Dataset Information

Lepr+ mesenchymal cells sense diet to modulate intestinal stem cells via the Leptin-Igf1-Igf1r axis

ABSTRACT: We demonstrated that Lepr+ mesenchymal cells 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+ mesenchymal cells resulted in fewer ISCs, compromised architecture of crypt-villi axis and impaired intestinal regeneration. Furthermore, Lepr+ cell-derived Igf1 has been identified as an important effector that promotes the proliferation of ISCs and TA cells. Deletion of Igf1 in Lepr+ cells partially recapitulated Lepr+ cell-ablated intestinal phenotypes during both homeostasis and regeneration. Overall, Lepr+ mesenchymal cells sense diet alteration and function as a novel niche for ISCs via the stromal Igf1 - epithelial Igf1r axis, which is critical for intestinal homeostasis and regeneration. These findings revealed that Lepr+ mesenchymal cells are an important mediator that links diet to ISC function and might provide a novel therapeutic target for gut diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE165806 | GEO | 2022/03/07

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Decline in hematopoietic function in aged individuals is associated with expansion of phenotypic hematopoietic stem cells (HSCs) and a shift in their lineage potential toward production of myeloid cells. Both HSC-intrinsic changes, and extrinsic changes in the bone marrow (BM) microenvironment, have been identified in old mice and humans. However, to extend healthy and robust hematopoietic function from youth into older age, we need to understand and effectively target the processes that initiate functional hematopoietic decline. We recently identified decline in Insulin-Like Growth Factor 1 (IGF1) in the BM microenvironment as early as middle age to be an HSC-extrinsic initiating driver of HSC aging (Young et al., Cell Stem Cell 2021). As systemic IGF1 administration has significant undesirable side effects, we sought to comprehensively interrogate the cell population(s) in the BM microenvironment that are responsible for IGF1 decline, towards the goal of cell type-specific targeted therapy. We performed single cell RNA-seq to comprehensively profile hematopoietic and non-hematopoietic fractions of the BM in young (2-4mo; n = 5 biological replicates) and middle-aged (12-14mo; n = 10) mice. In young mice, we find Igf1 to be nearly entirely detected in the mesenchymal stromal cell populations Adipo-CAR and Osteo-CAR, and Igf1 is significantly reduced in expression in both populations in middle-aged mice. Using two independent mesenchymal stromal cell Cre mouse lines, Lepr-Cre and Prx1-CreERT2, we found that knockout of Igf1 resulted in myeloid-biased hematopoiesis that replicated aging phenotypes. This result was similar to our published work showing that knockout of Igf1 using Nestin-CreER causes myeloid-biased hematopoiesis. While these Cre models generally do not mark similar cell types, it has been shown that Lepr-Cre-expressing perisinusoidal stromal cells include cells that express certain Nestin transgenes. Using fluorescent reporters, we find that all three lines (Lepr-Cre, Prx1-CreERT2, and Nestin-CreER) overlap in expression in the CAR populations that abundantly express Igf1 in young mice. Taken together, our work identifies a new role for Cxcl12-abundant reticular cells in sustaining hematopoietic function through local IGF1 production and suggests that specifically targeting CAR cells to maintain or restore Igf1 expression during aging will have beneficial effects on lymphoid cell production and adaptive immunity.

Dataset Information

Lepr+ mesenchymal cells sense diet to modulate intestinal stem cells via the Leptin-Igf1-Igf1r axis

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure