Nestin prevents mesenchymal stromal cells from apoptosis in LPS-induced lung injury via inhibition of unfolded protein response sensor IRE1α

The clinical applications of MSC therapy have been intensely investigated in acute respiratory distress syndrome. However, clinical studies have fallen short of expectations despite encouraging preclinical results. One of the key problems is that transplanted stem cells can hardly survive in the harsh inflammatory environment. Prolonging the survival of transplanted MSCs might be a promising strategy to enhance the therapeutic efficacy of MSC therapy. Here, we identified Nestin, a class VI intermediate filament, as a positive regulator of MSC survival in the inflammatory microenvironment. We showed that Nestin knockout led to a significant increase of MSC apoptosis, which hampered the therapeutic effects in an LPS-induced lung injury model. Mechanistically, Nestin knockout induced a significant elevation of endoplasmic reticulum (ER) stress level. Further investigations showed that Nestin could bind to IRE1α and inhibit ER stress-induced apoptosis under stress. Furthermore, pretreatment with IRE1α inhibitor 4μ8C improved MSC survival and improved therapeutic effect. Our data suggests that Nestin enhances stem cell survival after transplantation by inhibiting ER stress-induced apoptosis, improving protection and repair of the lung inflammatory injury.