An NT-3-releasing bioscaffold supports the formation of TrkC-modified neural stem cell-derived neural network tissue with efficacy in repairing spinal cord injury

• Published in: Bioactive materials Vol. 6; no. 11; pp. 3766 - 3781
• Main Authors: Li, Ge, Zhang, Bao, Sun, Jia-hui, Shi, Li-yang, Huang, Meng-yao, Huang, Li-jun, Lin, Zi-jing, Lin, Qiong-yu, Lai, Bi-qin, Ma, Yuan-huan, Jiang, Bin, Ding, Ying, Zhang, Hong-bo, Li, Miao-xin, Zhu, Ping, Wang, Ya-qiong, Zeng, Xiang, Zeng, Yuan-shan
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.11.2021; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Neural network tissue; Neurotrophin-3; Self-organization; Spinal cord injury; Tropomyosin kinase receptor C; Tropomyosin kinase receptor C; Neural network tissue; Neurotrophin-3; Spinal cord injury; Self-organization
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2021.03.036

The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction, which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury. Herein, we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge (NF-GS) scaffold might improve tissue repair efficacy. To test this, we engineered tropomyosin receptor kinase C (TrkC)-modified neural stem cell (NSC)-derived neural network tissue with robust viability within an NF-GS scaffold. When NSCs were genetically modified to overexpress TrkC, the NT-3 receptor, a functional neuronal population dominated the neural network tissue. The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord. Additionally, host nerve fibers regenerated into the graft, making synaptic connections with the donor neurons. Accordingly, motor function recovery was significantly improved in rats with spinal cord injury (SCI) that received TrkC-modified NSC-derived neural network tissue transplantation. Together, the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI. Scheme 1. A neurotrophin-3 (NT-3) sustained-release bioscaffold supports the formation of tyrosine kinase receptor C (TrkC)-modified neural stem cell-derived neural network tissue with efficacy in repairing spinal cord injury. [Display omitted] •A NT-3 sustained-release scaffold confers a microenvironment partially simulating the developmental spinal cord.•The NT-3 microenvironment boosts neuronal differentiation of TrkC-modified NSCs by interactions between ligand and receptor.•TrkC-NSCs is self-organized into a neural network tissue with typical neural excitability in 3D bioactive scaffold in vitro.•The grafted neural network tissue can survive and maintain neural property, and improve motor function of paralyzed rats.