Metabolism and Epigenetic Regulation are Couples in Transdifferentiation and Vascular Regeneration

摘要 我们发现，体细胞的核重新编程到不同的体细胞谱系，或者 诱导多能干细胞，需要激活细胞内的炎症信号。具体来说， 模式识别受体(PRR)，如Toll样受体(TLRs)，介导细胞自主 通过NFkB和IRF3的先天免疫反应。我们发现这种炎症信号导致全球 改变表观遗传修饰物的表达和/或活性，以增加DNA的可及性 和细胞表型的流动性。后来的研究表明，这种“转化”的过程 可能与血管再生有关。具体地说，我们已经证明了成纤维细胞在缺血 区域可以通过一种我们称之为“血管生成”的过程转化为内皮细胞 转分化“。这一过程有助于缺血区血流灌注的恢复，因为 微血管系统的恢复和缺血区血流的恢复被拮抗 由血管生成转分化所需的因素(例如，炎症信号)决定。更新的工作 我们实验室的研究表明，细胞代谢可能是这一过程的重要贡献者。 具体地说，糖酵解转变是由炎症信号引起的。这种糖酵解转变是 成纤维细胞向内皮细胞的转分化。因此，调节成纤维细胞内的细胞代谢以 促进其转分化为修复性内皮细胞可能是一种新的治疗策略 缺血症。为了确定导致转分化的分子代谢途径，我们将 继续进行实验以追踪关键代谢物并证明它们在介导DNA中的重要性 可获得性和转分化。我们将改变一种关键代谢酶的功能来确认 我们提出的途径，并最终展示了转分化的代谢调节 小鼠外周动脉疾病模型(PAD)。这些研究的完成将证明 细胞内代谢调节决定细胞命运并提供新靶点的新概念 以加强这一过程，以治疗PAD。

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.