Qiuyun Yang1,2,8, Lingxuan Zhang3,8, Manrui Li1,8, Yang Xu1, Xiaogang Chen4, Ruixuan Yuan3, Xiaofeng Ou5, Min He5, Miao Liao1, Lin Zhang6, Hao Dai4, Meili Lv7, Xiaoqi Xie5, Weibo Liang1 and Xiameng Chen4 1Department of Forensic Genetics, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610000, China; 2West China Second University Hospital, Sichuan University, Chengdu 610041, China; 3West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610000, China; 4Department of Forensic Pathology and Forensic Clinical Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610000, China; 5Department of Critical Care Medicine, Sichuan University, Chengdu 610000, China; 6Sichuan University, Chengdu 610041, China; 7Department of Immunology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610000, China

↵8 These authors contributed equally to this work.

Corresponding authors: xmchen990gmail.com, liangweibogmail.com, xiaoqixie1898060163.com Abstract

The subventricular zone (SVZ) is a neurogenic niche that contributes to homeostasis and repair after brain injury. However, the effects of mild traumatic brain injury (mTBI) on the divergence of the regulatory DNA landscape within the SVZ and its link to functional alterations remain unexplored. In this study, we mapped the transcriptome atlas of murine SVZ and its responses to mTBI at the single-cell level. We observed cell-specific gene expression changes following mTBI and unveiled diverse cell-to-cell interaction networks that influence a wide array of cellular processes. Moreover, we report novel neurogenesis lineage trajectories and related key transcription factors, which we validate through loss-of-function experiments. Specifically, we validate the role of Tcf7l1, a cell cycle gene regulator, in promoting neural stem cell differentiation toward the neuronal lineage after mTBI, providing a potential target for regenerative medicine. Overall, our study profiles an SVZ transcriptome reference map, which underlies the differential cellular behavior in response to mTBI. The identified key genes and pathways that may ameliorate brain damage or facilitate neural repair serve as a comprehensive resource for drug discovery in the context of mTBI.

Received March 17, 2023. Accepted September 11, 2023.