Three-dimensional-printed hydrogel scaffolds with neuregulin-1 sustained-release microspheres for enhanced dedifferentiation and myelin regeneration in peripheral nerve injury

Abstract

Remyelination is critical for functional recovery following peripheral nerve injury. Although autologous Schwann cell transplantation promotes effective myelin repair, its clinical translation remains limited due to donor scarcity and associated morbidity. Bone marrow-derived Schwann-like cells (B-dSCs) offer a promising alternative; however, their limited 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 three-dimensional (3D)-printed hydrogel scaffold incorporating NRG1-loaded sustained-release microspheres to achieve localized, prolonged NRG1 delivery. In vitro studies demonstrated that NRG1 significantly enhanced the dedifferentiation and remyelination capacity of B-dSCs in a dorsal root ganglion 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 and underscore the therapeutic promise of combining sustained-release systems with engineered cell therapies to advance peripheral nerve repair.

Keywords

C-Jun N-terminal kinase pathway / Dedifferentiation / Neuregulin-1 / Peripheral nerve injury / Schwann cells / Sustained-release microspheres

Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 82201785), the Guangdong Basic and Applied Basic Research Foundation (supported by the Medical Scientific Research Foundation of Guangdong Province, China, Grant No. 20241120250; A2025267), the Provincial Enterprise Joint Fund—General Project (Grant No. 2022A1515220046), Guangzhou City-University (Institute)-Enterprise Joint Funding Project (Grant No. SL2023A03J00448) as well as Science and Technology Projects in Guangzhou and the City- University (Institute) Enterprise Joint Funded Project (Grant Nos. 202201020633; 2024A03J0277).

Conflict of Interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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