Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers.

Non-healing diabetic foot ulceration (DFU) is characterized by low grade chronic inflammation, both locally and systemically. We prospectively followed a group of DFU patients who either healed or developed non-healing chronic DFU. Serum and forearm skin analysis, both at protein expression and transcriptomic level, indicated that increased expression of factors such as IFNγ, VEGF and sVCAM-1 were associated with DFU healing. Furthermore, foot skin single-cell RNA-seq analysis showed multiple fibroblast cell clusters and increased inflammation in the dorsal skin of Diabetes Mellitus (DM) patients and DFU specimens when compared to controls. In addition, in myeloid cells of DM and DFU patients upstream regulator analysis, we observed inhibition of IL-13 and IFNγ and dysregulation of biological processes that included cell movement of monocytes, migration of dendritic cells and chemotaxis of antigen presenting cells pointing to an impaired migratory profile of immune cells in diabetic skin. The SLCO2A1 and CYP1A1 genes, which were up-regulated at the forearm of Non-Healers, were mainly expressed by the vascular endothelial cell cluster almost exclusively in DFU indicating a potential important role in wound healing. These results from integrated protein and transcriptome analyses identified individual genes and pathways that can potentially be targeted for enhancing DFU healing.