N-Cadherin-Functionalized Nanofiber Hydrogel Facilitates Spinal Cord Injury Repair by Building a Favorable Niche for Neural Stem Cells

Abstract The inhospitable niche at the injury site after spinal cord injury (SCI) brings several challenges to neural stem cell (NSC) therapy, such as limited NSC retention and neuronal differentiation. Biomaterial-based stem cell transplantation has become a promising strategy for building a favorable niche to stem cells. Herein, an aligned fibrin nanofiber hydrogel modified with N-Cadherin-Fc (AFGN) was fabricated by electrospinning and biochemical conjugation to deliver NSCs for SCI repair. The AFGN hydrogel provides multimodal cues, including oriented nanofibrous topography, soft stiffness, and specific cell binding ligand, for directing NSC functions and nerve regeneration. The conjugated N-Cadherin-Fc recapitulated the homophilic cell–cell interaction for NSCs’ adhesion on AFGN and modulated cellular mechanosensing in response to AFGN for NSC differentiation. In addition, the AFGN hydrogel carrying exogenous NSCs was implanted in a rat 2 mm-long complete transected SCI model and significantly promoted the grafted NSCs retention, immunomodulation, neuronal differentiation, and in vivo integration with inherent neurons, thus finally achieved renascent neural relay formation and an encouraging locomotor functional recovery. Altogether, this study represents a valuable strategy for boosting NSC-based therapy in SCI regeneration by engineering an NSC-specific niche. Graphical abstract