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Complications

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

  1. Georgios Theocharidis1,
  2. Dimitrios Baltzis1,
  3. Matthieu Roustit1,
  4. Ana Tellechea1,
  5. Seema Dangwal1,
  6. Radhika S. Khetani2,
  7. Bin Shu1,
  8. Wanni Zhao1,
  9. Jianfang Fu1,
  10. Swati Bhasin3,
  11. Antonios Kafanas1,
  12. Daniel Hui4,5,6,
  13. Shannan Ho Sui2,
  14. Nikolaos A. Patsopoulos4,5,6,
  15. Manoj Bhasin3 and
  16. Aristidis Veves1⇑
  1. 1Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
  2. 2Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA
  3. 3Department of Medicine, Division of Interdisciplinary Medicine and Biotechnology, and Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
  4. 4Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
  5. 5Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
  6. 6Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
  1. Corresponding author: Aristidis Veves, aveves{at}bidmc.harvard.edu
  1. G.T. and D.B. contributed equally to this work as co-first authors.

Diabetes 2020 Oct; 69(10): 2157-2169. https://doi.org/10.2337/db20-0188
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Abstract

Nonhealing diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation, both locally and systemically. We prospectively followed a group of patients who either healed or developed nonhealing chronic DFUs. Serum and forearm skin analysis, both at the protein expression and the transcriptomic level, indicated that increased expression of factors such as interferon-γ (IFN-γ), vascular endothelial growth factor, and soluble vascular cell adhesion molecule-1 were associated with DFU healing. Furthermore, foot skin single-cell RNA sequencing analysis showed multiple fibroblast cell clusters and increased inflammation in the dorsal skin of patients with diabetes mellitus (DM) and DFU specimens compared with control subjects. In addition, in myeloid cell DM and DFU upstream regulator analysis, we observed inhibition of interleukin-13 and IFN-γ 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 DM skin. The SLCO2A1 and CYP1A1 genes, which were upregulated at the forearm of nonhealers, 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.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12733235.

  • Received February 24, 2020.
  • Accepted July 29, 2020.
  • © 2020 by the American Diabetes Association
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Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers
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
Diabetes Oct 2020, 69 (10) 2157-2169; DOI: 10.2337/db20-0188

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Integrated Skin Transcriptomics and Serum Multiplex Assays Reveal Novel Mechanisms of Wound Healing in Diabetic Foot Ulcers
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
Diabetes Oct 2020, 69 (10) 2157-2169; DOI: 10.2337/db20-0188
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