Over the years our laboratory has made a number of important discoveries that advance the understanding of disordered diabetic wound healing.
Early work looked at impairments in angiogenesis and vasculogenesis in diabetic wounds and clarified the mechanisms underlying how endothelial progenitor cells (EPCs) in the bone marrow impact wounds expressing the chemokine SDF-1a during hyperbaric oxygen (HBO) therapy and also clarified the role of bone marrow endothelial nitric oxide synthase (eNOS) in mobilizing EPCs during HBO therapy.
We then began to investigate changes in immune cell phenotypes and chronic inflammation. That work led to the discovery that macrophage phenotypes are indeed altered in diabetic wounds. Investigating further, we were the first team to reveal that these changes in phenotype are driven by epigenetic changes, namely in histone methylation, in bone marrow stem cells and peripheral monocytes.
This work also led us to identify the role of a number of the enzymes involved, including chromatin modifying enzymes, the histone demethylase JMJD3, the histone methyltransferases, MLL1 and, importantly, SETDB2 in macrophage plasticity and inflammation in diabetic wounds. Further work led to the discovery that SETDB2 is involved in the uric acid pathways implicated in gout. Targeting this pathway in our experiments with an approved agent led to improved diabetic wound healing in our murine model. The results suggest a potential new therapeutic target to further investigate to improve healing in patients with diabetes.
Our lab has also clarified the role of infiltrating monocytes on wound macrophage phenotype and how recruited monocytes affect inflammation and tissue repair. We were the first to show that Ly6CHi monocyte/macrophages are recruited to the tissue and, from our RNA sequencing data, showed that these have a different inflammatory profile from Ly6CHi cells from non-diabetic animals.
We also were one of the first groups to show involvement of impaired TLR4 (toll-like receptor) and Notch signaling pathways in macrophage phenotype in diabetic wounds. Further, we showed epigenetic changes in signaling were different in diabetes, promoting an inflammatory macrophage phenotype in these wounds. We also found that murine macrophage chemokine receptor CCR2 is a key player in macrophage recruitment, function and inflammation in diabetic wound healing, providing another potential therapeutic target.