Abstract
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.
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Data availability
The authors declare that all supporting data are available within the Article and its Supplementary Information files. 3ʹ-scRNA-seq data sets have been deposited in the Gene Expression Omnibus (GEO) database under the accession code: GSE165806. All generic and custom R, Python and MATLAB scripts are available on reasonable request.
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Acknowledgements
This work is funded by grants from the National Key R&D Program of China (2021YFF1000603), the National Natural Science Foundation of China (82025006, 82000498, 82103115), SKLAB Open Grant (2022SKLAB6-03), the fellowship of China National Postdoctoral Program for Innovative Talents (BX20200369) and Plan111 (B12008). C.F.G.-J. is supported by UC Irvine Chancellor’s ADVANCE Postdoctoral Fellowship Program, NSF-Simons Postdoctoral Fellowship, and by a kind gift from the Howard Hughes Medical Institute Hanna H. Gray Postdoctoral Fellowship Program.
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Z.Y. and C.L. designed the experiments. M.D., C.L., X.S., J. Xu, X.Y., X.W., K.Y., M.L., G.L., J. Xiao performed research. C.F.G.-J. conceptualized and performed computational experiments and analysis. C.F.G.-J., X.L., K.W., F.R., Q.N., M.V.P., C.L. and Z.Y. analyzed the data. M.D., C.F.G.-J., C.L. and Z.Y. wrote the manuscript.
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Deng, M., Guerrero-Juarez, C.F., Sheng, X. et al. Lepr+ mesenchymal cells sense diet to modulate intestinal stem/progenitor cells via Leptin–Igf1 axis. Cell Res 32, 670–686 (2022). https://doi.org/10.1038/s41422-022-00643-9
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DOI: https://doi.org/10.1038/s41422-022-00643-9
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