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Thyroid hormone T4 mitigates traumatic brain injury in mice by dynamically remodeling cell type specific genes, pathways, and networks in hippocampus and frontal cortex.
Zhang, Guanglin; Diamante, Graciel; Ahn, In Sook; Palafox-Sanchez, Victoria; Cheng, Jenny; Cheng, Michael; Ying, Zhe; Wang, Susanna Sue-Ming; Abuhanna, Kevin Daniel; Phi, Nguyen; Arneson, Douglas; Cely, Ingrid; Arellano, Kayla; Wang, Ning; Gomez-Pinilla, Fernando; Yang, Xia.
Afiliação
  • Zhang G; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Diamante G; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Ahn IS; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Palafox-Sanchez V; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Cheng J; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular, Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Cheng M; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Ying Z; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wang SS; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Abuhanna KD; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
  • Phi N; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Arneson D; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Cely I; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Arellano K; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Wang N; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Gomez-Pinilla F; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA 90095, USA; Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA 900
  • Yang X; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular, Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program,
Biochim Biophys Acta Mol Basis Dis ; : 167344, 2024 Jul 12.
Article em En | MEDLINE | ID: mdl-39004380
ABSTRACT
The 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 but the mechanism is poorly understood. To 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 in a mouse model of mTBI. We found 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 of 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 revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with 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. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article