Abstract

Embryonic stem cells (ESCs), and their artificial counterparts, induced pluripotent stem cells (iPSCs) give rise to all differentiated cell types in adult organism.Therefore, pluripotent cells are an inexhaustible cell source for regenerative medicine. However, the successful clinical application of ESCs and iPSCs is associated with the risk of teratoma formation after transplantation of their differentiated products. Oncogenic potential is believed to be associated with the preservation of pluripotent cells resistant to differentiation. For unknown reason under mitogenic stimuli these defective cells did not activate the mechanisms of exit from pluripotency and remained undifferentiated. During embryogenesis, there are special mechanisms for eliminating the abnormal cells unsuitable for embryo development, which are massively triggered before gastrulation, the initial stage of cell differentiation into germ layers. It is known that, prior to implantation, autophagy plays a critical role in embryo formation and can be considered as one of the main cellular strategies aimed at large-scale restructuring of intracellular material after fertilization. It can be proposed that unless massive intracellular reorganization of embryonic cells occur effective, such cells will have defective proteostasis, affecting their differentiation potential. Therefore, the high level of apoptosis observed before gastrulation in embryogenesis is associated with the elimination of mutant cells that are not suitable for differentiation. Damaged cells are marked with the activated p53 protein indicating the p53-dependent elimination mechanisms. And, apparently, the mechanism of the p53 activation is associated with damaged cellular proteostasis, regulated by autophagy. Thus, the p53-dependent autophagy can play a key role in determining the fate of pluripotent cells: induction of cell death and/or resistance to differentiation. We have shown that the p53 protein is tightly integrated with autophagy and, under defective proteostasis, p53 effectively induces autophagy-mediated cell death in pluripotent cells.

中文翻译：

---

P53依赖自噬在多潜能细胞行为调节中的作用。

摘要

胚胎干细胞（ESC）及其人工对应物诱导的多能干细胞（iPSC）会在成年生物中产生所有分化的细胞类型，因此，多能细胞是再生医学的不竭之源。但是，ESC和iPSC的成功临床应用与移植其分化产物后畸胎瘤形成的风险有关。据信致癌潜力与抗分化的多能细胞的保存有关。出于未知原因，在促有丝分裂刺激下，这些缺陷细胞没有激活多能性退出机制，并保持未分化状态。在胚胎发生过程中，有特殊的机制可以消除不适合胚胎发育的异常细胞，在胃化之前大量触发，这是细胞分化为胚层的初始阶段。已知在植入之前，自噬在胚胎形成中起着至关重要的作用，并且可以被认为是旨在在受精后大规模重组细胞内物质的主要细胞策略之一。可以提出除非胚胎细胞大规模的细胞内重组发生有效，否则此类细胞将具有缺陷的蛋白稳态，影响其分化潜能。因此，在胚发生中的胃化之前观察到的高水平细胞凋亡与不适合分化的突变细胞的消除有关。受损的细胞被激活的p53蛋白标记，表明p53依赖的消除机制。而且，显然 p53激活的机制与受损的细胞蛋白变性有关，由自噬调节。因此，依赖p53的自噬可以在决定多能细胞的命运中起关键作用：诱导细胞死亡和/或对分化的抵抗力。我们已经表明，p53蛋白与自噬紧密结合，并且在有缺陷的蛋白稳态下，p53在多能细胞中有效诱导自噬介导的细胞死亡。