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

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

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Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence 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 intesti-nal 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 impor-tant 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.

MiR-29a/bIntestinal stem cellsRegenerationMitochondrial oxidative phosphorylationFatty acid oxidationHnf4g

Yingying Lin、Yao Lu、Yuqi Wang、Cong Lv、Juan Chen、Yongting Luo、Heng Quan、Weiru Yu、Lining Chen、Ziyu Huang、Yanling Hao、Qingyu Wang、Qingfeng Luo、Jingyu Yan、Yixuan Li、Wei Zhang、Min Du、Jian He、Fazheng Ren、Huiyuan Guo

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National Center of Technology Innovation for Dairy,Beijing 100193,China

Key Laboratory of RNA Biology,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China

Food Lab Zhongyuan,Luohe 462333,China

Department of Food Science,University of Aarhus,Aarhus DK-8200,Denmark

The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital & National Center of Gerontology of National Health Commission,Beijing 100730,China

Department of Gastroenterology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Science,Beijing 100730,China

Dalian Institute of Chemical Physics,Chinese Academy of Science,Dalian 116011,China

Washington University School of Medicine in St.Louis,St.Louis,MO 63130,USA

Department of Animal Sciences,Washington State University,Pullman,WA 99164,USA

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2024

10.1016/j.eng.2024.08.008

工程(英文)

工程(英文)

CSTPCDEI
ISSN：2095-8099
年,卷(期)：2024.42(11)