Schwann Cell Response to Nerve Injury 1 views

Peripheral nerve injuries remain a major clinical challenge, with recovery limited by the degeneration of injured axons and the inadequacy of current regenerative therapies. While the pro-degenerative NADase SARM1 has been extensively characterized in neurons as a central executioner of Wallerian degeneration, its role in Schwann cells (SCs)—one of the primary glial cells of the peripheral nervous system responsible for response to injury —remains largely unexplored. This dissertation investigates SC-autonomous functions of SARM1 in shaping the peripheral nerve response to injury. We first demonstrate that SC-expressed SARM1 promotes axon degeneration non-cell-autonomously, using in vitro co-culture systems, a SC-specific Sarm1 conditional knockout mouse model, and glial-specific dSarm knockdown in Drosophila—collectively showing that glial-mediated axon protection is evolutionarily conserved and independent of neuronal SARM1. To understand the transcriptional basis of this protection, we performed single-nucleus RNA sequencing of wild-type and Sarm1 knockout mouse sciatic nerves across a post-injury timecourse. This reveals a previously unrecognized transient SC phenotype we term the Protection-Associated Schwann Cell (PASC), characterized by upregulation of axon protection genes and enhanced oxidative phosphorylation. Pseudotime analysis positions the PASC as an intermediate state between homeostatic (myelinating and non-myelinating) and Repair SCs, suggesting that SARM1 gates this transition. We propose that the timing of SARM1 inhibition is therefore critical: acute inhibition may extend the protective PASC window, while prolonged inhibition could impair the glial environment needed for regeneration. As a complementary study, we examine Death Receptor 6 (DR6) in the SC injury response. Building on previous findings that DR6 knockout animals show reduced axon degeneration yet aberrant SC demyelination, we find that these animals display enhanced macrophage recruitment, potentially driven by increased chemokine release from SCs, further supporting the notion that glial reprogramming and axon degeneration can be uncoupled. Together, these studies challenge a neuron-centric view of nerve injury and have direct relevance to the design and timing of SARM1 inhibitors currently advancing through clinical development.

PHD (Doctor of Philosophy)

Schwann Cell; Peripheral Nerve Injury; Sarm1; DR6; Axon Degeneration

English

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2026-04-20