Morimoto Keisuke, Nakashima Ayumu, Ishiuchi Naoki, Miyasako Kisho, Tanaka Yoshiki, Sasaki Kensuke, Matsuda Go, Maeda Satoshi, Miyaki Shigeru, Masaki Takao
Department of Nephrology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan.
Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
Stem Cells. 2025 May 15;43(5). doi: 10.1093/stmcls/sxaf022.
Acute kidney injury (AKI) is involved in subsequent chronic kidney disease (CKD) development, and effective treatments to prevent AKI to CKD progression are lacking. Mesenchymal stem cells (MSCs) are emerging as a promising cellular therapy to impede such progression through the secretion of various humoral factors. Among these factors, tumor necrosis factor-α-induced protein 6 (TSG-6) has a central role in the anti-inflammatory effects of MSCs. However, the mechanisms by which MSCs secrete TSG-6 and exert anti-inflammatory effects are not fully clarified. Here, we investigated these mechanisms using TSG-6-overexpressing MSCs (TSG-6 MSCs) with an adeno-associated virus. Extracellular vesicles (EVs) were isolated from MSC culture supernatants by ultracentrifugation. MSCs were injected through the abdominal aorta into rats with ischemia-reperfusion injury (IRI) to evaluate their anti-inflammatory and anti-fibrotic effects. Additionally, we explored natural compounds that increased TSG-6 expression in MSCs. Most TSG-6 was immediately secreted in EVs and was not stored intracellularly. Administration of TSG-6 MSCs strongly suppressed renal fibrosis and inflammation in IRI rats. Although EVs and conditioned medium from TSG-6 MSCs (TSG-6 MSC-CM) strongly promoted polarization of M2 macrophages, TSG-6 MSC-CM after EV depletion promoted it only slightly. Moreover, TSG-6 MSC-CM enhanced regulatory T-cell induction. MSCs treated with indole-3-carbinol had enhanced TSG-6 expression and markedly suppressed IRI-induced renal fibrosis. Taken together, TSG-6 is secreted in EVs from MSCs and exerts potent anti-inflammatory effects by promoting M2 macrophage polarization and regulatory T-cell induction. Administration of MSCs with enhanced TSG-6 secretion is a promising therapeutic strategy to impede AKI to CKD progression.
急性肾损伤（AKI）与随后慢性肾脏病（CKD）的发生发展有关，且缺乏预防AKI进展为CKD的有效治疗方法。间充质干细胞（MSCs）作为一种有前景的细胞疗法，正通过分泌多种体液因子来阻止这种进展。在这些因子中，肿瘤坏死因子-α诱导蛋白6（TSG-6）在MSCs的抗炎作用中起核心作用。然而，MSCs分泌TSG-6并发挥抗炎作用的机制尚未完全阐明。在此，我们使用腺相关病毒转染过表达TSG-6的MSCs（TSG-6 MSCs）来研究这些机制。通过超速离心从MSC培养上清液中分离细胞外囊泡（EVs）。将MSCs经腹主动脉注射到缺血再灌注损伤（IRI）大鼠体内，以评估其抗炎和抗纤维化作用。此外，我们还探索了能增加MSCs中TSG-6表达的天然化合物。大多数TSG-6立即分泌到EVs中，而非储存在细胞内。给予TSG-6 MSCs可强烈抑制IRI大鼠的肾纤维化和炎症。尽管来自TSG-6 MSCs的EVs和条件培养基（TSG-6 MSC-CM）强烈促进M2巨噬细胞极化，但去除EVs后的TSG-6 MSC-CM仅轻微促进其极化。此外，TSG-6 MSC-CM增强了调节性T细胞的诱导。用吲哚-3-甲醇处理的MSCs TSG-6表达增强，并显著抑制IRI诱导的肾纤维化。综上所述，TSG-6从MSCs分泌到EVs中，并通过促进M2巨噬细胞极化和调节性T细胞诱导发挥强大的抗炎作用。给予分泌TSG-6增强的MSCs是一种有前景的治疗策略，可阻止AKI进展为CKD。
