiation propensities come at the expense of other lineages and cannot be overcome with stimuli for alternative cell fates. Although incomplete DNA methylation and distinct histone modifications of lineage-specific loci correlate to lineage-specific transcriptome priming, transitioning hiPSCs into naive state of pluripotency removes iPSC-memorized transcriptome. Upon re-entry to the primed state, transcriptome memory is restored, indicating a human-specific phenomenon whereby lineage gated developmental potential is not permanently erased, but can be modulated by the pluripotent state.