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

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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Fig. 1: Lepr+ MCs surround intestinal crypts and expand upon irradiation.
Fig. 2: Ablation of Lepr+ cells led to disrupted intestinal homeostasis and regeneration.
Fig. 3: Lepr+ MCs sustain the proliferation of ISCs.
Fig. 4: scRNA-seq analysis identified Lepr+ cell-derived Igf1 as an important niche signal.
Fig. 5: Deletion of Igf1 in Lepr+ cells partially recapitulates Lepr+ cell-ablated gross phenotypes during homeostasis and regeneration.
Fig. 6: Exogenous Igf1 rescued the impaired regeneration of intestine caused by ablation of Lepr+ cells.
Fig. 7: The abundance of Lepr+ cells was reduced upon fasting and increased upon HFD administration.
Fig. 8: The physiological significance of Igf1 in Lepr+ MCs upon HFD.
Fig. 9: The working model of the mechanism by which Lepr+ cells modulate ISCs under conditions of HFD regime, fasting regime and post-irradiation.

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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Correspondence to Zhengquan Yu or Cong Lv.

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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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