Differential Lung Protective Capacity of Exosomes Derived from Human Adipose Tissue, Bone Marrow, and Umbilical Cord Mesenchymal Stem Cells in Sepsis-Induced Acute Lung Injury.
Differential Lung Protective Capacity of Exosomes Derived from Human Adipose Tissue, Bone Marrow, and Umbilical Cord Mesenchymal Stem Cells in Sepsis-Induced Acute Lung Injury.
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人脂肪组织、骨髓和脐带间充质干细胞来源的外泌体在脓毒症引起的急性肺损伤中的差异肺保护能力
DOI：
10.1155/2022/7837837
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发表时间：
2022
影响因子：
--
通讯作者：
Lv X
中科院分区：
文献类型：
--
作者：
Deng H;Zhu L;Zhang Y;Zheng L;Hu S;Zhou W;Zhang T;Xu W;Chen Y;Zhou H;Li Q;Wei J;Yang H;Lv X
源自人间充质干细胞（hMSCs）的外泌体具有调节与脓毒症诱导的急性呼吸窘迫综合征（ARDS）相关的多种生物学过程的能力，包括细胞免疫代谢、促炎细胞因子的产生，从而发挥治疗作用。然而，对于哪种类型的hMSCs来源的外泌体（hMSC - exo）在治疗脓毒症诱导的ARDS方面更有效且适用，目前知之甚少。本研究旨在比较源自人脂肪组织（hADMSC - exo）、人骨髓（hBMMSC - exo）和人脐带（hUCMSC - exo）的hMSCs外泌体在治疗脓毒症诱导的ARDS中的疗效。我们将脂多糖（LPS）刺激的RAW264.7巨噬细胞与这三种hMSCs共培养，发现所有hMSCs均降低了巨噬细胞的糖酵解水平和乳酸含量。相应地，促炎细胞因子的表达也有所下降。值得注意的是，脂肪组织来源的hMSCs的保护作用比骨髓和脐带来源的hMSCs更为明显。然而，当添加外泌体抑制剂GW4869时，这种保护作用就消失了。随后，我们提取了hMSCs来源的外泌体并与LPS刺激的RAW264.7细胞共培养，发现这三种外泌体均发挥了与其亲代细胞类似的保护作用，其中脂肪组织来源的hMSCs外泌体的保护作用最强。最后，我们建立了小鼠脓毒症实验模型，发现这三种hMSCs均具有明显的肺保护作用，可降低肺损伤评分、肺组织中的乳酸和促炎细胞因子水平，减少支气管肺泡灌洗液（BALF）中的总蛋白含量和炎症细胞计数，还能减轻全身炎症反应并提高小鼠的存活率。静脉注射这三种类型的hMSC - exo，尤其是源自脂肪组织的hADMSCs外泌体，在小鼠中也显示出肺保护作用。这些研究结果表明，不同来源的hMSCs外泌体能够有效下调脓毒症诱导的巨噬细胞糖酵解和炎症反应，改善肺部病理损伤，并提高脓毒症小鼠的存活率。值得注意的是，hADMSC - exo的保护作用优于hBMMSC - exo和hUCMSC - exo。
Exosomes derived from human mesenchymal stem cells (hMSCs) have the capacity to regulate various biological events associated with sepsis-induced acute respiratory distress syndrome (ARDS), including cellular immunometabolism, the production of proinflammatory cytokines, allowing them to exert therapeutic effects. However, little is known about which type of hMSC-derived exosomes (hMSC-exo) is more effective and suitable for the treatment of sepsis-induced ARDS. The purpose of this study is to compare the efficacy of hMSC-derived exosomes from human adipose tissue (hADMSC-exo), human bone marrow (hBMMSC-exo), and human umbilical cord (hUCMSC-exo) in the treatment of sepsis-induced ARDS. We cocultured lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells with the three kinds of hMSCs and found that all hMSCs reduced the glycolysis level and the content of lactic acid in macrophages. Accordingly, the expression of proinflammatory cytokines also decreased. Notably, the protective effects of hMSCs from adipose tissue were more obvious than those of bone marrow and umbilical cord hMSCs. However, this protective effect was eliminated when an exosome inhibitor, GW4869, was added. Subsequently, we extracted and cocultured hMSC-derived exosomes with LPS-stimulated RAW264.7 cells and found that all three kinds of exosomes exerted a similar protective effect as their parental cells, with exosomes from adipose hMSCs showing the strongest protective effect. Finally, an experimental sepsis model in mice was established, and we found that all three types of hMSCs have obvious lung-protective effects, in reducing lung injury scores, lactic acid, and proinflammatory cytokine levels in the lung tissues and decreasing the total protein content and inflammatory cell count in the bronchoalveolar lavage fluid (BALF), and also can attenuate the systemic inflammatory response and improve the survival rate of mice. Intravenous injection of three types of hMSC-exo, in particular those derived from adipose hADMSCs, also showed lung-protective effects in mice. These findings revealed that exosomes derived from different sources of hMSCs can effectively downregulate sepsis-induced glycolysis and inflammation in macrophages, ameliorate the lung pathological damage, and improve the survival rate of mice with sepsis. It is worth noting that the protective effect of hADMSC-exo is better than that of hBMMSC-exo and hUCMSC-exo.