BMI1 Regulation of Self-Renewal and Multipotency in Human Mesenchymal Stem Cells.
BMI1 Regulation of Self-Renewal and Multipotency in Human Mesenchymal Stem Cells.
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DOI：
10.2174/1574888x1102160107171432
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发表时间：
2016
影响因子：
2.7
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中科院分区：
文献类型：
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我们先前已经描述了从人胚胎和诱导多能干细胞产生间充质干细胞（MSC）。干细胞生物学的核心问题之一是了解干细胞如何在分子水平上调节自我更新与分化的决定。在目前的研究中，我们在原代人MSC中使用了功能丧失和功能获得分析，以证明BMI1是这种有趣的细胞类型中自我更新和多能性的关键调节因子。骨髓间充质干细胞中BMI1的敲低通过上调p16INK4A减少了自我更新，并增加了凋亡。敲除p16INK4A部分挽救了BMI1缺失的MSC的自我更新缺陷。过表达的BMI1通过抑制p16INK4A而减少细胞凋亡和增加细胞增殖。BMI1的缺失导致脂肪形成因子PPARγ和印迹基因网络（IGN）的失调，从而阻断骨生成。在BMI1缺陷模型中，PPARγ或IGN的敲低恢复了骨生成。BMI1的过表达抑制了RUNX2和PPARγ的转录，分别在成骨和脂肪形成中，这导致MSC的谱系特异性潜力降低。这些数据表明，BMI 1调节人MSC的细胞增殖、凋亡和分化。
We have previously described generation of mesenchymal stem cells (MSCs) from human embryonic and induced pluripotent stem cells. One of the central questions in stem cell biology is to understand how stem cells regulate the decision to self-renew vs. differentiate, at the molecular level. In the current studies we used loss-of-function and gain-of-function analyses in primary human MSCs to demonstrate that BMI1 is a critical regulator for self-renewal and multipotency in this interesting cell type. Knockdown of BMI1 in MSCs reduced self-renewal by upregulation of p16INK4A and increased apoptosis. Knockdown of p16INK4A partially rescued the self-renewal defect in MSCs with loss of BMI1. Overexpressed BMI1 reduced apoptosis and increased cell proliferation by repressing p16INK4A. Loss of BMI1 resulted in deregulation of PPARγ, an adipogenic factor, and imprinted gene network (IGN), which blocks osteogenesis. Knockdown of PPARγ or IGN in BMI1 defect models restored osteogenesis. Overexpression of BMI1 repressed transcripts of RUNX2 and PPARγ, in osteogenesis and adipogenesis, respectively, which lead to decreased lineage specification potential in MSCs. These data show that BMI1 regulates cell proliferation, apoptosis, and differentiation of human MSCs.