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

Ningbo Wu, Hongxiang Sun, Xiaoyun Zhao, Yao Zhang, Jianmei Tan, Yuanyuan Qi, Qun Wang, Melissa Ng, Zhaoyuan Liu, Lingjuan He, Xiaoyin Niu, Lei Chen, Zhiduo Liu, Hua-Bing Li, Yi Arial Zeng, Manolis Roulis, Dou Liu, Jinke Cheng, Bin Zhou, Lai Guan Ng, Duowu Zou, Youqiong Ye, Richard A. Flavell, Florent Ginhoux and Bing Su ()
Additional contact information
Ningbo Wu: Shanghai Jiao Tong University School of Medicine
Hongxiang Sun: Shanghai Jiao Tong University School of Medicine
Xiaoyun Zhao: Shanghai Jiao Tong University School of Medicine
Yao Zhang: Shanghai Jiao Tong University School of Medicine
Jianmei Tan: Shanghai Jiao Tong University School of Medicine
Yuanyuan Qi: Shanghai Jiao Tong University School of Medicine
Qun Wang: Shanghai Jiao Tong University School of Medicine
Melissa Ng: Technology and Research (A*STAR)
Zhaoyuan Liu: Shanghai Jiao Tong University School of Medicine
Lingjuan He: University of Chinese Academy of Sciences
Xiaoyin Niu: Shanghai Jiao Tong University School of Medicine
Lei Chen: Shanghai Jiao Tong University School of Medicine
Zhiduo Liu: Shanghai Jiao Tong University School of Medicine
Hua-Bing Li: Shanghai Jiao Tong University School of Medicine
Yi Arial Zeng: University of Chinese Academy of Sciences
Manolis Roulis: Howard Hughes Medical Institute, Yale University School of Medicine
Dou Liu: Howard Hughes Medical Institute, Yale University School of Medicine
Jinke Cheng: Shanghai Jiao Tong University School of Medicine
Bin Zhou: University of Chinese Academy of Sciences
Lai Guan Ng: Technology and Research (A*STAR)
Duowu Zou: Shanghai JiaoTong University School of Medicine
Youqiong Ye: Shanghai Jiao Tong University School of Medicine
Richard A. Flavell: Shanghai Jiao Tong University School of Medicine
Florent Ginhoux: Shanghai Jiao Tong University School of Medicine
Bing Su: Shanghai Jiao Tong University School of Medicine

Nature, 2021, vol. 592, issue 7855, 606-610

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03283-y

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