Gene expression profiles of skin basal layer in young, aged, and Tunicamycin treated killifish
The endoplasmic reticulum (ER) stress-response is an adaptive cellular mechanism activated by unfolded protein accumulation within the ER. Although recent evidence shows that ER stress-response is activated in aged tissues and therefore ER stress is considered as a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress-response during aging remains unclear, especially in vertebrates. Using imaging, analysis we discovered that the expression of Ire1-Xbp1s in the basal layer of epidermis decline during aging, suggesting that ER stress response is involved in epidermal basal layer regulation. Furthermore, treatment with tunicamycin, a pharmacological ER stress inducer, significantly increase cell proliferation, while genetic abaltion decrease cell proliferation in epidermal basal layer. To uncover the mechanism in which Ire1-Xbp1s regulates epidermal stem cell proliferation, a novel spatial transcriptomics, the Photo-Isolation Chemistry (PIC) is conducted in young, aged, and tunicamycin treated aged epidermal basal layer of the killifish. As a result, we identified that the Ire1-Xbp1s pathway maintains young epidermal stem cell proliferation through activating a cell cycle regulator Vcp, while the age-dependent decline of glucose metabolism reduces the Ire1-Xbp1s activity, which consequently downregulates stem cells proliferation. Collectively, our study shows a previously unidentified role of ER stress-response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin. Overall design: Aged killifish were treated with 1µg/mL Tunicamycin for one night alongside with young and control aged killifish treated in DMSO. Trunk and fin were cryosectioned, and RNA expression in the basal layer epidermis of the fin were read using Photo-Isolation Chemistry (PIC) method, described in the following sections.