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MicroRNA Profiling Reveals Distinct Mechanisms Governing Cardiac and Neural Lineage-Specification of Pluripotent Human Embryonic Stem Cells

机译：MicroRNA分析揭示了具有多能人胚胎干细胞的心脏和神经谱系的明显机制

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Realizing the potential of human embryonic stem cells (hESCs) has been hindered by the inefficiency and instability of generating desired cell types from pluripotent cells through multi-lineage differentiation. We recently reported that pluripotent hESCs maintained under a defined platform can be uniformly converted into a cardiac or neural lineage by small molecule induction, which enables lineage-specific differentiation direct from the pluripotent state of hESCs and opens the door to investigate human embryonic development using in vitro cellular model systems. To identify mechanisms of small molecule induced lineage-specification of pluripotent hESCs, in this study, we compared the expression and intracellular distribution patterns of a set of cardinal chromatin modifiers in pluripotent hESCs, nicotinamide (NAM)-induced cardiomesodermal cells, and retinoic acid (RA)-induced neuroectodermal cells. Further, genome-scale profiling of microRNA (miRNA) differential expression patterns was used to monitor the regulatory networks of the entire genome and identify the development-initiating miRNAs in hESC cardiac and neural lineage-specification. We found that NAM induced nuclear translocation of NAD-dependent histone deacetylase SIRT1 and global chromatin silencing, while RA induced silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family to high levels. Genome-scale miRNA profiling indentified that a unique set of pluripotence-associated miRNAs was down-regulated, while novel sets of distinct cardiac- and neural-driving miRNAs were up-regulated upon the induction of lineage-specification direct from the pluripotent state of hESCs. These findings suggest that a predominant epigenetic mechanism via SIRT1-mediated global chromatin silencing governs NAM-induced hESC cardiac fate determination, while a predominant genetic mechanism via silencing of pluripotence-associated hsa-miR-302 family and drastic up-regulation of neuroectodermal Hox miRNA hsa-miR-10 family governs RA-induced hESC neural fate determination. This study provides critical insight into the earliest events in human embryogenesis as well as offers means for small molecule-mediated direct control and modulation of hESC pluripotent fate when deriving clinically-relevant lineages for regenerative therapies.
机译：通过多谱系分化从多能细胞产生所需细胞类型的效率低下和不稳定，阻碍了人类胚胎干细胞（hESCs）潜力的实现。我们最近报道，维持在定义平台上的多能性hESC可以通过小分子诱导均匀地转化为心脏或神经谱系，这使得直接从hESCs的多能性状态进行谱系特异性分化成为可能，并为研究使用人类胚胎发育的人打开了大门体外细胞模型系统。为了确定小分子诱导多能hESC谱系特异性的机制，在这项研究中，我们比较了多能hESC，烟酰胺（NAM）诱导的心肌细胞和视黄酸中一组主要染色质修饰剂的表达和细胞内分布模式。 RA）诱导的神经外胚层细胞。此外，microRNA（miRNA）差异表达模式的基因组规模分析用于监测整个基因组的调控网络，并在hESC心脏和神经谱系特异性中鉴定启动发育的miRNA。我们发现NAM诱导NAD依赖的组蛋白脱乙酰基酶SIRT1的核易位和整体染色质沉默，而RA诱导多潜能相关的hsa-miR-302家族沉默，神经外胚层Hox miRNA hsa-miR-10家族急剧上调。水平。基因组规模的miRNA分析表明，一组独特的与多能性相关的miRNA被下调，而新的一组独特的心脏和神经驱动miRNA受hESC的多能状态直接诱导的谱系特异性上调。 。这些发现表明，主要的表观遗传机制是通过SIRT1介导的全球染色质沉默来控制NAM诱导的hESC心脏命运的确定，而主要的遗传机制是通过沉默多能相关的hsa-miR-302家族和神经外胚层Hox miRNA的急剧上调来进行的。 hsa-miR-10家族控制RA诱导的hESC神经命运测定。这项研究为人类胚胎发生的最早事件提供了重要的见解，并为衍生与临床相关的谱系提供了小分子介导的hESC多能命运的直接控制和调节手段。

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