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Skin wound closure delay in metabolic syndrome correlates with SCF deficiency in keratinocytes
Zhenping Wang1, Yanhan Wang2, Nicholas Bradbury1
1Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Abstract:
Poor wound closure due to diabetes, aging, stress, obesity, alcoholism, and chronic disease affects millions of people worldwide. Reasons wounds will not close are still unclear, and current therapies are limited. Although stem cell factor (SCF), a cytokine, is known to be important for wound repair, the cellular and molecular mechanisms of SCF in wound closure remain poorly understood. Here, we found that SCF expression in the epidermis is decreased in mouse models of delayed wound closure intended to mimic old age, obesity, and alcoholism. By using SCF conditionally knocked out mice, we demonstrated that keratinocytes' autocrine production of SCF activates a transient c-kit receptor in keratinocytes. Transient activation of the c-kit receptor induces the expression of growth factors and chemokines to promote wound re-epithelialization by increasing migration of skin cells (keratinocytes and fibroblasts) and immune cells (neutrophils) to the wound bed 24-48 h post-wounding. Our results demonstrate that keratinocyte-produced SCF is essential to wound closure due to the increased recruitment of a unique combination of skin cells and immune cells in the early phase after wounding. This discovery is imperative for developing clinical strategies that might improve the body's natural repair mechanisms for treating patients with wound-closure pathologies.
Insights
Stem cell factor (SCF) is crucial for wound healing. This study shows that SCF produced by skin cells (keratinocytes) activates a receptor, promoting skin and immune cell migration for effective wound closure.
Area of Science:
- Dermatology
- Cell Biology
- Regenerative Medicine
Background:
- Millions suffer from poor wound closure linked to chronic conditions like diabetes and aging.
- Current therapies for non-healing wounds are limited, and underlying mechanisms remain unclear.
- Stem cell factor (SCF) is recognized for its role in wound repair, but its precise functions are not fully understood.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms of stem cell factor (SCF) in promoting wound closure.
- To investigate the role of epidermal SCF in models of delayed wound healing.
- To identify therapeutic targets for improving wound repair.
Main Methods:
- Utilized mouse models with delayed wound closure mimicking aging, obesity, and alcoholism.
- Employed SCF conditionally knocked out mice to assess keratinocyte-derived SCF.
- Analyzed the activation of the c-kit receptor and subsequent gene expression changes post-wounding.
Main Results:
- Reduced SCF expression was observed in the epidermis of delayed wound closure models.
- Keratinocyte-autocrine SCF production was found to activate a transient c-kit receptor.
- This activation led to the expression of growth factors and chemokines, enhancing skin and immune cell migration.
Conclusions:
- Keratinocyte-derived SCF is essential for effective wound closure.
- SCF signaling promotes early-phase wound healing by recruiting specific skin and immune cells.
- This research offers insights for developing novel clinical strategies to enhance wound repair in patients.
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