Parsons Xuejun H
San Diego Regenerative Medicine Institute, San Diego, USA ; Xcelthera, San Diego, USA.
J Regen Med. 2013 Jan 25;1(2). doi: 10.4172/2325-9620.1000103.
The growing number of identified stem cell derivatives and escalating concerns for safety and efficacy of these cells towards clinical applications have made it increasingly crucial to be able to assess the relative risk-benefit ratio of a given stem cell from a given source for a particular disease. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations might reside in chromatin modifications that shape the respective epigenomes of their derivation routes. Previously, we have generated engraftable human neuronal progenitors direct from pluripotent human embryonic stem cells (hESCs) by small molecule induction (hESC-I hNuPs). Unlike the prototypical neuroepithelial-like nestin-positive human neural stem cells (hNSCs), these neuroectoderm-derived Nurr1-positive hESC-I hNuPs are a more neuronal lineage-specific and plastic hESC derivative. In this study, the global chromatin landscape changes in pluripotent hESCs and their neuronal lineage-specific derivative hESC-I hNuPs were profiled using genome-wide mapping and compared to CNS tissue-derived hNSCs. This study found that the broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds closely with those of acetylated nucleosomes genome-wide. The epigenomic transition from pluripotency to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Tissue-resident CNS-derived hNSCs have acquired a substantial number of additional histone H3K9 methylation, therefore, more silenced chromatin. These data suggest that the intrinsic plasticity and regenerative potential of human stem cell derivatives can be differentiated by their epigenomic landscape features, and that human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs than from the CNS tissue .
已鉴定出的干细胞衍生物数量不断增加，且人们对这些细胞在临床应用中的安全性和有效性的担忧日益加剧，因此，能够评估特定来源的给定干细胞针对特定疾病的相对风险效益比变得越来越重要。识别人类干细胞群体的内在可塑性和再生潜力可能在于染色质修饰，这些修饰塑造了其分化途径各自的表观基因组。此前，我们通过小分子诱导从多能性人类胚胎干细胞（hESCs）直接生成了可移植的人类神经祖细胞（hESC-I hNuPs）。与典型的神经上皮样巢蛋白阳性人类神经干细胞（hNSCs）不同，这些源自神经外胚层的Nurr1阳性hESC-I hNuPs是一种更具神经元谱系特异性和可塑性的hESC衍生物。在本研究中，利用全基因组图谱分析了多能性hESCs及其神经元谱系特异性衍生物hESC-I hNuPs的全基因组染色质景观变化，并与中枢神经系统组织来源的hNSCs进行了比较。本研究发现，多能性hESCs的广泛潜能由一种表观基因组定义，该表观基因组由染色质的开放构象构成，这种构象由Oct-4全局分布模式介导，与全基因组范围内乙酰化核小体的分布模式密切对应。从多能性到谱系选择受限的表观基因组转变的特征是全基因组范围内组蛋白H3K9甲基化增加，这介导了全局染色质沉默和体细胞特性。因此，组织驻留的中枢神经系统来源的hNSCs获得了大量额外的组蛋白H3K9甲基化，从而具有更多沉默染色质。这些数据表明，人类干细胞衍生物的内在可塑性和再生潜力可以通过其表观基因组景观特征来区分，并且当从hESCs而非中枢神经系统组织衍生时，人类干细胞衍生物保留了更开放的表观基因组景观，因此具有更大的放大再生发育潜力。
