Vitamin D-mediated Regulation of Intestinal Stem Cells 2297

Abstract Description We recently reported that de novo synthesis of locally high 1,25(OH)2D concentrations enhanced the differentiation of Lgr5+ intestinal stem cells (ISCs) in vitro and in vivo. Importantly, it does not cause hypercalcemia. Hypercalcemia is blood calcium levels significantly higher than physiological levels, which is associated with systemically high 1,25(OH)2D concentrations and can cause serious consequences. Hence, de novo synthesis of locally high 1,25(OH)2D concentrations represents a promising strategy for repairing damaged intestines caused by inflammatory bowel disease and radiation therapy. Although high 1,25(OH)2D concentrations do not alter the stemness of Lgr5+ ISCs in our studies, their accelerated differentiation can diminish the Lgr5+ ISC pool, and radiation therapy has been shown to deplete the Lgr5+ ISCs. In this regard, recent data suggest that in the absence of Lgr5+ ISCs, other reserved ISCs take over to regenerate intestinal epithelia. Hence, this study investigates how high 1,25(OH)2D concentrations affect reserved ISCs. Our analysis of RNA sequencing data and intestinal organoids shows that high 1,25(OH)2D concentrations upregulate the gene markers for several reported reserved ISCs, such as Bmi1 and Mex3a. Ongoing research will reveal how de novo synthesized locally high 1,25(OH)2D concentrations orchestrate the development of different ISC subsets under various disease conditions that compromise the intestinal stem cell niche. Funding Sources This study was partially supported by the National Institute of Health (NIH, USA) grant (1R21AI142170). Topic Categories Therapeutic Approaches to Autoimmunity (THER)