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Regulating Astrocytes via Short Fibers for Spinal Cord Repair

Qianyi Li,Shuaiyun Gao,Yang Qi,Nuo Shi,Zhenzhen Wang,Qimanguli Saiding,Liang Chen,Yawei Du,Bo Wang,Wenfei Yao,Bruno Sarmento,Jie Yu,Yiming Lu,Juan Wang,Wenguo Cui

Reactive astrogliosis is the main cause of secondary injury to the central nerves. Biomaterials can effectively suppress astrocyte activation, but the mechanism remains unclear. Herein, Differentially Expressed Genes (DEGs) are identified through whole transcriptome sequencing in a mouse model of spinal cord injury, revealing the VIM gene as a pivotal regulator in the reactive astrocytes. Moreover, DEGs are predominantly concentrated in the extracellular matrix (ECM). Based on these, 3D injectable electrospun short fibers are constructed to inhibit reactive astrogliosis. Histological staining and functional analysis indicated that fibers with unique 3D network spatial structures can effectively constrain the reactive astrocytes. RNA sequencing and single-cell sequencing results reveal that short fibers downregulate the expression of the VIM gene in astrocytes by modulating the “ECM receptor interaction” pathway, inhibiting the transcription of downstream Vimentin protein, and thereby effectively suppressing reactive astrogliosis. Additionally, fibers block the binding of Vimentin protein with inflammation-related proteins, downregulate the NF-κB signaling pathway, inhibit neuron apoptosis, and consequently promote the recovery of spinal cord neural function. Through mechanism elucidation-material design-feedback regulation, this study provides a detailed analysis of the mechanism chain by which short fibers constrain the abnormal spatial expansion of astrocytes and promote spinal cord neural function.