Mesenchymal stem cells reduce ER stress via PERK-Nrf2 pathway in aged mouse model

Mesenchymal stem cells (MSCs) have been shown to ameliorate the deleterious effects of bleomycin. However, the mechanism responsible for protection of stem cells therapy in pulmonary fibrosis is still poorly understood especially in terms of the endoplasmic reticulum (ER) stress. We hypothesized that ER stress could increase after a certain time elapse and then decrease to the baseline, resembling the fibrosis after bleomycin exposure. We also attempted to clarify the exact role of MSCs upon the ER stress by a timely sacrifice of animals at the period of peak ER stress. Female old (>20 months) C57BL/6J mice were used. In order to study the peak time in ER stress, old mice were divided into 5 groups based on their sacrifice day (day 0, 3, 7, 14, and 21 after bleomycin exposure). For evaluation of the MSCs toward ER stress, old mice were divided into 3 groups (control group, bleomycin-only group, bleomycin-plus-MSC group) and sacrificed on day 7. Bleomycin (1.5 U/Kg) or normal saline was given via an intratracheal route on day 0. MSCs (5×105 cells) or normal saline was intravenously injected on day 0 after bleomycin administration. Among various ER stress markers, BiP and XBP-1 were selected. The levels of both BiP and XBP-1 started to increase on day 7 and increased until day 21. MSCs ameliorated the BiP elevation of bleomycin-induced ER stress. MSCs operate on ER stress among several pathways, but the PERK-Nrf2 pathway revealed to be the main functioning pathway. In the meantime, the rest of ER stress markers were not reduced by MSCs. In conclusion, we demonstrated that MSCs seem to attenuate the ER stress via PERK-Nrf2 pathway.