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Integrated skin transcriptomics and serum multiplex assays reveal novel mechanisms of wound healing in diabetic foot ulcers

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posted on 06.08.2020 by Ada Admin, Georgios Theocharidis, Dimitrios Baltzis, Matthieu Roustit, Ana Tellechea, Seema Dangwal, Radhika S. Khetani, Bin Shu, Wanni Zhao, Jianfang Fu, Swati Bhasin, Antonios Kafanas, Daniel Hui, Shannan Ho Sui, Nikolaos A. Patsopoulos, Manoj Bhasin, Aristidis Veves
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

Funding

This work was supported by grants from the National Institutes of Health, 1R01DK091949 (A.V.) and the NIDDK Diabetic Complications Consortium, 17AU3773 (A.V.). A.V. received funding from the National Rongxiang Xu Foundation. G.T. received a George and Marie Vergottis Foundation Postdoctoral Fellowship. M.R. received funding from the Fondation AGIR pour les Maladies Chroniques. S.D. received funding from German Research Foundation (DFG). The data analysis performed by R.S.K. was supported by Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH award #UL1 RR 025758 and financial contributions from participating institutions).

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