Biology subjects

Borschel, G. H.

Publications and source records attributed to Borschel, G. H..

3 recordsLinked to original sources

bioRxiv2026

A Nerve-Dependent NGF Receptor Switch Controls Corneal Epithelial Renewal In Neurotrophic Keratopathy

Corneal epithelial integrity depends on continuous epithelial renewal by limbal epithelial stem cells (LESCs), a process tightly linked to sensory innervation. Loss or impairment of innervation causes neurotrophic keratopathy (NK), a sight-threatening degenerative disease for which rhNGF, the only FDA-approved pharmacologic therapy, often has limited efficacy in advanced or refractory disease. The mechanistic basis for this limited response remains unclear. Using surgical, genetic, and pharmacologic approaches in a rodent model of NK with corneal Schwann cell ablation or structural and functional denervation, together with primary human LESCs, we examined how denervation alters NGF receptor signaling during epithelial repair. In innervated corneas, NGF promoted epithelial regeneration through TrkA. Denervation, however, increased expression of a second NGF receptor, anti-regenerative p75NTR, and activation of its effector JNK, and reduced the activity of the TrkA effector AKT in LESCs. In this altered receptor context, denervation-induced elevation of endogenous NGF amplified p75NTR signaling, thereby explaining the failure of topical rhNGF to rescue severely denervated NK phenotype corneas. Conversely, selective TrkA activation, either with the clinical-stage agonist tavilermide, or pharmacologic or genetic inhibition/ablation of p75NTR, restored AKT signaling and rescued epithelial healing in denervated corneas independent of reinnervation. These findings identify a nerve-dependent NGF receptor switch as a key regulator of corneal epithelial renewal and establish receptor-selective modulation as a mechanistically rational therapeutic strategy for treating NK. One Sentence SummaryCorneal denervation shifts limbal epithelial stem cell signaling from pro-regenerative TrkA-AKT toward anti-regenerative p75NTR-JNK, explaining the limited efficacy of recombinant human nerve growth factor (rhNGF; cenegermin), the only approved pharmacologic therapy for neurotrophic keratopathy, in severely denervated corneas and identifying receptor-selective modulation as a mechanistically distinct therapeutic strategy.

cell biology↗

bioRxiv2021

A Biodegradable, Tacrolimus-releasing Nerve Wrap Promotes Peripheral Nerve Regeneration

Axonal regeneration following nerve repair is slow and often incomplete, resulting in poor functional recovery and sometimes lifelong disability. Yet, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side-effects presently outweigh its potential benefits for peripheral nerve surgery. We have developed a biodegradable drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for large-scale manufacturing and clinical application, aiming to promote axonal regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated in polycarbonate-urethane nanofibers and electrospun to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while systemic drug exposure is reduced by 80% compared to systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

neuroscience↗

bioRxiv2021

Optical Tissue Clearing Enables Rapid, Precise and Comprehensive Assessment of Three-Dimensional Morphology in Experimental Nerve Regeneration Research

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 h while preserving tissue architecture and fluorescence. Optical clearing is compatible with conventional laboratory techniques, including retrograde labelling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enable three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches and mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies.

neuroscience↗