A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets

• DOI: 10.1016/j.neuron.2024.06.021
• Publication Date: 2024-07-16T15:16:14Z
• Authors: Ruchira M. Jha; Dhivyaa Rajasundaram; Chaim Sneiderman; Brent T. Schlegel; Casey O’Brien; Zujian Xiong; Keri Janesko-Feldman; Ria Trivedi; Vincent Vagni; Benjamin E. Zusman; Joshua S. Catapano; Adam Eberle; Shashvat M. Desai; Ashutosh P. Jadhav; Sandra Mihaljevic; Margaux Miller; Sudhanshu Raikwar; Anupama Rani; Jarrod Rulney; Shima Shahjouie; Itay Raphael; Aditya Kumar; Chia-Ling Phuah; Ethan A. Winkler; Dennis W. Simon; Patrick M. Kochanek; Gary Kohanbash

Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.