MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche

  • Nature. 2021 Apr;592(7855):606-610. doi: 10.1038/s41586-021-03283-y.
Ningbo Wu  #  1  2 ,  Hongxiang Sun  #  1  2 ,  Xiaoyun Zhao  1  2 ,  Yao Zhang  1  3 ,  Jianmei Tan  1  2 ,  Yuanyuan Qi  1 ,  Qun Wang  1 ,  Melissa Ng  4 ,  Zhaoyuan Liu  1  2 ,  Lingjuan He  5 ,  Xiaoyin Niu  1 ,  Lei Chen  1  2  6 ,  Zhiduo Liu  1  2 ,  Hua-Bing Li  1  2  7 ,  Yi Arial Zeng  5 ,  Manolis Roulis  8 ,  Dou Liu  8 ,  Jinke Cheng  9 ,  Bin Zhou  5 ,  Lai Guan Ng  4 ,  Duowu Zou  3 ,  Youqiong Ye  1  2  7 ,  Richard A Flavell  7  8 ,  Florent Ginhoux  1  4  10 ,  Bing Su  11  12  13  14  15
Affiliations
  • 1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. The State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
  • 4. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 5. The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 6. Center for Microbiota & Immunological Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7. Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
  • 9. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 10. Translational Immunology Institute, SingHealth/Duke-NUS Academic Medical Centre, Singapore, Singapore.
  • 11. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 12. The State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 13. Center for Microbiota & Immunological Diseases, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 14. Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 15. Key Laboratory of Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 33658717 DOI: 10.1038/s41586-021-03283-y
Abstract

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the Wnt agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the Bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment Wnt signalling for the regeneration of damaged intestine.