FOXO1 differentially regulates both normal and diabetic wound healing

Area of Science:

• Cell biology
• Molecular biology
• Wound healing research

Background:

• Diabetic wounds exhibit delayed healing.
• Previous studies showed Foxo1 deletion in keratinocytes impaired normal wound healing.
• Unexpectedly, Foxo1 deletion improved healing in diabetic wounds.

Purpose of the Study:

• To investigate the dual role of forkhead box O1 (FOXO1) in keratinocyte migration and wound healing under normal and high glucose conditions.
• To elucidate the molecular mechanisms underlying FOXO1's differential regulation of keratinocyte migration in diabetes.

Main Methods:

• Utilized lineage-specific Foxo1 deletion in keratinocytes.
• Assessed keratinocyte migration in normal and high glucose media.
• Analyzed gene expression of TGFβ1, SERPINB2, and CCL20.
• Investigated the effects of insulin, advanced glycation end products, and tumor necrosis factor.

Main Results:

• In normal glucose, FOXO1 enhanced keratinocyte migration via TGFβ1.
• In high glucose, FOXO1 localized to the nucleus but did not upregulate TGFβ1.
• High glucose induced FOXO1-dependent expression of SERPINB2 and CCL20, inhibiting migration.
• Silencing FOXO1, reducing SERPINB2/CCL20, or insulin treatment rescued high glucose-induced migration defects.
• Advanced glycation end products and TNF mimicked high glucose effects on FOXO1 and migration.

Conclusions:

• FOXO1's role in keratinocyte migration and wound healing is context-dependent, influenced by glucose levels.
• In diabetic conditions, FOXO1 promotes healing through SERPINB2 and CCL20, contrasting its role in normal glucose metabolism.
• Targeting FOXO1 pathways offers potential therapeutic strategies for improving diabetic wound healing.