Abstract
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.
Highlights
Human embryonic stem cells originate from the inner cell mass formed during the post-fertilization blastocyst stage [1,2] Human-induced pluripotent stem cells exhibit highly similar characteristics to hESCs, and both cell types are crucial resources for identifying genetic information for early embryogenesis and organogenesis [3]
endoplasmic reticulum (ER) stress may have a direct role in promoting homeostasis and cell death. These findings suggest that ER stress and subsequent unfolded protein response (UPR) induction is more critical to Human pluripotent stem cells (hPSCs) than to fibroblasts, making hPSCs more susceptible to ER stress-mediated apoptosis
To understand whether hPSCs and adult somatic cells respond differently to ER stress, we examined the structural features of hPSCs and fibroblasts, which were used as control cells representing adult somatic cells
Summary
Human embryonic stem cells (hESCs) originate from the inner cell mass formed during the post-fertilization blastocyst stage [1,2] Human-induced pluripotent stem cells (hiPSCs) exhibit highly similar characteristics to hESCs, and both cell types are crucial resources for identifying genetic information for early embryogenesis and organogenesis [3]. Cells 2020, 9, 1078 data on early embryogenesis [4,5] These studies have improved the potential for cell therapy by providing data on the transcriptomic and epigenetic modifications throughout differentiation, several questions remain unanswered. We examined the differential susceptibility of hPSCs to apoptosis according to the cell organelle structure. HPSCs contain immature cell organelles and a specific transcriptome that determines cell fate. Mitochondria are small and round with immature cristae forms [6]. Such morphological features are known to drive adenosine tri-phosphate (ATP) production in hPSCs, which relies more on glycolysis in the cytoplasm than on the oxidative phosphorylation (OXPHOS) metabolic pathway [7]. The morphological features of the endoplasmic reticulum (ER) in hPSCs and consequent susceptibility of stem cells have not been reported
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