Thyroid Hormone T4 Mitigates Traumatic Brain Injury via Dynamically Remodeling Cell Type Specific Genes and Pathways

BackgroundThe complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice. MethodTo understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages. FindingsOur multi-tissue multi-stage results showed that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks recapitulated the roles of App, Hmgb1, Fn1, and Tnf in mTBI, the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI, supporting T4 as a potential mTBI treatment. InterpretationOur systems-level approach elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications through which T4 mitigates cognitive dysfunction induced by mTBI. FundingThis work was funded by NIHR01NS117148 to X.Y. and F.G.P. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDysfunction in the brain resulting from traumatic brain injury can display immediately as well as several years post-injury. It also impacts various brain regions, including the hippocampus and frontal cortex, which are linked to distinct disease pathologies. The complexity of spatiotemporal and molecular dynamics of perturbation caused by TBI hinder our ability to establish an effective therapeutic approach. Recently, thyroid hormone poses promise as a potential therapeutic target based on our previous scRNA-seq studies. Yet, the mechanisms by which T4 alleviates mTBI, specifically those related to spatial, temporal, and cell-type specificity, remain unexplored. Added value of this studyWe examined the impact of T4 intervention in mitigating mTBI by investigating the transcriptome and functional pathways across two affected brain regions, the frontal cortex and hippocampus, in different stages of injury. Utilizing a systems biology approach, we conducted within- and between-cell-type network modeling, cell-cell communication and integrating human genome-wide association studies (GWAS) analysis. This comprehensive strategy aimed to elucidate the cellular and molecular mechanisms through which T4 averts cognitive impairments induced by mTBI. Implications of all the available evidenceOur findings offer molecular evidence that the administration of T4 impacts a wide range of genes, biological processes, and networks, thereby preventing the advancement of mTBI-induced brain dysfunction and associated diseases. This comprehensive impact of T4 suggests potential advantages in efficacy compared to other therapeutic options that concentrate on specific pathways and targets.