Cheng Xiaoyan, Ge Maolin, Zhu Shouhai, Li Dan, Wang Ruiheng, Xu Qiongyu, Chen Zhihong, Xie Shufeng, Liu Han
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, China.
FEBS Lett. 2021 Feb;595(4):462-475. doi: 10.1002/1873-3468.14008. Epub 2020 Dec 8.
Transplantation of in vitro-manipulated cells is widely used in hematology. While transplantation is well recognized to impose severe stress on transplanted cells, the nature of transplant-induced stress remains elusive. Here, we propose that the lack of amino acids in serum is the major cause of transplant-induced stress. Mechanistically, amino acid deficiency decreases protein synthesis and nutrient consummation. However, in cells with overactive AKT and ERK, mTORC1 is not inhibited and protein synthesis remains relatively high. This impaired signaling causes nutrient depletion, cell cycle block, and eventually autophagy and cell death, which can be inhibited by cycloheximide or mTORC1 inhibitors. Thus, mTORC1-mediated amino acid signaling is critical in cell fate determination under transplant-induced stress, and protein synthesis inhibition can improve transplantation efficiency.
体外操作细胞的移植在血液学中被广泛应用。虽然移植对移植细胞会施加严重应激这一点已得到广泛认可，但移植诱导应激的本质仍不清楚。在此，我们提出血清中氨基酸的缺乏是移植诱导应激的主要原因。从机制上讲，氨基酸缺乏会减少蛋白质合成和营养消耗。然而，在AKT和ERK过度活跃的细胞中，mTORC1未被抑制，蛋白质合成仍相对较高。这种受损的信号传导会导致营养耗竭、细胞周期阻滞，并最终引发自噬和细胞死亡，而环己酰亚胺或mTORC1抑制剂可抑制这些现象。因此，mTORC1介导的氨基酸信号传导在移植诱导应激下的细胞命运决定中至关重要，抑制蛋白质合成可提高移植效率。
