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PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties.
Scientific Reports ( IF 3.8 ) Pub Date : 2020-07-10 , DOI: 10.1038/s41598-020-68347-x
R A Contreras-Lopez 1, 2 , R Elizondo-Vega 3 , M J Torres 4 , A M Vega-Letter 5, 6 , N Luque-Campos 1 , M J Paredes-Martinez 1 , C Pradenas 1 , G Tejedor 2 , K Oyarce 7 , M Salgado 3 , C Jorgensen 2 , M Khoury 5, 6 , G Kronke 8 , M A Garcia-Robles 3 , C Altamirano 4 , P Luz-Crawford 1 , F Djouad 2
Affiliation  

Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.



中文翻译:

PPARβ/δ依赖的MSC代谢决定了它们的免疫调节特性。

基于MSC的免疫调节特性,基于间充质干细胞(MSC)的治疗正日益被认为是多种疾病的强大机会。但是,MSC是通用的塑料细胞,需要对其特征和功能进行有效控制以使其在临床上得到最佳使用。最近,我们已经证明PPARβ/δ对于MSC的免疫调节和治疗功能至关重要。然而,尚未解决PPARβ/δ对MSC代谢活性的作用以及PPARβ/δ代谢控制与MSC免疫抑制特性的相关性。在这里,我们证明PPARβ/δ缺乏会迫使MSC代谢适应性增加,从而增加其对Th1和Th17细胞的免疫调节功能所需的糖酵解活性。另外,我们表明抑制表达PPARβ/δ的MSC中ATP的线粒体产生,促进了它们向有氧糖酵解的代谢转换,从而稳定地显着增强了其免疫抑制能力。总而言之,这些数据表明PPARβ/δ通过指示其代谢重编程来控制MSC的免疫调节潜力,并为增强MSC的免疫调节特性和抵消其多功能性铺平了道路。

更新日期:2020-07-10
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