Leptin impairs the therapeutic efficacy of adipose-derived mesenchymal stem cells by inducing apoptosis through NLRP3 inflammasomes activation

Mesenchymal stem cells (MSC) have been widely applied for regenerative medicine and the treatment of immune-disorders due to their multilineage differentiation and potent immunomodulatory properties. The therapeutic application of MSC post transplantation are influenced by various endogenous modulators. Leptin, a hormone primarily derived from adipose tissue, exerts a variety of physiological functions, in addition to the metabolic effects. In this study, we examined the effects of Leptin on the viability of adipose-derived mesenchymal stem cells (ADSC) and its underlying molecular mechanisms with a particular focus on NLRP3 inflammasomes, which serve as signaling platform of the innate immune system. Leptin significantly decreased the viability of ADSC and induced Apoptosis. Mechanistically, NLRP3 inflammasomes signaling critically contributes to leptin-induced Apoptosis of ADSC by upregulating p53 and Puma. In addition, NLRP3 inflammasomes activation by Leptin is mediated via ER stress induction and ROS accumulation. Finally, suppression of ADSC therapeutic efficacy by Leptin and the critical role of NLRP3 inflammasomes in this phenomenon were confirmed in DSS-induced colitis model. Pre-conditioning with Leptin before transplantation impaired the therapeutic efficacy and immunomodulatory function of ADSC, which were restored by treatment with a pharmacological inhibitor of NLRP3 inflammasomes. Taken together, the results suggest that Leptin induces apoptotic cell death in ADSC and impairs the therapeutic effectiveness of ADSC by activating NLRP3 inflammasomes.

Adipose-derived MSC; Colitis; Inflammasomes; Leptin; ROS.