Abstract
Various types of stress stimuli have been shown to threaten the normal development of embryos during embryogenesis. Prolonged heat exposure is the most common stressor that poses a threat to embryo development. Despite the extensive investigation of heat stress control mechanisms in the cytosol, the endoplasmic reticulum (ER) heat stress response remains unclear. In this study, we used human embryonic stem cells (hESCs) to examine the effect of heat stress on early embryonic development, specifically alterations in the ER stress response. In a hyperthermic (42 °C) culture, ER stress response genes involved in hESC differentiation were induced within 1 h of exposure, which resulted in disturbed and delayed differentiation. In addition, hyperthermia increased the expression levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) genes, which are associated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway. Furthermore, we demonstrated that tauroursodeoxycholic acid, a chemical chaperone, mitigated the delayed differentiation under hyperthermia. Our study identified novel gene markers in response to hyperthermia-induced ER stress on hESCs, thereby providing further insight into the mechanisms that regulate human embryogenesis.
Highlights
Hyperthermia or fever refers to a temporary rise in body temperature as a complex, systemic physiological response to infection or injury, serving as a defense mechanism to cellular stress [1]
To determine the optimal exposure time to hyperthermia for this in vitro model, we first compared the induction of unfolded protein response (UPR)-related genes under exposure to 42 ◦ C for different lengths of time while maintaining embryoid body (EB) formation without causing human embryonic stem cells (hESCs) death
There was no change in the expression levels of stemness marker genes for the first 16 h under heat stress, whereas the expression level of NANOG slightly decreased in EBs exposed to hyperthermic conditions for 8 and 16 h
Summary
Hyperthermia or fever refers to a temporary rise in body temperature as a complex, systemic physiological response to infection or injury, serving as a defense mechanism to cellular stress [1]. Free active HSF1 induces the transcription of heat shock genes, which encode cytosolic chaperones such as HSPA1A (HSP70) and DNAJB1 (HSP40) [5]. During heat stress, these HSPs function as chaperones in the cytosol, combine with unfolded proteins, and contribute to maintaining cellular homeostasis by preserving these proteins until the heat stress is alleviated, or by degrading denatured proteins to minimize the accumulation of abnormal proteins [6,7,8]
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