Suppressing Mesenchymal Stromal Cell Ferroptosis Via Targeting a Metabolism-Epigenetics Axis Corrects their Poor Retention and Insufficient Healing Benefits in the Injured Liver Milieu.
Suppressing Mesenchymal Stromal Cell Ferroptosis Via Targeting a Metabolism-Epigenetics Axis Corrects their Poor Retention and Insufficient Healing Benefits in the Injured Liver Milieu.
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DOI：
10.1002/advs.202206439
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发表时间：
2023-05
期刊：
影响因子：
15.1
通讯作者：
Zhang, Fuyang
中科院分区：
文献类型：
--
作者：
Hu, Guangyu;Cui, Zhe;Chen, Xiyao;Sun, Fangfang;Li, Tongzheng;Li, Congye;Zhang, Ling;Guo, Xiong;Zhao, Hang;Xia, Yunlong;Yan, Wenjun;Yi, Wei;Fan, Miaomiao;Yang, Rongjin;Wang, Shan;Tao, Ling;Zhang, Fuyang
关键词：
间充质间质细胞（MSC）移植是肝脏修复的一种很有前途的选择，但它们在受损肝脏环境中的潴留不良严重影响了治疗效果。目的是阐明植入后骨髓间充质干细胞大量丢失的机制，并建立相应的改善策略。间充质干细胞的损失主要发生在植入损伤肝脏环境后的最初几个小时内或在活性氧（ROS）应激下。令人惊讶的是，铁下垂被认为是快速衰竭的罪魁祸首。在引发铁下垂或ROS的MSCs中，支链氨基酸转氨酶- 1 （BCAT1）显著降低，其下调通过抑制谷胱甘肽过氧化物酶- 4 （GPX4）的转录使MSC对铁下垂敏感，GPX4是一种重要的铁下垂防御酶。BCAT1下调通过快速反应的代谢-表观遗传学协调机制阻碍GPX4的转录，包括α -酮戊二酸积累、组蛋白3赖氨酸9三甲基化缺失和早期生长反应蛋白- 1上调。抑制铁下垂的方法（例如，在注射溶剂中加入铁下垂抑制剂和过表达BCAT1）可显著改善植入后MSC的保留和肝脏保护作用。本研究提供了第一个证据，表明过度的MSC铁下垂是其在植入损伤肝环境后迅速耗竭和治疗效果不足的不可忽视的罪魁祸首。抑制MSC铁下垂的策略有助于优化基于MSC的治疗。在这里，铁下垂被认为是移植到受损肝脏环境后间充质间质细胞（MSC）耗竭的罪魁祸首。涉及BCAT1介导的BCAA代谢和H3K9me3的代谢-表观遗传学轴通过调节GPX4（一种关键的铁死亡防御酶）转录来控制MSC铁死亡易感。抑制铁下垂的策略（结合铁下垂抑制剂或过表达BCAT1）可以改善MSC治疗。
Mesenchymal stromal cell (MSC) implantation is a promising option for liver repair, but their poor retention in the injured liver milieu critically blunts therapeutic effects. The aim is to clarify the mechanisms underlying massive MSC loss post‐implantation and establish corresponding improvement strategies. MSC loss primarily occurs within the initial hours after implantation into the injured liver milieu or under reactive oxygen species (ROS) stress. Surprisingly, ferroptosis is identified as the culprit for rapid depletion. In ferroptosis‐ or ROS‐provoking MSCs, branched‐chain amino acid transaminase‐1 (BCAT1) is dramatically decreased, and its downregulation renders MSC susceptible to ferroptosis via suppressing the transcription of glutathione peroxidase‐4 (GPX4), a vital ferroptosis defensing enzyme. BCAT1 downregulation impedes GPX4 transcription via a rapid‐responsive metabolism‐epigenetics coordinating mechanism, involving α‐ketoglutarate accumulation, histone 3 lysine 9 trimethylation loss, and early growth response protein‐1 upregulation. Approaches to suppress ferroptosis (e.g., incorporating ferroptosis inhibitors in injection solvent and overexpressing BCAT1) significantly improve MSC retention and liver‐protective effects post‐implantation. This study provides the first evidence indicating that excessive MSC ferroptosis is the nonnegligible culprit for their rapid depletion and insufficient therapeutic efficacy after implantation into the injured liver milieu. Strategies suppressing MSC ferroptosis are conducive to optimizing MSC‐based therapy. Here, ferroptosis is identified as the culprit for mesenchymal stromal cell (MSC) depletion post‐implantation into the injured liver milieu. A metabolism‐epigenetics axis involving BCAT1‐mediated BCAA metabolism and H3K9me3 controls MSC ferroptosis vulnerability via regulating GPX4 (a key ferroptosis‐defensing enzyme) transcription. Strategies inhibiting ferroptosis (incorporating ferroptosis inhibitors or overexpressing BCAT1) are feasible to improve MSC therapy.
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影响因子：
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作者：
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