3D-Printed hydrogel scaffolds with NRG1 sustained-release microspheres for enhanced dedifferentiation and myelin regeneration in peripheral nerve injury

Remyelination is critical for functional recovery following peripheral nerve injury (PNI). Although autologous Schwann cell (ASC) transplantation promotes effective myelin repair, its clinical translation remains limited by donor availability and associated morbidity. Bone marrow-derived Schwann-like cells (B-dSCs) offer a promising alternative; however, their inadequate dedifferentiation capacity significantly constrains therapeutic outcomes. Neuregulin-1 (NRG1), a key axonal signal, effectively induces Schwann cell dedifferentiation but requires precise, sustained delivery to exert optimal effects. Here, we developed a 3D-printed hydrogel scaffold incorporating NRG1-loaded sustained-release microspheres (NRG1-SRMs) to achieve localized, prolonged NRG1 release. In vitro studies demonstrated that NRG1 significantly enhanced dedifferentiation and remyelination capacity of B-dSCs in a dorsal root ganglion (DRG) co-culture system. Mechanistically, NRG1 promoted dedifferentiation by activating the c-Jun N-terminal kinase (JNK) signaling pathway—a pivotal regulator of Schwann cell plasticity. Pharmacological inhibition of JNK markedly suppressed NRG1-induced dedifferentiation and downregulated myelin-associated gene expression, confirming pathway specificity. Furthermore, the 3D-printed scaffold effectively maintained uniform NRG1 distribution, facilitating enhanced axonal regeneration and improved myelin integrity. Collectively, these findings highlight the essential role of JNK signaling in NRG1-driven Schwann cell dedifferentiation, underscoring the therapeutic promise of combining sustained-release systems with engineered cell therapies to advance peripheral nerve repair.