Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance

Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2. These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.