Mesenchymal Stem Cells Promote Intestinal Mucosal Repair by Positively Regulating the Nrf2/Keap1/ARE Signaling Pathway in Acute Experimental Colitis.

BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) are a type of adult pluripotent stem cell that has anti-inflammatory and immunomodulatory effects, and whose conditioned medium (CM) has also been found to be effective. We used MSC and CM enemas to investigate their ameliorative effects in a mouse model of colitis.

METHODS

We employed MSCs, CM, and MSCs + ML385 (an inhibitor of Nrf2) in dextran sodium sulfate (DSS)-induced colitis. Mice were sacrificed on day 8, and the effects of MSC or CM treatment on the levels of inflammation and oxidative stress in colonic epithelial cells were evaluated by histological analyses.

RESULTS

MSCs inhibited inflammatory cell infiltration and proinflammatory cytokine expression in the colon. In addition, MSCs reduced extracellular matrix deposition and maintained the mechanical barrier and permeability of colonic epithelial cells. Mechanistically, MSCs activated Nrf2, which then increased HO-1 and NQO-1 levels and downregulated the expression of Keap1 to suppress reactive oxygen species production and MDA generation, accompanied by increases in components of the enzymatic antioxidant system, including SOD, CAT, GSH-Px, and T-AOC. However, after administering an Nrf2 inhibitor (ML385) to block the Nrf2/Keap1/ARE pathway, we failed to observe protective effects of MSCs in mice with colitis. CM alone also produced some of the therapeutic benefits of MSCs but was not as effective as MSCs.

CONCLUSIONS

Our data confirmed that MSCs and CM can effectively improve intestinal mucosal repair in experimental colitis and that MSCs can improve this condition by activating the Nrf2/Keap1/ARE pathway.