Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.
Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.
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体细胞中特定转录因子的过表达导致其重编程为诱导多能干细胞（iPS）。体外重编程的极低效率和缓慢动力学表明，需要额外的罕见事件来产生iPS细胞。然而，这些事件的性质和身份仍然难以捉摸。我们注意到，原代成纤维细胞重编程为iPS细胞的潜力在连续传代和伴随的衰老开始时降低。与复制潜能丧失为重编程提供障碍的观点一致，我们在此证明，与野生型（WT）细胞相比，内源性ARF水平低的细胞和p16 INK 4a/ARF/p53通路组分缺陷的永生成纤维细胞产生的iPS集落具有3倍的动力学速度和显著更高的效率，赋予几乎每一个体细胞形成iPS细胞的潜力。重要的是，在通常不能重编程的细胞亚群中，p53的急性遗传消融挽救了它们产生iPS细胞的能力。我们的研究结果表明，获得永生是在体细胞中建立多能状态的关键和限速步骤，并强调了多能细胞系和肿瘤细胞之间的相似性。
The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that additional rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary fibroblasts into iPS cells decreases upon serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, we here demonstrate that cells with low endogenous ARF levels and immortal fibroblasts deficient for components of the p16INK4a/ARF/p53 pathway yield iPS colonies with a 3-fold faster kinetics and at a significantly higher efficiency compared with wild-type (WT) cells, endowing almost every somatic cell with the potential to form iPS cells. Importantly, acute genetic ablation of p53 in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between pluripotent cell lines and tumor cells.
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