Metabolism and Epigenetic Regulation are Couples in Transdifferentiation and Vascular Regeneration

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.

抽象的 我们发现将体细胞的核重编程为不同的体细胞谱系，或 诱导的多能干细胞需要激活细胞内炎症信号。具体来说， 图案识别受体（PRR），例如Toll样受体（TLR）介导细胞自主 NFKB和IRF3的先天免疫反应。我们发现这种炎症信号导致全局 表观遗传修饰剂的表达和/或活性的变化，以增加DNA的可及性 和细胞表型的流动性。随后的工作表明，这种“转炎”过程 可能参与血管再生。具体而言，我们已经表明缺血性成纤维细胞 可以通过我们称为“血管生成的过程”将区域转化为内皮细胞（EC） 转变”。这个过程有助于缺血区域的灌注恢复，因为 恢复微脉管系统，缺血区域中血流的恢复被拮抗 通过血管生成转分化所需的因素（例如炎症信号传导）。最新的工作 在我们的实验室中表明，细胞代谢可能是该过程的重要贡献。 具体而言，炎症信号传导诱导糖酵解转移。需要这种糖酵解的转移 成纤维细胞转变为EC。那就是调节成纤维细胞内的细胞代谢为 促进他们将其转分化为修复的EC可能是治疗的新策略 缺血。为了确定导致转分化的分子代谢途径，我们将 进行实验以追踪关键代谢物并证明其在介导DNA中的重要性 可访问性和差异化。我们将改变关键代谢酶的功能以确认 我们提出的途径，最后证明了A中转分化的代谢调节 外周动脉疾病（PAD）的小鼠模型。这些研究的完成将证明 细胞内代谢调节的新颖概念有助于其命运并提供新的目标 为了增强这一处理垫的过程。