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Impaired skin reinnervation in Epidermolysis Bullosa due to neurotrophic deficiency
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DOI：10.1097/j.pain.0000000000004001.png)
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Abstract
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The skin is densely innervated by peripheral sensory neurons that detect various stimuli through specialized nerve endings in the dermis and epidermis. In recessive dystrophic epidermolysis bullosa (RDEB), repeated skin injury disrupts epidermal nerve fibers, leading to neuropathic pain and reduced thermal sensitivity. Normally, keratinocyte-derived neurotrophic signals guide sensory fiber re-entry into healed epidermis. We hypothesized that impaired neurotrophic support underlies failed reinnervation in RDEB. To investigate the mechanisms behind failed reinnervation, we assessed neurotrophic factor expression in a human skin wound model. We analyzed the secretome of primary keratinocytes from healthy donors and patients with RDEB and tested its effects on neurite outgrowth in sensory neurons derived from embryonic rodents and human induced pluripotent stem cells. We also evaluated the regenerative potential of tropomyosin receptor kinase A (TrkA) and glial cell derived neurotrophic factor (GDNF) receptor agonists (gambogic amide and XIB4035) in vitro and in a mouse model of RDEB. In healthy skin, injury triggered robust neurotrophic factor secretion, whereas RDEB skin did not. Secretomes from healthy keratinocytes promoted neurite outgrowth, whereas those from RDEB keratinocytes failed to do so. Receptor agonist treatment restored neurite growth in vitro, enhanced intraepidermal innervation, and reversed thermal hyposensitivity in RDEB mice.
Keywords:
Neurotrophic factors
Epidermal reinnervation
RDEB
Keratinocytes
Small fibre neuropathy
Peripheral nervous system
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