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Lepr⁺ mesenchymal cells sense diet to modulate intestinal stem/progenitor cells via Leptin–Igf1 axis

Min Deng^1,† , Christian F. Guerrero-Juarez^2,3,† , Xiaole Sheng¹ , Jiuzhi Xu¹ , Xi Wu¹ , Kai Yao¹ , Mengzhen Li¹ , Xu Yang¹ , Guilin Li¹ , Jintao Xiao⁴ , Xiaowei Liu⁴ , Kaichun Wu⁵ , Fazheng Ren¹ , Qing Nie³ , Maksim V. Plikus² , Zhengquan Yu^6,* , Cong Lv^1,*

¹Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, China
²Department of Mathematics, NSF-Simons Center for Multiscale Cell Fate Research, Center for Complex Biological Systems, University of California, Irvine, CA, USA
³Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA
⁴Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan, China
⁵Department of Gastroenterology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, China
⁶State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
^†These authors contributed equally: Min Deng, Christian F. Guerrero-Juarez
* Correspondence: Zhengquan Yu(zyu@cau.edu.cn)Cong Lv(lvc@cau.edu.cn)

Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr+ mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr+ MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt–villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr+ MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr+ MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1–epithelial IGF1R axis. These findings reveal that Lepr+ MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases.

https://doi.org/10.1038/s41422-022-00643-9

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