Targeting tfeb to promote bridge schwann cell function in peripheral nerve GAP repair

The National Institute of Neurological Disorders and Stroke awarded Rutgers, The State University of New Jersey, Newark Division $431,750 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to conduct research on transcription factor EB (TFEB) regulation of bridge Schwann cell function in peripheral nerve gap repair.

The research addresses traumatic peripheral nerve injuries that create nerve gaps, a condition for which autologous nerve grafts remain the clinical standard but are limited by donor nerve availability and diminished Schwann cell function with age or increased gap length. The project investigates how TFEB regulates the generation, migration, and survival of bridge Schwann cells—specialized repair cells that migrate from cut nerve ends—and whether augmenting TFEB activity enhances regeneration across long nerve gaps. Preliminary findings indicate that TFEB is rapidly activated after nerve injury and controls gene networks involved in plasticity, mesenchymal transition, proliferation, and autophagy. Work aims to use inducible Schwann cell-specific TFEB/TFE3 loss-of-function mice combined with in vivo lineage tracing and single-cell RNA sequencing to define TFEB-dependent transcriptional programs and determine how TFEB regulates bridge Schwann cell expansion and migration.

Performance occurs at Newark, New Jersey. The period of performance runs from September 1, 2026, through August 31, 2028.

Abstract

Traumatic peripheral nerve injuries that create nerve gaps remain a major clinical challenge. Autologous nerve grafts, the current gold standard, are limited by donor nerve availability, additional morbidity, and diminished schwann cell function with age or increasing GAP length. Acellular nerve conduits offer an alternative, but their success is severely limited for long-GAP injuries because host bridge schwann cells (BSCS), the specialized repair SCS that migrate from the cut nerve ends, often fail to expand, migrate, or survive within the hypoxic, nutrient-poor GAP. When BSCS lose viability or stall, regenerating axons lose their cellular scaffold and retract, leading to poor functional outcomes. Strategies that enhance BSC generation, motility, and metabolic resilience represent a critical unmet need for improving long-GAP nerve repair. Our preliminary findings identify tfeb as a promising regulator of BSC biology. Tfeb is rapidly activated after nerve injury and controls gene networks involved in plasticity, mesenchymal transition, proliferation, and autophagy, processes that closely match the cellular demands placed on BSCS. Tfeb promotes schwann cell migration, increases N-cadherin expression, and is required for induction of SOX2, a driver of the BSC migratory phenotype. Because BSCS operate within a metabolically stressed environment, tfeb-mediated metabolic adaptation may be essential for their survival. The overall objective of this study is to define how tfeb regulates BSC generation, migration, and survival, and to determine whether augmenting tfeb activity enhances regeneration across long nerve gaps. Aim 1 will use inducible schwann cell-specific tfeb/TFE3 loss-of-function mice combined with in vivo lineage tracing (ROSA-TDTOMATO) and scrna-SEQ to define tfeb-dependent transcriptional programs and determine how tfeb regulates BSC expansion, migration, autophagy, and survival during GAP repair. Aim 2 will use schwann cell-specific tfeb gain-of-function mice to determine whether tfeb activation enhances BSC metabolic capacity, stress resilience, motility, and long-GAP regeneration in a clinically relevant collagen conduit model. Successful completion of this work will establish tfeb as a master regulator of BSC biology and provide mechanistic insight into how BSCS regenerate severed nerves. These findings will enable new therapeutic strategies to enhance endogenous repair or improve the performance of engineered nerve conduits, reducing reliance on autografts.