Clinical application of a FOXO1 inhibitor improves connective tissue healing in a diabetic minipig model

Hyeran H. Jeon, Quan Yu, Lukasz Witek, Yongjian Lu, Tianshou Zhang, Olga Stepanchenko, Victoria J. Son, Evelyn Spencer, Temitope Oshilaja, Min K. Shin, Faizan Alawi, Paulo G. Coelho, Dana T. Graves

Research output: Contribution to journalArticlepeer-review

Abstract

The forkhead box O1 (FOXO1) transcription factor plays a key role in wound healing process. Recently it has been reported that lineage-specific genetic ablation of FOXO1 significantly improves diabetic wound healing in a mouse model. To investigate the clinical usefulness of these findings, translational preclinical studies with a large animal model are needed. We report for the first time that the local application of a FOXO1 inhibitor (AS1842856) significantly improves connective tissue healing in a preclinical T2DM minipig model, reflected by increased collagen matrix formation, increased myofibroblast numbers, improved angiogenesis, and a shift in cell populations from pro-inflammatory (IL-1β+, TNF-α+and iNOS+) to pro-healing (CD163+). Our results set up the basis for the clinical application of a FOXO1 antagonist in early diabetic wounds where there is impaired connective tissue healing.

Original languageEnglish (US)
Pages (from-to)781-791
Number of pages11
JournalAmerican Journal of Translational Research
Volume13
Issue number2
StatePublished - 2021

Keywords

  • Diabetes
  • Forkhead box O1 (FOXO1)
  • Hyperglycemia
  • Inflammation skin
  • Minipig
  • Wound healing

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

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