The Regeneration of Intestinal Stem Cells Is Driven by miR-29-Induced Metabolic Reprogramming
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
Affiliations
Yingying Lin
National Center of Technology Innovation for Dairy, Beijing 100193, China
Yao Lu
National Center of Technology Innovation for Dairy, Beijing 100193, China
Yuqi Wang
National Center of Technology Innovation for Dairy, Beijing 100193, China
Cong Lv
National Center of Technology Innovation for Dairy, Beijing 100193, China
Juan Chen
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Yongting Luo
Food Lab Zhongyuan, Luohe 462333, China
Heng Quan
National Center of Technology Innovation for Dairy, Beijing 100193, China
Weiru Yu
National Center of Technology Innovation for Dairy, Beijing 100193, China
Lining Chen
National Center of Technology Innovation for Dairy, Beijing 100193, China
Ziyu Huang
Department of Food Science, University of Aarhus, Aarhus DK-8200, Denmark
Yanling Hao
Food Lab Zhongyuan, Luohe 462333, China
Qingyu Wang
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
Qingfeng Luo
Department of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
Jingyu Yan
Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116011, China
Yixuan Li
Food Lab Zhongyuan, Luohe 462333, China
Wei Zhang
Washington University School of Medicine in St. Louis, St. Louis, MO 63130, USA
Min Du
Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Jian He
National Center of Technology Innovation for Dairy, Beijing 100193, China
Fazheng Ren
National Center of Technology Innovation for Dairy, Beijing 100193, China; Food Lab Zhongyuan, Luohe 462333, China
Huiyuan Guo
National Center of Technology Innovation for Dairy, Beijing 100193, China; Food Lab Zhongyuan, Luohe 462333, China; Correspondence author.
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.
