Zou Yuan-Xia, Kantapan Jiraporn, Wang Hong-Lian, Li Jian-Chun, Su Hong-Wei, Dai Jian, Dechsupa Nathupakorn, Wang Li
Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand.
Research Center for Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
Regen Ther. 2024 Dec 17;28:169-182. doi: 10.1016/j.reth.2024.12.003. eCollection 2025 Mar.
Acute kidney injury (AKI) is a life-threatening clinical syndrome with no effective treatment currently available. This study aims to investigate whether Iron-Quercetin complex (IronQ) pretreatment can enhance the therapeutic efficacy of Mesenchymal stem cells (MSCs) in AKI and explore the underlying mechanisms.
A cisplatin-induced AKI model was established in male C57BL/6 mice, followed by the intravenous administration of 1x10ˆ6 MSCs or IronQ-pretreated MSCs (MSC). Renal function, histology, and tubular cell apoptosis were analyzed three days post-treatment. In vitro, apoptosis was induced in mouse tubular epithelial cells (mTECs) using cisplatin, followed by treatment with MSCs or MSC conditioned medium (CM). Apoptosis was evaluated using TUNEL assay, RT-PCR, and western blotting. Furthermore, RNA sequencing (RNA-seq) was performed on MSC to explore the underlying mechanisms.
Compared to MSC-treated AKI mice, those treated with MSC showed significantly improved renal function and histological outcomes, with reduced tubular cell apoptosis. A similar effect was observed in cisplatin-treated mTECs exposed to MSC-CM. Mechanistically, RNA-seq and subsequent validation revealed that IronQ treatment markedly upregulated the expression and secretion of hepatocyte growth factor (HGF) in MSCs. Furthermore, RNA interference or antibody-mediated neutralization of HGF effectively abolished the anti-apoptotic effects of MSC on mTECs. This mechanistic insight was reinforced by pharmacological inhibition of c-Met, the specific receptor of HGF, in both in vitro and in vivo models.
IronQ pretreatment enhances MSCs efficacy in AKI by promoting HGF expression and secretion, activating the HGF/c-Met pathway to suppress tubular cell apoptosis. These findings indicate that IronQ improves MSC-based therapies and offers insights into molecular mechanisms, supporting the development of better AKI treatments.
急性肾损伤（AKI）是一种危及生命的临床综合征，目前尚无有效的治疗方法。本研究旨在探讨铁 - 槲皮素复合物（IronQ）预处理是否能增强间充质干细胞（MSCs）对AKI的治疗效果，并探索其潜在机制。
在雄性C57BL / 6小鼠中建立顺铂诱导的AKI模型，随后静脉注射1×10⁶个MSCs或经IronQ预处理的MSCs（MSC）。治疗三天后分析肾功能、组织学和肾小管细胞凋亡情况。在体外，用顺铂诱导小鼠肾小管上皮细胞（mTECs）凋亡，然后用MSCs或MSC条件培养基（CM）进行处理。使用TUNEL检测、RT - PCR和蛋白质印迹法评估细胞凋亡情况。此外，对MSCs进行RNA测序（RNA - seq）以探索潜在机制。
与接受MSC治疗的AKI小鼠相比，接受MSC治疗的小鼠肾功能和组织学结果显著改善，肾小管细胞凋亡减少。在暴露于MSC - CM的顺铂处理的mTECs中也观察到类似效果。从机制上讲，RNA - seq及后续验证表明，IronQ处理显著上调了MSCs中肝细胞生长因子（HGF）的表达和分泌。此外，RNA干扰或抗体介导的HGF中和有效地消除了MSC对mTECs的抗凋亡作用。在体外和体内模型中，对HGF的特异性受体c - Met进行药理学抑制进一步证实了这一机制。
IronQ预处理通过促进HGF表达和分泌，激活HGF/c - Met途径来抑制肾小管细胞凋亡，从而增强MSCs对AKI的治疗效果。这些发现表明IronQ改善了基于MSC的治疗方法，并为分子机制提供了见解，支持开发更好的AKI治疗方法。
