Biology subjects

John, J. V.

Publications and source records attributed to John, J. V..

3 recordsLinked to original sources

bioRxiv2025

Topical Delivery of 4-Aminopyridine Enhances Skin Regeneration in Burn Wounds

Burn wounds are a common traumatic injury that impair cellular function and hinder the healing process, often resulting in significant skin loss. While autologous skin grafting is considered the gold standard for treating burns, its widespread use is limited due to donor site morbidity and the requirement for large amounts of tissue. Traditional wound dressings and treatments often fail to ensure complete recovery. Being initially FDA-approved to treat multiple sclerosis, 4-aminopyridine (4-AP) has also been shown to accelerate burn wound closure by transforming keratinocytes and fibroblasts when administered systemically. However, prolonged systemic use of 4-AP can lead to significant side effects. In this study, we aimed to repurpose 4-AP for treating skin burn wounds by delivering it topically using a laponite-gelatin gel formulation. This method allows for non-invasive and localized drug delivery on burn wound site. We evaluated the physical properties of the 4-AP gel shear thinning behavior, drug release kinetics, biocompatibility, and functional wound closure using a scratch assay. Moreover, our in vivo experiments showed that the 4-AP loaded gel accelerates wound healing by enhancing re-epithelialization and hair follicle regeneration and promoting fibroblast to myofibroblast transformation, which supports extracellular matrix remodeling after skin burns. This novel application of the 4-AP gel could offer a promising alternative to current burn wound therapies, potentially leading to improved outcomes for burn patients.

bioengineering↗

bioRxiv2025

Schwann cells modified to secrete MANF is a potential cellular therapy for peripheral nerve regeneration

Despite several decades of research, an effective therapy for peripheral nerve regeneration is still lacking. The lack of knowledge of molecular candidates that equally promote axon regeneration and glial cell dynamics essential for regeneration poses challenges in developing effective therapies. Improper optimization of potential therapies leading to failures in ensuring their local availability in nerves also poses additional challenges. Here, we showed that the neurotrophic factor, the mesencephalic astrocyte-derived neurotrophic factor (MANF), equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration. We showed that while endogenous expression of MANF is primarily restricted to non-peptidergic sensory neurons in adult rats, exogenous MANF promotes the growth of all subtypes of adult rat sensory neurons. We also demonstrated that exogenous MANF promotes the proliferation and migration of adult rat primary Schwann Cells (SCs). Further, we found that local and repeated administration of exogenous MANF to injured mouse nerve promote axon regeneration. Finally, we devised a therapeutic approach by programming nerve resident SCs to locally and continuously deliver MANF to injured rat nerves and showed that this approach improved nerve regeneration indices. Overall, this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system of MANF for improving nerve regeneration.

neuroscience↗

bioRxiv2025

Partial Input Loss Differentially Modifies Neural Pathways

Following input loss from degeneration, injury, and/or aging, downstream circuits undergo modifications that can impact neural computations. How neural computations across different pathways are affected by common input loss remain understudied. To leverage known cell types, well-defined circuitry, and molecular tools, we use the mouse retina to show how multiple pathways adjust their functional properties differently to common input loss and further locate these changes within each pathway. Specifically, we asked if two OFF ganglion cell types, alpha OFF-sustained (AOFF-S) and OFF-transient (AOFF-T) cells, and their respective dominant presynaptic partners, type 2 and type 3a cone bipolar cells, respond differentially to partial cone loss. We find that AOFF-T ganglion cells exhibit more circuit changes than AOFF-S ganglion cells, resulting in altered spatiotemporal tuning following partial cone loss. We show that the underlying mechanisms include changes in glutamatergic, GABAergic, and glycinergic circuits in the pathway of AOFF-T ganglion cells. In response to common input loss, our study finds different locations of circuit modifications across OFF pathways. These findings provide insight into how sensory pathways can compensate differentially to common input loss.

neuroscience↗