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间充质干细胞通过细胞外囊泡介导的 M2 巨噬细胞和脾肾网络的调节发挥肾保护作用。

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

机构信息

Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan.

Division of Molecular Genetics, Shigei Medical Research Institute, Minami-ku, Okayama, Japan.

出版信息

Commun Biol. 2022 Jul 28;5(1):753. doi: 10.1038/s42003-022-03712-2.

DOI:10.1038/s42003-022-03712-2
PMID:35902687
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9334610/
Abstract

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 insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

摘要

脂肪间充质干细胞（ASCs）在治疗难治性疾病方面显示出了巨大的潜力。然而，其详细的治疗机制仍不清楚。在这里，我们报告了人源性 ASCs 在肾炎中的治疗作用，重点关注细胞动力学和多器官网络。静脉注射的 ASCs 会在脾脏中积累，但不会在肾脏中积累。然而，ASCs 会增加肾脏中的 M2 巨噬细胞和 Tregs，并产生强烈的肾脏保护作用。脾切除术会消除这些治疗效果。ASC 衍生的细胞外囊泡（EVs）会转移到 M2 巨噬细胞中，然后从脾脏进入血液。EVs 会诱导 M2 巨噬细胞中极化和 PGE2 刺激的转录组特征，并改善肾小球肾炎。ASCs、ASC 衍生的 EVs 和 EV 转移的 M2 巨噬细胞增强了 Treg 的诱导。这些发现表明，从脾脏聚集的 ASCs 中转移的 EV 到 M2 巨噬细胞，并随后调节肾脏免疫环境，是 ASCs 产生肾脏保护作用的基础。我们的研究结果为 ASC 的治疗作用提供了新的见解，重点关注 EV 介导的巨噬细胞和脾脏-肾脏免疫网络的调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/bd686204c0bb/42003_2022_3712_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/c0f54d809a11/42003_2022_3712_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/7bcd81b147ef/42003_2022_3712_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/1cd81fca4245/42003_2022_3712_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/ec1c87082e2c/42003_2022_3712_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/141f2cc3aee8/42003_2022_3712_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/d1b8d633d0e0/42003_2022_3712_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/7e4a4dcd85e1/42003_2022_3712_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/c665e2e45be5/42003_2022_3712_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/bd686204c0bb/42003_2022_3712_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/c0f54d809a11/42003_2022_3712_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/7bcd81b147ef/42003_2022_3712_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/1cd81fca4245/42003_2022_3712_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/ec1c87082e2c/42003_2022_3712_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/141f2cc3aee8/42003_2022_3712_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/d1b8d633d0e0/42003_2022_3712_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/7e4a4dcd85e1/42003_2022_3712_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/c665e2e45be5/42003_2022_3712_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/624e/9334610/bd686204c0bb/42003_2022_3712_Fig9_HTML.jpg

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