Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
Cell Death Differ. 2013 Dec;20(12):1698-708. doi: 10.1038/cdd.2013.122. Epub 2013 Sep 6.
Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. ΔNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.
体细胞可以通过强制表达各种转录因子组合转化为诱导多能干细胞（iPSCs），但重编程的分子机制仍知之甚少。具体来说，证明重编程过程可以走许多不同的途径的证据才刚刚开始出现。可以明确的是，p53 缺失极大地增强了重编程，揭示了 p53 对诱导多能性的屏障功能，但它的同源物 p63 和 p73 的作用尚不清楚。在这里，我们报告与 p53 形成鲜明对比的是，p73 在重编程中没有作用。然而，p63 是 Oct4、Sox2 和 Klf4（OSK）和 Oct4 和 Sox2（OS）重编程的有效（而非障碍）因素，但不是 Oct4 和 Klf4（OK）重编程的有效因素。具体来说，p63 在重编程过程中对于最大效率是必不可少的，尽管对于本身的重编程能力不是必需的，并且对于建立的 iPSC 集落的稳定性和多能性是可有可无的。ΔNp63，但不是 TAp63，是涉及的主要同工型。p63 的缺失会通过几种机制影响重编程，例如间充质上皮转化和多能性基因的表达减少、低增殖和最易重编程细胞群的丧失。在 OSK 和 OS 重编程过程中，似乎有不同的机制很关键，例如在 OSK 重编程中调节上皮和多能性基因，而在 OS 重编程中调节增殖。最后，我们的数据根据它们对 iPSC 效率和多能性标志物表达的不同 p63 需求，揭示了 OSK、OS 或 OK 三种不同的重编程途径。这支持了存在许多不同的重编程途径的概念。
