Department of Neurology, Dresden University of Technology, Dresden, Germany.
Exp Cell Res. 2010 Oct 15;316(17):2760-78. doi: 10.1016/j.yexcr.2010.06.012. Epub 2010 Jun 23.
Tissue-specific stem cells, such as bone-marrow-derived human mesenchymal stem cells (hMSCs), are thought to be lineage restricted and therefore, could only be differentiated into cell types of the tissue of origin. Several recent studies however have suggested that these types of stem cells might be able to break barriers of germ layer commitment and differentiate in vitro into cells with neuroectodermal properties. We reported earlier about efficient conversion of adult hMSCs into a neural stem cell (NSC)-like population (hmNSCs, for human marrow-derived NSC-like cells) with all major properties of NSCs including functional neuronal differentiation capacity. Here we compared the transcriptomes from hMSCs and hmNSCs using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses to shed light on regulatory protein networks involved in this neuroectodermal conversion process. We found differential regulation of extracellular matrix protein transcripts, up-regulation of distinct neuroectodermal and NSCs marker genes and local chromosomal transcriptional up-regulation at chromosome 4q13.3. In comparison to hMSCs and primary adult hippocampal NSCs, the transcriptome of hmNSCs displayed minor overlap with both other cell populations. Advanced bioinformatics of regulated genes upon neuroectodermal conversion identified transcription factor networks with HIF-1 and microRNA miR-124a as potential major regulators. Together, transgerminal neuroectodermal conversion of hMSCs into NSC-like cells is accompanied by extensive changes of their global gene expression profile, which might be controlled in part by transcription factor networks related to HIF-1 and miR-124a.
组织特异性干细胞，如骨髓来源的人间质干细胞（hMSCs），被认为是谱系受限的，因此只能分化为组织来源的细胞类型。然而，最近的几项研究表明，这些类型的干细胞可能能够突破胚层承诺的障碍，并在体外分化为具有神经外胚层特性的细胞。我们之前报道过，将成人 hMSCs 有效地转化为具有神经干细胞（NSC）特性的类似群体（hmNSCs，用于人骨髓来源的 NSC 样细胞），具有 NSCs 的所有主要特性，包括功能性神经元分化能力。在这里，我们使用一种新的策略，将经典的 Affymetrix 寡核苷酸微阵列分析与调控和蛋白质相互作用网络分析相结合，比较了 hMSCs 和 hmNSCs 的转录组，以揭示参与这种神经外胚层转化过程的调控蛋白网络。我们发现细胞外基质蛋白转录物的差异调节，独特的神经外胚层和 NSCs 标记基因的上调，以及染色体 4q13.3 上的局部染色体转录上调。与 hMSCs 和原代成年海马 NSCs 相比，hmNSCs 的转录组与其他两种细胞群体的重叠较少。神经外胚层转化后受调控基因的高级生物信息学分析确定了转录因子网络，其中 HIF-1 和 microRNA miR-124a 作为潜在的主要调节剂。总之，hMSCs 向 NSC 样细胞的跨胚层神经外胚层转化伴随着其整体基因表达谱的广泛变化，这可能部分受到与 HIF-1 和 miR-124a 相关的转录因子网络的控制。
