Key Laboratory of Precision Nutrition and Food Quality, Ministry of Education, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, China.
Department of Mathematics, NSF-Simons Center for Multiscale Cell Fate Research, Center for Complex Biological Systems, University of California, Irvine, CA, USA.
Cell Res. 2022 Jul;32(7):670-686. doi: 10.1038/s41422-022-00643-9. Epub 2022 Mar 16.
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.
饮食可以通过调节肠道干细胞（ISCs）来影响肠道健康和疾病。然而，目前还很大程度上不清楚 ISC 龛位是否以及如何响应饮食变化并影响 ISC 功能。在这里，我们证明了围绕肠隐窝的瘦素间质细胞（MCs）能够感知饮食变化，并提供一种新的龛位信号来维持 ISC 和祖细胞的增殖。高脂肪饮食（HFD）给药后，这些 MCs 的丰度增加，但禁食后则急剧减少。Lepr MCs 的耗竭导致肠道干细胞/祖细胞减少，破坏隐窝-绒毛轴的结构，并损害肠道再生。此外，我们表明，Lepr MCs 分泌的 IGF1 是一种重要的效应因子，可促进肠道隐窝中 ISC 和祖细胞的增殖。我们得出结论，Lepr MCs 能够感知饮食变化，并通过基质 IGF1-上皮 IGF1R 轴来调节肠道干细胞/祖细胞的功能。这些发现表明，Lepr MCs 是将全身饮食变化与局部 ISC 功能联系起来的重要介质，可能成为肠道疾病的新治疗靶点。
