Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

Abstract

AbstractNWD1, a purified rodent diet establishing mouse exposure to key nutrients recapitulating levels that increase risk for intestinal cancer, reproducibly causessporadicintestinal and colonic tumors in the mouse, reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 reprogramming of stem cells and lineages was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5histem cells, epigenetically down-regulatingPpargc1aexpression, altering mitochondrial structure and function. This suppressed Lgr5histem cell functions and developmental maturation of Lgr5hicell progeny as cells progressed through progenitor cell compartments, recapitulated byPpargc1agenetic inactivation in Lgr5hicellsin vivo. MobilizedBmi1+, Ascl2hicells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lg5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Thus, although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.