Beldi Ghada, Bahiraii Sheyda, Lezin Chloé, Nouri Barkestani Mahsa, Abdelgawad Mohamed Essameldin, Uzan Georges, Naserian Sina
INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.
Department of Pharmacognosy, University of Vienna, Vienna, Austria.
Front Cell Dev Biol. 2020 Dec 4;8:596831. doi: 10.3389/fcell.2020.596831. eCollection 2020.
Mesenchymal stem cells (MSCs) have drawn lots of attention as gold standard stem cells in fundamental and clinical researches during the last 20 years. Due to their tissue and vascular repair capacities, MSCs have been used to treat a variety of degenerative disorders. Moreover, MSCs are able to modulate immune cells' functions, particularly T cells while inducing regulatory T cells (iTregs). MSCs are very sensitive to inflammatory signals. Their biological functions could remarkably vary after exposure to different pro-inflammatory cytokines, notably TNFα. In this article, we have explored the importance of TNFR2 expression in a series of MSCs' biological and functional properties. Thus, MSCs from wild-type (WT) and TNFR2 knockout (TNFR2 KO) mice were isolated and underwent several experiments to investigate the biological significance of TNFR2 molecule in MSC main functions. Hampering in TNFR2 signaling resulted in reduced MSC colony-forming units and proliferation rate and diminished the expression of all MSC characteristic markers such as stem cell antigen-1 (Sca1), CD90, CD105, CD44, and CD73. TNFR2 KO-MSCs produced more pro-inflammatory cytokines like TNFα, IFNγ, and IL-6 and less anti-inflammatory mediators such as IL-10, TGFβ, and NO and induced Tregs with less suppressive effect. Furthermore, the TNFR2 blockade remarkably decreased MSC regenerative functions such as wound healing, complex tube formation, and endothelial pro-angiogenic support. Therefore, our results reveal the TNFα-TNFR2 axis as a crucial regulator of MSC immunological and regenerative functions.
在过去20年里，间充质干细胞（MSCs）作为基础研究和临床研究中的金标准干细胞备受关注。由于其组织修复和血管修复能力，MSCs已被用于治疗多种退行性疾病。此外，MSCs能够调节免疫细胞的功能，尤其是T细胞，同时诱导调节性T细胞（iTregs）。MSCs对炎症信号非常敏感。在暴露于不同的促炎细胞因子，尤其是TNFα后，它们的生物学功能可能会有显著差异。在本文中，我们探讨了TNFR2表达在一系列MSCs生物学和功能特性中的重要性。因此，我们分离了野生型（WT）和TNFR2基因敲除（TNFR2 KO）小鼠的MSCs，并进行了多项实验，以研究TNFR2分子在MSCs主要功能中的生物学意义。TNFR2信号传导受阻导致MSCs集落形成单位减少、增殖率降低，并使所有MSCs特征性标志物如干细胞抗原-1（Sca1）、CD90、CD105、CD44和CD73的表达减少。TNFR2 KO-MSCs产生更多的促炎细胞因子，如TNFα、IFNγ和IL-6，而产生更少的抗炎介质，如IL-10、TGFβ和NO，并且诱导的Tregs具有较低的抑制作用。此外，TNFR2阻断显著降低了MSCs的再生功能，如伤口愈合、复杂管形成和内皮促血管生成支持。因此，我们的结果揭示了TNFα-TNFR2轴是MSCs免疫和再生功能的关键调节因子。
