Adiponectin restores the obesity-induced impaired immunomodulatory function of mesenchymal stromal cells via glycolytic reprogramming.

Obesity has been known to negatively modulate the life-span and immunosuppressive potential of mesenchymal stromal cells (MSC). However, it remains unclear what drives the compromised potency of obese MSC. In this study, we examined the involvement of adiponectin, an adipose tissue-derived hormone, in obesity-induced impaired therapeutic function of MSC. Diet-induced obesity leads to a decrease in serum adiponectin, accompanied by impairment of survival and immunomodulatory effects of adipose-derived MSC (ADSC). Interestingly, priming with globular adiponectin (gAcrp) improved the immunomodulatory potential of obese ADSC. Similar effects were also observed in lean ADSC. In addition, gAcrp potentiated the therapeutic effectiveness of ADSC in a mouse model of DSS-induced colitis. Mechanistically, while obesity inhibited the glycolytic capacity of MSC, gAcrp treatment induced a metabolic shift toward glycolysis through activation of adiponectin receptor type 1/p38 MAPK/hypoxia inducible factor-1α axis. These findings suggest that activation of adiponectin signaling is a promising strategy for enhancing the therapeutic efficacy of MSC against immune-mediated disorders.

Adipokines at the crossroads of obesity and mesenchymal stem cell therapy.

Mesenchymal stem cell (MSC) therapy is an emerging treatment strategy to counteract metabolic syndromes, including obesity and its comorbid disorders. However, its effectiveness is challenged by various factors in the obese environment that negatively impact MSC survival and function. The identification of these detrimental factors will provide opportunities to optimize MSC therapy for the treatment of obesity and its comorbidities. Dysregulated production of adipokines, a group of cytokines and hormones derived from adipose tissue, has been postulated to play a pivotal role in the development of obesity-associated complications. Intriguingly, adipokines have also been implicated in the modulation of viability, self-renewal, proliferation, and other properties of MSC. However, the involvement of adipokine imbalance in impaired MSC functionality has not been completely understood. On the other hand, treatment of obese individuals with MSC can restore the serum adipokine profile, suggesting the bidirectionality of the adipokine-MSC relationship. In this review, we aim to discuss the current knowledge on the central role of adipokines in the crosstalk between obesity and MSC dysfunction. We also summarize recent advances in the use of MSC for the treatment of obesity-associated diseases to support the hypothesis that adipokines modulate the benefits of MSC therapy in obese patients.

Modulation of NLRP3 inflammasomes activation contributes to improved survival and function of mesenchymal stromal cell spheroids.

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells that exhibit significant therapeutic potentials in a variety of disorders. Nevertheless, their clinical efficacy is limited owing to poor survival, low rate of engraftment, and impaired potency upon transplantation. Spheroidal three-dimensional (3D) culture of MSCs (MSC3D) has been proven to better preserve their in vivo functional properties. However, the molecular mechanisms underlying the improvement in MSC function by spheroid formation are not clearly understood. NLRP3 inflammasomes, a key component of the innate immune system, have recently been shown to play a role in cell fate decision of MSCs. The present study examined the role of NLRP3 inflammasomes in the survival and potency of MSC spheroids. We found that MSC3D led to decreased activation of NLRP3 inflammasomes through alleviation of ER stress in an autophagy-dependent manner. Importantly, downregulation of NLRP3 inflammasomes signaling critically contributes to the enhanced survival rate in MSC3D through modulation of pyroptosis and apoptosis. The critical role of NLRP3 inflammasome suppression in the enhanced therapeutic efficacy of MSC spheroids was further confirmed in an in vivo mouse model of DSS-induced colitis. These findings suggest that 3D culture confers survival and functional advantages to MSCs by suppressing NLRP3 inflammasome activation.