Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network.. Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network.

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide new insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network. Overall design: RNA sequencing (RNA-seq) to study the impacts of ASCs-derived EVs on M2 macrophages in a rat nephritis model.

脂肪来源间充质干细胞（Adipose-derived mesenchymal stem cells, ASCs）已被证实具备对抗难治性疾病的治疗潜力，但其具体的治疗机制仍未明确。本研究针对肾炎模型探究了人源ASCs的治疗作用，重点关注细胞动态变化与多器官免疫网络。经静脉输注的ASCs会富集于脾脏而非肾脏，尽管如此，ASCs可增加肾脏内的M2巨噬细胞与调节性T细胞（Tregs）比例，并发挥显著的肾脏保护作用。脾脏切除术可完全消除上述治疗效应。ASCs来源的细胞外囊泡（extracellular vesicles, EVs）可被转运至M2巨噬细胞，而此类巨噬细胞可从脾脏进入血液循环。EVs可在M2巨噬细胞中诱导超极化与前列腺素E2（prostaglandin E2, PGE2）刺激相关的转录组特征，并改善肾小球肾炎。ASCs、ASCs来源的EVs以及经EV处理的M2巨噬细胞均可促进调节性T细胞的诱导生成。上述研究结果表明，从脾脏富集的ASCs向M2巨噬细胞传递EV，并由此调控肾脏免疫微环境，这正是ASCs发挥肾脏保护作用的核心机制。本研究结果为ASCs的治疗作用机制提供了全新视角，重点揭示了EV介导的巨噬细胞调控与脾-肾免疫网络的关联。实验整体设计：通过RNA测序（RNA-seq）探究ASCs来源的EVs对大鼠肾炎模型中M2巨噬细胞的影响。