miR-29介导的代谢重编驱动小肠干细胞的再生过程

林莹莹, 陆瑶, 王宇琦, 吕聪, 陈娟, 罗永挺, 全亨, 于伟茹, 陈俪宁, 黄子彧, 郝彦玲, 王清宇, 罗庆锋, 闫竞宇, 李依璇, 张伟, 杜敏, 何剑, 任发政, 郭慧媛

工程（英文） ›› 2024, Vol. 42 ›› Issue (11) : 39-58.

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工程（英文） ›› 2024, Vol. 42 ›› Issue (11) : 39-58. DOI: 10.1016/j.eng.2024.08.008
研究论文
Article

miR-29介导的代谢重编驱动小肠干细胞的再生过程

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The Regeneration of Intestinal Stem Cells Is Driven by miR-29-Induced Metabolic Reprogramming

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摘要

肠道干细胞 (Intestinal stem cells, ISCs) 是肠道上皮更新及肠道肿瘤的原动力，当受到损伤时，它们会快速补充丢失的库存，从而支持上皮的修复或肿瘤的再生过程。 揭示这种可塑性的机制对于肠道健康至关重要。近年来，研究表明代谢途径可以控制稳态下干细胞的命运，但是代谢对于ISCs损伤后再生的作用尚不明确。在本研究中，我们发现miR-29a和miR-29b (miR-29a/b) 在人结直肠肿瘤数据库中是与肠道成瘤及放疗后不良愈后高度相关的代谢调控因子。 我们还发现，这两种小RNA对维持小鼠肠道干性所必需的，并且它们的表达会在辐照损伤后的新生ISCs中升高，驱使ISCs的命运从分化向自我更新转移。ISCs中上调的miR-29a/b 会抑制脂肪酸氧化 (fatty acid oxidation, FAO), 降低氧化磷酸化水平，从而调控ISCs的分化更新平衡。 敲除 miR-29a/b 会妨碍上述作用，导致ISCs介导的肠道上皮修复受阻。最后，我们筛选了miR-29a/b的潜在靶点，确定了转录因子Hnf4g 为关键靶基因，能够通过调控FAO相关酶的表达来实现代谢重塑。该研究为ISCs介导的再生提供了一个重要的代谢调控机制，并为肠道修复及肿瘤治疗挖掘了更多针对性的有效策略

Abstract

Intestinal stem cells (ISCs) initiate intestinal epithelial regeneration and tumorigenesis, and they experience rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence. It is crucial to reveal the mechanism underlying such plasticity for intestinal health. Recent studies have found that metabolic pathways control stem cell fate in homeostasis, but the role of metabolism in the regeneration of ISCs after damage has not been clarified. Here, we find that in a human colorectal cancer dataset, miR-29a and b (miR-29a/b) are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy. We also show that these two microRNAs are required for intestinal stemness maintenance in mice, and their expression is induced in regenerated ISCs after irradiation injury, resulting in skewed ISC fate from differentiation towards self-renewal. This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation (FAO) and depression of oxidative phosphorylation, which in turn controls the balance between self-renewal and differentiation of ISCs. Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery. Finally, we filter the potential targets of miR-29a/b and identify Hnf4g, a transcription factor, that drives this metabolic reprogramming through regulating FAO-related enzymes. Our work discovers an important metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.

关键词

MiR-29a/b / 肠道干细胞 / 再生 / 线粒体氧化磷酸化 / 脂肪酸氧化 / Hnf4g

Keywords

MiR-29a/b / Intestinal stem cells / Regeneration / Mitochondrial oxidative phosphorylation / Fatty acid oxidation / Hnf4g

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林莹莹, 陆瑶, 王宇琦. miR-29介导的代谢重编驱动小肠干细胞的再生过程. Engineering. 2024, 42(11): 39-58 https://doi.org/10.1016/j.eng.2024.08.008

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