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Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target
- Source :
- Cellular and molecular life sciences : CMLS, vol 79, iss 9
- Publication Year :
- 2022
- Publisher :
- eScholarship, University of California, 2022.
-
Abstract
- Background The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. Methods We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24-h) and subacute (7-day) phases of mTBI at single-cell resolution. Results We demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling implied astrocytes as a key regulator of the cell–cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Conclusions Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.
- Subjects :
- Traumatic
Biochemistry & Molecular Biology
Physical Injury - Accidents and Adverse Effects
Physiology
1.1 Normal biological development and functioning
Clinical Sciences
Bioengineering
Traumatic Brain Injury (TBI)
Hippocampus
Single-cell RNA sequencing
Cellular and Molecular Neuroscience
Mice
Traumatic brain injury
Underpinning research
Brain Injuries, Traumatic
TBI
Animals
2.1 Biological and endogenous factors
Aetiology
Mt-Rnr2
Molecular Biology
Traumatic Head and Spine Injury
Pharmacology
Intracellular Signaling Peptides and Proteins
Neurosciences
Brain
Cell Biology
Humanin
Brain Disorders
Brain Injuries
Astrocytes
Neurological
Molecular Medicine
Mental health
Biochemistry and Cell Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Cellular and molecular life sciences : CMLS, vol 79, iss 9
- Accession number :
- edsair.doi.dedup.....1ab12c1d3318d20d96f96b42e6cd2baa