Dysfunctional latent transforming growth factor β activation after corneal injury in a classical Ehlers-Danlos model

Area of Science:

• Biomedical Engineering
• Ophthalmology
• Genetics

Background:

• Classical Ehlers-Danlos syndrome (cEDS) is characterized by impaired wound healing and atrophic scarring.
• COL5A1 haploinsufficiency causes systemic alterations, affecting tissue repair.
• Corneal injuries in cEDS patients present significant surgical challenges due to poor healing.

Purpose of the Study:

• To investigate the mechanisms underlying impaired corneal wound healing in a mouse model of cEDS.
• To examine the role of collagen V and Transforming Growth Factor (TGF)-β in corneal tissue repair in cEDS.

Main Methods:

• Utilized a Col5a1^+/- mouse model to simulate cEDS.
• Assessed corneal wound healing following full-thickness lacerations.
• Employed second harmonic imaging microscopy to analyze extracellular matrix structure.
• Investigated collagen V expression and TGF-β activation in corneal myofibroblasts.

Main Results:

• Col5a1^+/- mice exhibited delayed and impaired corneal wound healing, resulting in atrophic scars.
• Collagen V reexpression was upregulated during corneal repair.
• Dysregulated activation of latent TGF-β was observed in a matrix with 50% collagen V content.
• Corneal myofibroblasts with collagen V haploinsufficiency failed to mechanically activate latent TGF-β.
• Second harmonic imaging revealed a disorganized, undulated, and denser collagen matrix.

Conclusions:

• A regenerated collagen matrix with reduced collagen V content (50%) is mechanically insufficient for adequate latent TGF-β activation by fibroblasts and myofibroblasts.
• This mechanical deficiency in the extracellular matrix contributes to impaired wound healing and atrophic scarring in cEDS.
• Findings highlight the critical role of collagen V in maintaining matrix integrity and facilitating TGF-β mediated repair processes.