Abstract
Recent studies from our group and others have characterized the phenomenon of "angiogenic transdifferentiation” from fibroblasts to endothelial cells as a novel endogenous mechanism for microvasculature expansion and perfusion restoration in murine models of hindlimb ischemia and myocardial infarction. Metabolic regulation of epigenetic reprogramming has emerged as a key regulatory process controlling cell fate transition. To study the comprehensive role of metabolism in this healing process, we conducted liquid chromatography-mass spectrometry (LC-MS) based untargeted and targeted metabolomics during transdifferentiation. Our analysis revealed the upregulation of key metabolites, including UDP-GlcNAc (substrate for post-translational modification O-GlcNAcylation) and acetyl-CoA (substrate for histone acetylation). With our in vitro transdifferentiation protocol, we found that pharmacologic or genetic inhibition of OGT (O-GlcNAc transferase, the enzyme responsible for protein O-GlcNAcylation) or ACL (ATP citrate lyase, the enzyme converting citrate to acetyl-CoA) in human BJ fibroblasts impairs transdifferentiation. Employing a preclinical peripheral arterial disease (PAD) hindlimb ischemia model with fibroblast lineage tracing mice, we discovered that O-GlcNAcylation and ACL were accumulated in fibroblast lineage cells in ischemic limbs, and pharmacologic inhibition of OGT or ACL diminished the transdifferentiation cell population in the ischemic tissue. Furthermore, we identified fibroblast-specific OGT or ACL KO impaired vascular recovery post femoral artery ligation in the mice. Finally, we showed that metabolism-dependent post-translational modifications on histones (acetylation of H3K9, H3K27, H3K14) or histone chaperons (O-GlcNAcylation of HIRA, a histone H3.3 chaperone) mechanistically enhanced chromatin openness, thereby facilitating cell fate plasticity and vascular regeneration. In conclusion, our studies demonstrate the significant regulatory potential of metabolic factors in angiogenic transdifferentiation which presents an innovative avenue to enhance vascular recovery in ischemic vascular diseases such as PAD.
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