Human spindle-shaped urine-derived stem cell exosomes alleviate severe fatty liver ischemia-reperfusion injury by inhibiting ferroptosis via GPX4.

IF 7.1 2区医学 Q1 CELL & TISSUE ENGINEERING

Stem Cell Research & Therapy Pub Date : 2025-02-21 DOI:10.1186/s13287-025-04202-y

Shangheng Shi, Cunle Zhu, Shangxuan Shi, Xinqiang Li, Imran Muhammad, Qingguo Xu, Xinwei Li, Ziyin Zhao, Huan Liu, Guangming Fu, Meiying Song, Xijian Huang, Feng Wang, Jinzhen Cai

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引用次数: 0

Abstract

Background: Severe hepatic steatosis can exacerbate Ischemia-reperfusion injury (IRI), potentially leading to early graft dysfunction and primary non-function. In this study, we investigated the heterogeneity of different subpopulations of Urine-derived stem cells (USCs) to explore the most suitable cell subtype for treating severe steatotic liver IRI.

Methods: This study utilized scRNA-seq and Bulk RNA-seq to investigate the transcriptional heterogeneity between Spindle-shaped USCs (SS-USCs) and Rice-shaped USCs (RS-USCs). Additionally, rat fatty Liver transplantation (LT) model, mouse fatty liver IRI model, and Steatotic Hepatocyte Hypoxia-Reoxygenation (SHP-HR) model were constructed. Extracellular vesicles derived from SS-USCs and RS-USCs were isolated and subjected to mass spectrometry analysis. The therapeutic effects of Spindle-shaped USCs Exosomes (SS-USCs-Exo) and Rice-shaped USCs Exosomes (RS-USCs-Exo) were explored, elucidating their potential mechanisms in inhibiting ferroptosis and alleviating IRI.

Results: Multiple omics analyses confirmed that SS-USCs possess strong tissue repair and antioxidant capabilities, while RS-USCs have the potential to differentiate towards specific directions such as the kidney, nervous system, and skeletal system, particularly showing great application potential in renal system reconstruction. Further experiments demonstrated in vivo and in vitro models confirming that SS-USCs and SS-USCs-Exo significantly inhibit ferroptosis and alleviate severe fatty liver IRI, whereas the effects of RS-USCs/RS-USCs-Exo are less pronounced. Analysis comparing the proteomic differences between SS-USCs-Exo and RS-USCs-Exo revealed that SS-USCs-Exo primarily inhibit ferroptosis and improve cellular viability by secreting exosomes containing Glutathione Peroxidase 4 (GPX4) protein. This highlights the most suitable cell subtype for treating severe fatty liver IRI.

Conclusions: SS-USCs possess strong tissue repair and antioxidant capabilities, primarily alleviating ferroptosis in the donor liver of fatty liver through the presence of GPX4 protein in their exosomes. This highlights SS-USCs as the most appropriate cell subtype for treating severe fatty liver IRI.

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背景：严重的肝脏脂肪变性会加重缺血再灌注损伤（IRI），可能导致早期移植物功能障碍和原发性无功能。在这项研究中，我们调查了尿源性干细胞（USCs）不同亚群的异质性，以探索最适合治疗严重脂肪肝IRI的细胞亚型：本研究利用scRNA-seq和Bulk RNA-seq研究纺锤形USCs（SS-USCs）和米粒形USCs（RS-USCs）之间的转录异质性。此外，还构建了大鼠脂肪肝移植（LT）模型、小鼠脂肪肝IRI模型和脂肪肝肝细胞缺氧-再氧合（SHP-HR）模型。从 SS-USCs 和 RS-USCs 中分离出细胞外囊泡并进行质谱分析。探讨了纺锤形USCs外泌体（SS-USCs-Exo）和米粒形USCs外泌体（RS-USCs-Exo）的治疗效果，阐明了它们抑制铁突变和缓解IRI的潜在机制：多种全局分析证实，SS-USCs具有很强的组织修复和抗氧化能力，而RS-USCs则具有向肾脏、神经系统和骨骼系统等特定方向分化的潜力，特别是在肾脏系统重建方面显示出巨大的应用潜力。进一步的实验证明，体内和体外模型证实，SS-USCs 和 SS-USCs-Exo 能显著抑制铁变态反应，缓解严重的脂肪肝 IRI，而 RS-USCs/RS-USCs-Exo 的效果则不太明显。比较 SS-USCs-Exo 和 RS-USCs-Exo 蛋白质组差异的分析表明，SS-USCs-Exo 主要通过分泌含有谷胱甘肽过氧化物酶 4（GPX4）蛋白的外泌体来抑制铁变态反应和提高细胞活力。这凸显了治疗重度脂肪肝 IRI 的最合适细胞亚型：结论：SS-USCs具有强大的组织修复和抗氧化能力，主要通过其外泌体中的GPX4蛋白缓解脂肪肝供体肝脏的铁突变。这表明 SS-USCs 是治疗严重脂肪肝 IRI 的最合适细胞亚型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Stem Cell Research & Therapy CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

13.20

自引率

8.00%

发文量

525

审稿时长

1 months

期刊介绍： Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.