Direct cell reprogramming is a stochastic process amenable to acceleration.
Direct cell reprogramming is a stochastic process amenable to acceleration.
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通过Oct4、Sox2、Klf4和c-Myc转录因子的过表达可以实现体细胞直接重编程为诱导多能干细胞(IPSCs)，但只有少数供体体细胞可以重编程为多能干细胞。在这里，我们证明了重新编程是一个连续的随机过程，几乎所有的供体细胞最终都会在持续生长和转录因子表达的情况下产生IPSCs。另外，抑制P53/p21通路或过表达Lin28会增加细胞分裂率，并导致IPSC形成的动力学加速，这与细胞增殖的增加成正比。相比之下，Nanog过度表达以一种主要与细胞分裂率无关的方式加速了重编程。定量分析定义了不同的细胞分裂速率依赖和独立的模式，以加速重编程的随机过程，并表明细胞分裂的数量是推动表观遗传重编程达到多能性的关键参数。
Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming is a continuous stochastic process where almost all donor cells eventually give rise to iPSCs upon continued growth and transcription factor expression. Additional inhibition the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPSC formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell division rate independent manner. Quantitative analyses define distinct cell division rate dependent and independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.
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