体细胞转录组启动子赋予人诱导多能干细胞状态的谱系特异性分化潜能。

Somatic transcriptome priming gates lineage-specific differentiation potential of human-induced pluripotent stem cell states.

机构信息

McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1200 Main Street West, MDCL 5029, Hamilton, Ontario, Canada L8N 3Z5.

1] McMaster Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, 1200 Main Street West, MDCL 5029, Hamilton, Ontario, Canada L8N 3Z5 [2] Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

出版信息

Nat Commun. 2014 Dec 3;5:5605. doi: 10.1038/ncomms6605.

DOI:10.1038/ncomms6605

PMID:25465724

Abstract

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.

摘要

人类诱导多能干细胞（hiPSCs）为再生医学提供了宝贵的资源，但受到高效谱系特异性分化的限制。在这里，我们发现源自人成纤维细胞（Fibs）和人脐血（CB）的 hiPSCs 表现出相同的多能性，但具有偏向性的分化倾向。源自 Fib 或 CB 的 iPSCs 中与胚层特化相关的基因是相同的，而谱系特异性标记则在 hiPSCs 分化诱导时出现，这与起始细胞的来源有关。分化倾向是以牺牲其他谱系为代价的，并且不能通过诱导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 甲基化和独特的组蛋白修饰与谱系特异性转录组的启动有关，但将 hiPSCs 转变为原始的多能状态会消除 iPSC 记忆的转录组。当重新进入初始状态时，转录组记忆被恢复，表明存在一种人类特有的现象，即谱系门控的发育潜能不会被永久抹去，而是可以通过多能状态进行调节。