Turku Centre for Biotechnology, University of Turku, Turku 20520, Finland.
Turku Centre for Biotechnology, University of Turku, Turku 20520, Finland; Division of Medical Genetics, Department of Medicine, Department of Genome Sciences, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Stem Cell Reports. 2017 Sep 12;9(3):999-1015. doi: 10.1016/j.stemcr.2017.07.018. Epub 2017 Aug 24.
Human bone marrow stromal cells, or mesenchymal stem cells (BM-MSCs), need expansion prior to use as cell-based therapies in immunological and tissue repair applications. Aging and expansion of BM-MSCs induce epigenetic changes that can impact therapeutic outcomes. By applying sequencing-based methods, we reveal that the breadth of DNA methylation dynamics associated with aging and expansion is greater than previously reported. Methylation changes are enriched at known distal transcription factor binding sites such as enhancer elements, instead of CpG-rich regions, and are associated with changes in gene expression. From this, we constructed hypo- and hypermethylation-specific regulatory networks, including a sub-network of BM-MSC master regulators and their predicted target genes, and identified putatively disrupted signaling pathways. Our genome-wide analyses provide a broader overview of age- and expansion-induced DNA methylation changes and a better understanding of the extent to which these changes alter gene expression and functionality of human BM-MSCs.
人骨髓基质细胞，或间充质干细胞（BM-MSCs），在用于免疫和组织修复应用的细胞治疗之前需要扩增。BM-MSCs 的衰老和扩增会引起表观遗传变化，从而影响治疗效果。通过应用基于测序的方法，我们揭示了与衰老和扩增相关的 DNA 甲基化动态的广度大于以前的报告。甲基化变化在已知的远端转录因子结合位点（如增强子元件）处富集，而不是在富含 CpG 的区域富集，并与基因表达的变化相关。由此，我们构建了低甲基化和高甲基化特异性调控网络，包括 BM-MSC 主调控因子及其预测靶基因的子网络，并鉴定了潜在的信号通路。我们的全基因组分析提供了更广泛的年龄和扩增诱导的 DNA 甲基化变化概述，更好地了解这些变化在多大程度上改变了人类 BM-MSCs 的基因表达和功能。
