GPNMB enables lysosomal adaptation required for myelin clearance and nerve regeneration after peripheral nerve injury
Year: 2026
Type: preprint
Abstract: Recovery from peripheral nerve injury involves coordinated axonal and immune repair programs that promote tissue regeneration. However, the mechanisms regulating immune-mediated repair remain incompletely understood. Here, we demonstrate that glycoprotein non-metastatic melanoma protein B (GPNMB) is a key regulator of repair processes following peripheral nerve injury. In a mouse sciatic nerve crush model, loss of Gpnmb impaired functional recovery after injury. MRI and histological analyses revealed persistent myelin debris accumulation, defective debris clearance, and impaired macrophage lysosomal function within injured nerves. Mechanistic studies showed that GPNMB-deficient human iPSC-derived macrophages exhibited impaired lysosomal adaptation, reduced lysosomal fitness, and defective processing of myelin-associated cargo, resulting in inefficient degradation of injury-associated material. These defects were accompanied by impaired acquisition of repair-associated cellular programs. Together, our findings identify GPNMB as a critical regulator of lysosome-dependent repair programs during nerve regeneration and demonstrate that efficient GPNMB-dependent myelin processing is required for functional recovery following peripheral nerve injury. Graphical abstract GPNMB enables efficient nerve regeneration after injury GPNMB promotes lysosomal adaptation in injury-responsive macrophages and microglia, enabling efficient myelin debris clearance and successful nerve regeneration. GPNMB coordinates injury-responsive myeloid and glial remodeling following peripheral nerve injury. After sciatic nerve crush, GPNMB is induced in macrophages, Schwann cells, and spinal cord microglia, where it promotes lysosomal adaptation and efficient myelin debris processing. By supporting reparative cellular states and sustained debris clearance, GPNMB enables axonal regeneration and functional recovery.
Authors: Najwa Ouali Alami, Moh Panesar, Michael Obrecht, Thierry Doll, Ivan Osinni, Gilles Sansig, Zacharias Thiel, Isabelle Claerr, Daniel Greenwood, Claudia Patino, Laurent Klein, Daniela Condeescu-Ivan, Elisa Giorgetti, Christian Lambert, Georgios Kalamakis, Valerie Van Steenbergen, Lukas Hils, Carole Manneville, Matthias Müller, Mark Nash, Marie Labouesse, Derya Shimshek, Nicolau Beckmann, Oleksandr Dergai, Michael Bidinosti
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7222935728