A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.
Document Type
Article
Abstract
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.
Publication Date
7-11-2024
Publication Title
Neuron
ISSN
1097-4199
PubMed ID
39019041
Digital Object Identifier (DOI)
10.1016/j.neuron.2024.06.021
Recommended Citation
Jha, Ruchira M; Rajasundaram, Dhivyaa; Sneiderman, Chaim; Schlegel, Brent T; O'Brien, Casey; Xiong, Zujian; Janesko-Feldman, Keri; Trivedi, Ria; Vagni, Vincent; Zusman, Benjamin E; Catapano, Joshua S; Eberle, Adam; Desai, Shashvat M; Jadhav, Ashutosh P; Mihaljevic, Sandra; Miller, Margaux; Raikwar, Sudhanshu; Rani, Anupama; Rulney, Jarrod; Shahjouie, Shima; Raphael, Itay; Kumar, Aditya; Phuah, Chia-Ling; Winkler, Ethan A; Simon, Dennis W; Kochanek, Patrick M; and Kohanbash, Gary, "A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets." (2024). Translational Neuroscience. 2391.
https://scholar.barrowneuro.org/neurobiology/2391