Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China.
Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, Shandong, China.
Immunol Invest. 2022 Aug;51(6):1785-1803. doi: 10.1080/08820139.2022.2055478. Epub 2022 Mar 25.
Previous studies have implicated that the transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) effectively alleviates systemic lupus erythematosus (SLE) primarily due to immunomodulatory effects. However, little is known about the role of hUC-MSC-derived exosomes in SLE. This study is carried out to investigate the modifying effects of hUC-MSC-exosomes on the differentiation and function of immune cells in SLE. hUC-MSC-derived exosomes were extracted from the cultural supernatant of hUC-MSCs by ultrahigh speed centrifugation. Quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and flow cytometry were performed to estimate the effect of hUC-MSC-derived exosomes on macrophage and regulatory T cell (Treg) polarization. , hUC-MSC-exosomes were injected intravenously into 28-week-old MRL/lpr mice. We had found that exosomes derived from hUC-MSC restrained the proliferation and inflammation of macrophages . Besides, MSC-exosomes inhibited CD68M1 and HLA-DRM1 but promoted CD206M2 and CD163M2 . Moreover, MRL/lpr mice administrated by intravenous injection of MSC-exosomes had less infiltration of CD14CD11cM1 cells but more CD14CD163M2 cells as well as Tregs in spleens compared with those in MRL/lpr mice treated by PBS. Additionally, MSC-exosomes could alleviate nephritis, liver and lung injuries of MRL/lpr mice. The survival of lupus mice could be improved after MSC-exosome treatment. This study has suggested that MSC-derived exosomes exert anti-inflammatory and immunomodulatory effects in SLE. MSC-exosomes ameliorate nephritis and other key organ injuries by inducing M2 macrophages and Tregs polarization. As natural nanocarriers, MSC-exosomes may serve as a promising cell-free therapeutic strategy for SLE. SLE: Systemic lupus erythematosus; hUC-MSCs: Human umbilical cord mesenchymal stem cells; MSCs: Mesenchymal stem cells; qRT-PCR: Quantitative real-time polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; Tregs: Regulatory cells; TNF-α: Tumor necrosis factor alfa; IL: Interleukin; COVID-19: Coronavirus disease 2019; pTHP-1: PMA-induced THP-1 macrophages; TEM: Transmission electron microscopy; LPS: Lipopolysaccharide; EVs: Extracellular vesicles; TRAF1: Tumor necrosis factor receptor-associated factor 1; IRAK1: Interferon-α-interleukin-1 receptor-associated kinase 1; NF-κB: Nuclear factor-κB; BLyS: B lymphocyte stimulator; APRIL: A proliferation-inducing ligand.
先前的研究表明，人脐带间充质干细胞（hUC-MSCs）的移植可有效缓解全身性红斑狼疮（SLE），主要是由于其免疫调节作用。然而，hUC-MSC 衍生的外泌体在 SLE 中的作用知之甚少。本研究旨在探讨 hUC-MSC 衍生的外泌体对 SLE 中免疫细胞分化和功能的调节作用。通过超速离心从 hUC-MSCs 的培养上清液中提取 hUC-MSC 衍生的外泌体。通过定量实时聚合酶链反应、western blot、酶联免疫吸附试验和流式细胞术来评估 hUC-MSC 衍生的外泌体对巨噬细胞和调节性 T 细胞（Treg）分化的影响。将 hUC-MSC 衍生的外泌体静脉注射到 28 周龄的 MRL/lpr 小鼠体内。我们发现外泌体抑制了巨噬细胞的增殖和炎症反应。此外，MSC 外泌体抑制 CD68M1 和 HLA-DRM1，但促进 CD206M2 和 CD163M2。此外，与 PBS 处理的 MRL/lpr 小鼠相比，静脉注射 MSC 外泌体的 MRL/lpr 小鼠脾脏中浸润的 CD14CD11cM1 细胞减少，而 CD14CD163M2 细胞和 Tregs 增多。此外，MSC 外泌体可减轻 MRL/lpr 小鼠的肾炎、肝和肺损伤。MSC 外泌体治疗后狼疮小鼠的存活率提高。本研究表明，MSC 衍生的外泌体在 SLE 中具有抗炎和免疫调节作用。MSC 外泌体通过诱导 M2 巨噬细胞和 Treg 极化来改善肾炎和其他关键器官损伤。作为天然的纳米载体，MSC 外泌体可能成为 SLE 有前途的无细胞治疗策略。SLE：全身性红斑狼疮；hUC-MSCs：人脐带间充质干细胞；MSCs：间充质干细胞；qRT-PCR：实时定量聚合酶链反应；ELISA：酶联免疫吸附试验；Tregs：调节性 T 细胞；TNF-α：肿瘤坏死因子-α；IL：白细胞介素；COVID-19：2019 年冠状病毒病；pTHP-1：PMA 诱导的 THP-1 巨噬细胞；TEM：透射电子显微镜；LPS：脂多糖；EVs：细胞外囊泡；TRAF1：肿瘤坏死因子受体相关因子 1；IRAK1：干扰素-α-白细胞介素-1 受体相关激酶 1；NF-κB：核因子-κB；BLyS：B 淋巴细胞刺激物；APRIL：增殖诱导配体。
