Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency.
Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency.
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DOI：
10.18632/aging.100428
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Ikeda Y
中科院分区：
文献类型：
--
作者：
Ohmine S;Squillace KA;Hartjes KA;Deeds MC;Armstrong AS;Thatava T;Sakuma T;Terzic A;Kudva Y;Ikeda Y
核重编程使患者能够从成人组织中获得诱导的多能干细胞(IPS)。然而，2型糖尿病(T2D)患者产生的iPS尚未得到证实。在这里，我们报告了来自老年T2D患者的表皮角质形成细胞(HK)的可重复性iPS来源。在无血清和无饲养层条件下，通过转导人OCT4、SOX2、KLF4和c-MYC干细胞因子，重新编程的细胞经历了去分化和线粒体重组，诱导了内源性多能基因-包括NANOG、LIN28和TERT，并下调了细胞骨架、MHC I类-和凋亡相关基因。值得注意的是，衍生的iPS克隆获得了恢复活力的状态，其特征是端粒延长，并抑制了与衰老相关的p15INK4b/p16INK4a基因表达和氧化应激信号。在包括吲哚内酰胺V和GLP-1在内的谱系特定因子的逐步指导下，将HK来源的iPS克隆重新分化为产生胰岛素的胰岛样子代。因此，在老年T2D患者中，角质形成细胞的重新编程确保了能够产生精通再生应用的iPS细胞的衰老特权状态。
Nuclear reprogramming enables patient-specific derivation of induced pluripotent stem (iPS) cells from adult tissue. Yet, iPS generation from patients with type 2 diabetes (T2D) has not been demonstrated. Here, we report reproducible iPS derivation of epidermal keratinocytes (HK) from elderly T2D patients. Transduced with human OCT4, SOX2, KLF4 and c-MYC stemness factors under serum-free and feeder-free conditions, reprogrammed cells underwent dedifferentiation with mitochondrial restructuring, induction of endogenous pluripotency genes - including NANOG, LIN28, and TERT, and down-regulation of cytoskeletal, MHC class I- and apoptosis-related genes. Notably, derived iPS clones acquired a rejuvenated state, characterized by elongated telomeres and suppressed senescence-related p15INK4b/p16INK4a gene expression and oxidative stress signaling. Stepwise guidance with lineage-specifying factors, including Indolactam V and GLP-1, redifferentiated HK-derived iPS clones into insulin-producing islet-like progeny. Thus, in elderly T2D patients, reprogramming of keratinocytes ensures a senescence-privileged status yielding iPS cells proficient for regenerative applications.
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