Metabolism and Epigenetic Regulation are Couples in Transdifferentiation and Vascular Regeneration

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Abstract We discovered that nuclear reprogramming of somatic cells to a different somatic cell lineage, or induced pluripotent stem cells, requires activation of inflammatory signaling within the cell. Specifically, pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) mediate a cell-autonomous innate immune response via NFKb and IRF3. We found that this inflammatory signaling causes global changes in the expression and/or activity of epigenetic modifiers so as to increase DNA accessibility and fluidity of cell phenotype. Subsequent work has suggested that this process of “transflammation” may be involved in vascular regeneration. Specifically, we have shown that fibroblasts in an ischemic region can be transformed into endothelial cells (ECs) through a process we termed “angiogenic transdifferentiation”. This process contributes to the recovery of perfusion in the ischemic region, as the recovery of the microvasculature, and the restoration of blood flow in an ischemic region is antagonized by factors required for angiogenic transdifferentiation (e.g., inflammatory signaling). More recent work in our laboratory indicates that cell metabolism may be an important contributor to this process. Specifically, a glycolytic shift is induced by inflammatory signaling. This glycolytic shift is required for the transdifferentiation of fibroblasts to ECs. Thus, regulating cell metabolism within fibroblasts to facilitate their transdifferentiation into reparative ECs may be a novel strategy for the treatment of ischemia. To determine the molecular metabolic pathway that leads to transdifferentiation, we will pursue experiments to trace key metabolites and demonstrate their importance in mediating DNA accessibility and transdifferentiation. we will alter the function of a key metabolic enzyme to confirm our proposed pathway, and finally, demonstrate the metabolic regulation of transdifferentiation in a mouse model of peripheral artery disease (PAD). Completion of these studies will demonstrate the novel concept that metabolic regulation within cells contributes to their fate and provide novel targets to enhance this process for the treatment of PAD.