Abstract
High-throughput sequencing technologies could improve diagnosis and classification of TBI subgroups. Because recent studies showed that circulating microRNAs (miRNAs) may serve as noninvasive markers of TBI, we performed miRNA-seq to study TBI-induced changes in rat hippocampal miRNAs up to one year post-injury. We used miRNA PCR arrays to interrogate differences in serum miRNAs using two rat models of TBI (controlled cortical impact [CCI] and fluid percussion injury [FPI]). The translational potential of our results was evaluated by miRNA-seq analysis of human control and TBI (acute and chronic) serum samples. Bioinformatic analyses were performed using Ingenuity Pathway Analysis, miRDB, and Qlucore Omics Explorer. Rat miRNA profiles identified TBI across all acute and chronic intervals. Rat CCI and FPI displayed distinct serum miRNA profiles. Human miRNA profiles identified TBI across all acute and chronic time points and, at 24 hours, discriminated between focal and diffuse injuries. In both species, predicted gene targets of differentially expressed miRNAs are involved in neuroplasticity, immune function and neurorestoration. Chronically dysregulated miRNAs (miR-451a, miR-30d-5p, miR-145-5p, miR-204-5p) are linked to psychiatric and neurodegenerative disorders. These data suggest that circulating miRNAs in biofluids can be used as “molecular fingerprints” to identify acute, chronic, focal or diffuse TBI and potentially, presence of neurodegenerative sequelae.
Highlights
High-throughput sequencing technologies could improve diagnosis and classification of traumatic brain injuries (TBI) subgroups
We noted the prominence of neuro-restorative signaling in the gene targets of downregulated miRNAs. This proof-of-concept study began with the goal of deciphering the underlying molecular progression of chronic TBI in the rat hippocampus using miRNA sequencing
With several insights gained from these data and from analyses of serum miRNA profiling data generated in two rat TBI models, we conducted a pilot study of human TBI using a limited number of archived acute and chronic TBI serum samples
Summary
High-throughput sequencing technologies could improve diagnosis and classification of TBI subgroups. Since our objective was to evaluate the translational potential of rat miRNA-seq results, we sequenced a limited set of archived human TBI serum samples representing multiple acute and chronic post-injury intervals and age-matched control serum. In these exploratory studies with rat and human tissues, we tested three hypotheses, 1) miRNA-seq profiles would identify TBI at all acute and chronic post-injury intervals, 2) miRNA-seq profiles would discriminate between focal and diffuse TBI and 3) serum miRNA-seq would reveal potential miRNA markers of neuropsychiatric and neurodegenerative sequelae
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