Enhancing and stabilization of cord blood regulatory T-cell suppressive function by human mesenchymal stem cell (MSC)-derived exosomes
Enhancing and stabilization of cord blood regulatory T-cell suppressive function by human mesenchymal stem cell (MSC)-derived exosomes
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DOI：
10.1093/cei/uxac035
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发表时间：
2022-04-19
影响因子：
4.6
通讯作者：
Wang，Wei
中科院分区：
文献类型：
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作者：
Zhang，Juan;Ma，Xiaoqian;Wang，Wei
FOXP3+调节性T细胞（Tregs）是维持外周耐受性和免疫稳态的核心。它们有潜力发展成为一种细胞疗法，用于治疗各种临床疾病，如自身免疫性疾病、炎症性疾病，并改善移植结果。然而，一个主要的问题仍然是treg是否可以在疾病状态下持续存在并有效地发挥其功能，在疾病状态下，广泛的炎症介质可以使treg失活。在这项研究中，我们研究了间充质干细胞（MSC）衍生的外泌体促进和维持Tregs功能的潜力。与对照组相比，骨髓间充质干细胞条件培养基（MSC-CM）培养的Tregs在多克隆和异体反应中都具有更强的抑制作用，并且在体外对炎症刺激具有抵抗力。用msc衍生的外泌体单独培养Treg，也观察到Treg功能的类似增强。当外泌体从MSC-CM中去除时，培养在MSC-CM中的Treg的抑制活性和稳定性减弱。我们发现msc来源的外泌体可以上调LC3（II/I）的表达，磷酸化Jak3和Stat5以促进Treg的存活，并调节Treg中FOXP3的表达。总的来说，我们的研究表明，msc来源的外泌体能够通过激活自噬和Stat5信号通路来增强hub - tregs的功能和稳定性。我们的研究结果为利用msc衍生的外泌体作为增强Treg功能的有效策略，并改善整体基于Treg的细胞治疗前景提供了强有力的理论依据。
FOXP3+regulatory T cells (Tregs) are central to maintaining peripheral tolerance and immune homeostasis. They have the potential to be developed as a cellular therapy to treat various clinical ailments such as autoimmune disorders, inflammatory diseases and to improve transplantation outcomes. However, a major question remains whether Tregs can persist and exert their function effectively in a disease state, where a broad spectrum of inflammatory mediators could inactivate Tregs. In this study, we investigated the potential of mesenchymal stem cell (MSC)-derived exosomes to promote and sustain Tregs function. MSC-conditioned media (MSC-CM) cultured Tregs were more suppressive in both polyclonal and allogeneic responses and were resistant to inflammatory stimulationin vitrocompared with the controls. A similar enhancement of Treg function was also observed by culturing Tregs with MSC-derived exosomes alone. The enhanced suppressive activity and stability of Treg cultured in MSC-CM was reduced when exosomes were depleted from MSC-CM. We identified that MSC-derived exosomes could upregulate the expression of LC3(II/I), phosphorylate Jak3 and Stat5 to promote Treg survival, and regulate FOXP3 expression in Tregs. Overall, our study demonstrates that MSC-derived exosomes are capable of enhancing Hucb-Tregs function and stability by activating autophagy and Stat5 signalling pathways. Our findings provide a strong rationale for utilizing MSC-derived exosomes as an effective strategy to enhance Treg function, and improve the overall Tregs-based cell therapy landscape.