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Updated: May 22, 2026
Corneal Epithelial Abrasion with Ocular Burr As a Model for Cornea Wound Healing
Published on: July 10, 2018
Spontaneous skin erosions and reduced skin and corneal wound healing characterize CLIC4(NULL) mice
V C Padmakumar1, Kelsey Speer, Sonali Pal-Ghosh
1Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
Cutaneous wound healing is a complex process involving blood clotting, inflammation, migration of keratinocytes, angiogenesis, and, ultimately, tissue remodeling and wound closure. Many of these processes involve transforming growth factor-β (TGF-β) signaling, and mice lacking components of the TGF-β signaling pathway are defective in wound healing. We show herein that CLIC4, an integral component of the TGF-β pathway, is highly up-regulated in skin wounds. We genetically deleted murine CLIC4 and generated a colony on a C57Bl/6 background. CLIC4(NULL) mice were viable and fertile but had smaller litters than did wild-type mice. After 6 months of age, up to 40% of null mice developed spontaneous skin erosions. Reepithelialization of induced full-thickness skin wounds and superficial corneal wounds was delayed in CLIC4(NULL) mice, resolution of inflammation was delayed, and expression of β4 integrin and p21 was reduced in lysates of constitutive and wounded CLIC4(NULL) skin. The induced level of phosphorylated Smad2 in response to TGF-β was reduced in cultured CLIC4(NULL) keratinocytes relative to in wild-type cells, and CLIC4(NULL) keratinocytes migrated slower than did wild-type keratinocytes and did not increase migration in response to TGF-β. CLIC4(NULL) keratinocytes were also less adherent on plates coated with matrix secreted by wild-type keratinocytes. These results indicate that CLIC4 participates in skin healing and corneal wound reepithelialization through enhancement of epithelial migration by a mechanism that may involve a compromised TGF-β pathway.
Insights
CLIC4 is crucial for skin and corneal wound healing. Genetic deletion of CLIC4 impairs epithelial cell migration and delays healing, suggesting a role in transforming growth factor-β (TGF-β) signaling.
Area of Science:
- Cell biology
- Dermatology
- Molecular biology
Background:
- Cutaneous wound healing involves complex cellular processes like inflammation and keratinocyte migration.
- Transforming growth factor-β (TGF-β) signaling is vital for wound repair, with pathway deficiencies impairing healing.
- CLIC4 is identified as a key component of the TGF-β pathway, upregulated during skin wound responses.
Purpose of the Study:
- To investigate the role of CLIC4 in cutaneous wound healing and reepithelialization.
- To determine the impact of CLIC4 deficiency on TGF-β signaling and epithelial cell behavior.
Main Methods:
- Generation of CLIC4 knockout (CLIC4(NULL)) mice on a C57Bl/6 background.
- Induction of full-thickness skin wounds and superficial corneal wounds in CLIC4(NULL) and wild-type mice.
- Analysis of reepithelialization, inflammation resolution, and expression of key proteins (β4 integrin, p21).
- Assessment of TGF-β signaling pathway activation (phosphorylated Smad2) in cultured keratinocytes.
- Evaluation of keratinocyte migration and adhesion properties.
Main Results:
- CLIC4(NULL) mice exhibited delayed reepithelialization of skin and corneal wounds.
- Reduced resolution of inflammation and decreased expression of β4 integrin and p21 were observed in CLIC4(NULL) mice.
- Cultured CLIC4(NULL) keratinocytes showed diminished TGF-β-induced Smad2 phosphorylation, reduced migration, and impaired adhesion.
- A subset of CLIC4(NULL) mice developed spontaneous skin erosions after 6 months of age.
Conclusions:
- CLIC4 plays a significant role in skin and corneal wound healing by enhancing epithelial cell migration.
- The mechanism involves modulation of the TGF-β signaling pathway, as evidenced by impaired Smad2 phosphorylation in CLIC4-deficient cells.
- CLIC4 deficiency compromises epithelial barrier function and wound repair processes.
