Abstract
Background: Mesenchymal stem/stromal cells (MSCs) have shown significant therapeutic effects in a range of autoimmune and hyperinflammatory diseases through their strong immunomodulatory properties, both in animal models and clinical settings. Exposure to inflammatory cytokines is crucial for MSCs to acquire immunoregulatory functions; however, the detailed mechanisms underlying this process remain largely unexplored. Method: MSCs with pharmacological inhibition or genetic knockout of poly ADP-ribose polymerase1 (PARP1) were treated with the inflammatory factors IFNγ and TNFα for 24 h. The mRNA and protein expression of chemokines and immunosuppressive molecules were detected by qRT-PCR and Western blotting, respectively. The therapeutic efficacy of MSCs was evaluated using a mouse concanavalin A-induced acute liver injury model and a dextran sulfate sodium-induced inflammatory bowel disease model. The phosphorylation of signal transducer and activator of transcription 1 (STAT1) was analyzed in activated MSCs, and STAT1 inhibition through either a STAT1 inhibitor or STAT1 knockout was employed to confirm the role of STAT1 in enhancing the immunoregulatory function of MSCs during PARP inhibition. Results: PARP inhibition or genetic knockout of PARP1 further enhanced the immunoregulatory function of MSCs elicited by inflammatory cytokines IFNγ and TNFα, as evidenced by the upregulation of genes associated with immunoregulation in MSCs, augmentation of immunosuppressive functions of MSCs on T cells, and increased therapeutic effects of MSCs in mouse models of autoimmune and hyperinflammatory diseases. PARP inhibition was further shown to enhance the expression of immunosuppressive factors in primed MSCs through increased phosphorylation at the tyrosine 701 site on STAT1. Conclusion: Our study indicates that like its pro-inflammatory role in macrophages, PARP also functions to undermine the immunosuppressive effects of MSCs, and PARP inhibition represents a strategy to further unleash the immunoregulatory power of MSCs.