Soonchunhyang Institute of Medi-bio Science (SIMS), Soon Chun Hyang University, Cheonan 31151, Korea.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel.
Cells. 2020 Apr 26;9(5):1078. doi: 10.3390/cells9051078.
Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts. Compared to fibroblasts, electron microscopy showed simpler/fewer structures with fewer networks in the endoplasmic reticulum (ER) of hPSCs, as well as lower expression of ER-related genes according to meta-analysis. As hPSCs contain low levels of binding immunoglobulin protein (BiP), an ER chaperone, thapsigargin treatment sharply increased the gene expression of the unfolded protein response. Thus, hPSCs with decreased chaperone function reacted sensitively to ER stress and entered apoptosis faster than fibroblasts. Such ER stress-induced apoptotic processes were abolished by tauroursodeoxycholic acid, an ER-stress reliever. Hence, our results revealed that as PSCs have an underdeveloped structure and express fewer BiP chaperone proteins than somatic cells, they are more susceptible to ER stress-induced apoptosis in response to stress.
人类多能干细胞（hPSCs），如胚胎干细胞（ESCs）和诱导多能干细胞（iPSCs），具有分化和自我更新的协调程序。然而，hPSCs 中独特的蛋白质稳态维持机制的结构特征及其对细胞应激的反应特征与分化细胞不同仍不清楚。我们评估并比较了 hPSCs 和成纤维细胞的形态特征和应激反应。与成纤维细胞相比，电子显微镜显示 hPSCs 的内质网（ER）中结构更简单/更少，网络也更少，根据荟萃分析，ER 相关基因的表达也更低。由于 hPSCs 中结合免疫球蛋白蛋白（BiP），一种 ER 伴侣的水平较低，他莫昔芬处理会显着增加未折叠蛋白反应的基因表达。因此，具有降低的伴侣功能的 hPSCs 对 ER 应激反应更敏感，并且比成纤维细胞更快地进入凋亡。这种 ER 应激诱导的凋亡过程被 ER 应激缓解剂牛磺熊脱氧胆酸所消除。因此，我们的结果表明，由于 PSCs 的结构发育不良，并且表达的 BiP 伴侣蛋白比体细胞少，因此它们对 ER 应激诱导的凋亡更敏感，以应对应激。
