Lepr+ Mesenchymal Cells Sense Diet to Modulate Intestinal Stem Cells Via Leptin-Igf1 Axis

Diet can impact gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown how ISC niche responds to diet and influences ISC function. Here, we demonstrated that Lepr+ mesenchymal cells (MCs) surround intestinal crypts where ISCs and transit-amplifying (TA) cells localize. The abundance of these cells increased upon administration of a high-fat diet (HFD) but dramatically decreased upon fasting. Depletion of Lepr+ MCs resulted in fewer ISCs, compromised architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, IGF1 derived from Lepr+ MCs was found to be an important effector that promotes proliferation of ISCs. Overall, Lepr+ MCs sense diet alteration and function as a novel niche for ISCs via the stromal Igf1 - epithelial Igf1r axis. These findings revealed that Lepr+ MCs are an important mediator that links systemic diet changes to local ISC function and might provide a novel therapeutic target for gut diseases.