iPS 细胞来源的细胞外囊泡高效表达 HGF 和 TGF-β1，可通过固有免疫调节缓解干燥综合征。
Extracellular vesicles of iPS cells highly capable of producing HGF and TGF-β1 can attenuate Sjögren's syndrome via innate immunity regulation.
机构信息
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Dent-craniofacial Development and Regeneration Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Dentistry and Oral Surgery, Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga 847-8588, Japan.
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; OBT Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
出版信息
Cell Signal. 2024 Jan;113:110980. doi: 10.1016/j.cellsig.2023.110980. Epub 2023 Nov 18.
Previous studies have demonstrated that extracellular vesicles (EVs) from dental pulp stem cells (DPSCs), which release abundant hepatocyte growth factor (HGF) and transforming growth factor-β1 (TGF-β1), contribute to the pathogenesis of Sjögren's syndrome (SS). However, depending on the condition of DPSCs, this effect is often not achieved. In this study, we established induced pluripotent stem (iPS) cells highly capable of releasing HGF and TGF-β1 and iPS cells barely capable of releasing them, and administered each EV to SS model mice to see if there was a difference in therapeutic effect. EVs were collected from each iPS cell and their characteristics and shapes were examined. When they were administered to SS model mice, the EVs from iPS cells with higher concentrations of HGF and TGF-β1 showed significantly reduced inflammatory cell infiltration in salivary gland tissues, increased saliva volume, and decreased anti-SS-A and anti-SS-B antibodies. A comprehensive search of microRNA arrays for differences among those EVs revealed that EVs from iPS cells with higher concentrations of HGF and TGF-β1 contained more of the let-7 family. Thereafter, we examined the expression of toll-like receptors (TLRs), which are said to be regulated by the let-7 family, by qPCR, and found decreased TLR4 expression. Focusing on MAPK, a downstream signaling pathway, we examined cytokine concentrations in mouse macrophage culture supernatants and Western blotting of murine splenic tissues and found higher concentrations of anti-inflammatory cytokines in the EVs-treated group and decreased TLR4, NF-κB and phosphorylation (p)-p-38 MAPK expression by Western blotting. Alternatively, p-Smad2/3 was upregulated in the EVs-treated group. Our findings suggest that the let-7 family in EVs may suppress the expression of TLR4 and NF-κB, which may be involved in the suppression of MAPK-mediated pro-inflammatory cytokine production.
先前的研究表明，牙髓干细胞（DPSCs）来源的细胞外囊泡（EVs）释放大量肝细胞生长因子（HGF）和转化生长因子-β1（TGF-β1），有助于干燥综合征（SS）的发病机制。然而，根据 DPSCs 的情况，这种效果往往无法实现。在这项研究中，我们建立了能够大量释放 HGF 和 TGF-β1 的诱导多能干细胞（iPS）细胞和几乎不能释放它们的 iPS 细胞，并将每种 EV 施用于 SS 模型小鼠，以观察治疗效果是否存在差异。从每种 iPS 细胞中收集 EV，并检查其特征和形状。当将它们施用于 SS 模型小鼠时，HGF 和 TGF-β1 浓度较高的 iPS 细胞来源的 EV 显示唾液腺组织中炎症细胞浸润明显减少，唾液量增加，抗 SS-A 和抗 SS-B 抗体减少。对这些 EV 之间差异的 microRNA 阵列进行全面搜索表明，HGF 和 TGF-β1 浓度较高的 iPS 细胞来源的 EV 中含有更多的 let-7 家族。此后，我们通过 qPCR 检查了被认为受 let-7 家族调控的 toll 样受体（TLR）的表达，并发现 TLR4 表达降低。我们聚焦于 MAPK，这是下游信号通路，检查了小鼠巨噬细胞培养上清液中的细胞因子浓度和鼠脾组织的 Western 印迹，并发现 EV 处理组中抗炎细胞因子浓度较高，TLR4、NF-κB 和磷酸化（p）-p-38 MAPK 表达通过 Western 印迹降低。相反，EV 处理组中 p-Smad2/3 上调。我们的研究结果表明，EV 中的 let-7 家族可能抑制 TLR4 和 NF-κB 的表达，这可能参与抑制 MAPK 介导的促炎细胞因子产生。
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