Acetate as a Mediator of Hematopoietic Stem Cell Inflammatory Response and Clonal Hematopoiesis

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PROJECT SUMMARY Hematopoietic stem and progenitor cells (HSPCs) are responsible for the maintenance and regeneration of the adult hematopoietic system. These cells are responsive to systemic cues that influence their differentiation, such as inflammation, in the form of cytokines such as interferons and interleukins. Inflammation is particularly noteworthy for its influence not only in normal hematopoiesis, but as a driver of clonal hematopoiesis (CH), the overrepresentation of specific mutant clones in the hematopoietic system. Mutations in Tet2 represent a common driver of CH, and Tet2 mutant HSPCs expand preferentially in response to inflammatory stimuli. Recently, acetate has been implicated as an inflammation-associated metabolic signal. Acetate rises systemically during inflammation but is also elevated as a byproduct of dietary components, particularly fructose. I have found in preliminary studies that supplementing acetate, either directly or through fructose, along with inflammatory stimuli broadly exacerbates inflammation in the form of inflammatory serum cytokines and HSPC inflammatory gene expression. Together, these results suggest a role for acetate as a diet-associated metabolic mediator of inflammation, relevant to both normal and clonal hematopoiesis. Therefore, the focus of this proposal is to 1) interrogate the hematopoietic response to changes in systemic acetate levels during inflammation and to 2) interrogate acetate as a driver of clonal hematopoiesis during inflammation. These aims will be accomplished through a combination of functional, gene expression, and phenotypic studies of HSPCs in response to acetate during inflammation.