In the application of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) as clinical therapeutics, long term cells ex vivo expansion results in decline in their function. It has been widely concerned that cellular senescence is associated with UC-MSCs immunomodulatory ability. In this study, we evaluated the effects of consecutive passages on cellular senescence and the immunomodulatory abilities of UC-MSCs. Long term-cultured UC-MSCs showed decreased proliferation, senescence phenotypes and impaired immunosuppressive effects on PHA induced peripheral blood mononuclear cell (PBMC) proliferation. We found that Nrf2, a transcription factor that responds to oxidative stress, that showed decreased expression in long term-cultured UC-MSCs, and the further knock-down of Nrf2 in UC-MSCs induced premature senescence, decreased proliferation ability and immunosuppressive abilities. Furthermore, the protein expression of IDO-1 were decreased in response to the downregulation of Nrf2 in UC-MSCs, suggesting that Nrf2 regulates the immunosuppressive properties of UC-MSCs via Nrf2-mediated IDO-1 expression. In conclusion, our results demonstrate that Nrf2 plays a key role in the regulation of the immunosuppressive properties of UC-MSCs, and we suggest that these findings might provide a strategy to enhance the functionality of UC-MSCs for use in therapeutic applications. (C) 2020 Elsevier Inc. All rights reserved.