Department of Blood Transfusion, Naval Specialty Medical Center, Naval Medical University, Shanghai, 200050, People's Republic of China.
Special Food Equipment Research Laboratory, Naval Specialty Medical Center, Naval Medical University, Shanghai, 200050, People's Republic of China.
Stem Cell Rev Rep. 2024 Nov;20(8):2253-2267. doi: 10.1007/s12015-024-10784-6. Epub 2024 Sep 5.
The cytokine storm triggered by sepsis can lead to the development of acute lung injury (ALI). Human umbilical cord Mesenchymal stem cells derived exosomes (HucMSCs-EXOs) have been demonstrated to possess immunosuppressive and anti-inflammatory properties. Programmed cell death receptor 1 (PD-1) plays a crucial role in maintaining the inflammatory immune homeostasis. The aim of this study is to investigate the synergistic therapeutic effect of EXOs loaded with anti-PD-1 peptide on septic-ALI.
This study prepares a novel EXOs-based drug, named MEP, by engineering modification of HucMSCs-EXOs, which are non-immunogenic extracellular vesicles, loaded with anti-PD-1 peptide. The therapeutic effect and potential mechanism of MEP on septic-ALI are elucidated through in vivo and in vitro experiments, providing experimental evidence for the treatment of septic acute lung injury with MEP.
We found that, compared to individual components (anti-PD-1 peptide or EXOs), MEP treatment can more effectively improve the lung injury index of septic-ALI mice, significantly reduce the expression levels of inflammatory markers CRP and PCT, as well as pro-inflammatory cytokines TNF-α and IL-1β in serum, decrease lung cell apoptosis, and significantly increase the expression of anti-inflammatory cytokine IL-10 and CD68 macrophages. In vitro, MEP co-culture promotes the proliferation of CD206 macrophages, increases the M2/M1 macrophage ratio, and attenuates the inflammatory response. GEO data analysis and qRT-PCR validation show that MEP reduces the expression of inflammasome-related genes and M1 macrophage marker iNOS.
In both in vitro and in vivo settings, MEP demonstrates superior therapeutic efficacy compared to individual components in the context of septic-ALI.
脓毒症引发的细胞因子风暴可导致急性肺损伤（ALI）的发生。人脐带间充质干细胞衍生的外泌体（HucMSCs-EXOs）已被证实具有免疫抑制和抗炎特性。程序性细胞死亡受体 1（PD-1）在维持炎症免疫稳态中起着至关重要的作用。本研究旨在探讨负载抗 PD-1 肽的 EXOs 对脓毒症-ALI 的协同治疗作用。
本研究通过工程修饰 HucMSCs-EXOs（一种非免疫原性的细胞外囊泡），制备了一种新型 EXOs 药物，命名为 MEP，负载抗 PD-1 肽。通过体内和体外实验阐明了 MEP 对脓毒症-ALI 的治疗效果和潜在机制，为 MEP 治疗脓毒症急性肺损伤提供了实验依据。
与单独的成分（抗 PD-1 肽或 EXOs）相比，我们发现 MEP 治疗能更有效地改善脓毒症-ALI 小鼠的肺损伤指数，显著降低血清中 CRP 和 PCT 等炎症标志物以及 TNF-α和 IL-1β等促炎细胞因子的表达水平，减少肺细胞凋亡，并显著增加抗炎细胞因子 IL-10 和 CD68 巨噬细胞的表达。体外实验中，MEP 共培养促进了 CD206 巨噬细胞的增殖，增加了 M2/M1 巨噬细胞的比例，并减弱了炎症反应。GEO 数据分析和 qRT-PCR 验证表明，MEP 降低了炎症小体相关基因和 M1 巨噬细胞标志物 iNOS 的表达。
在体内外实验中，MEP 在脓毒症-ALI 中比单独的成分具有更优异的治疗效果。
