posted on 2020-08-06, 16:30authored byAda AdminAda 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).