Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Induction of TBI with Lateral Fluid-Percussion
2.3. Sampling of Plasma and Brain Tissue
2.4. Small RNA-Seq from Plasma
2.4.1. Library Preparation and Sequencing
2.4.2. Quantification of miRNAs and Differential Expression Analysis
2.4.3. Identification of Expression Pattern Differences with Machine Learning
2.5. Technical Validation of Small RNA-Seq Data
2.5.1. Selection of an Endogenous miRNA for Normalization of RT-qPCR
2.5.2. RT-qPCR of Selected miRNA Candidates
2.6. Analysis of Validated miRNAs in the Whole Cohort
2.6.1. Plasma Hemolysis Measurement
2.6.2. RT-qPCR of Validated miRNA Candidates
2.6.3. ddPCR of Validated miRNA Candidates
2.7. Analysis of the Validated miRNAs in Plasma from Human TBI Patients
2.7.1. ddPCR of Validated miRNA Candidates
2.7.2. ddPCR from Small RNA Concentration-Normalized Samples
2.8. Statistical Analysis
3. Results
3.1. Impact Severity, Mortality, Duration of Postimpact Apnea, and Time to Righting
3.2. Quality Control Analysis from Tail-Vein Plasma and Extracted RNA Prior to Small RNA-Seq
3.2.1. Hemolysis Measurement with NanoDrop
3.2.2. Hemolysis Measurement with the ΔCq (miR-23a–miR-451) Method
3.2.3. Amplification of Endogenous miRNAs and Spike-In Controls
3.3. Primary miRNA Quantification
3.4. Differential Expression Analysis
3.5. Expression Pattern Differences from Machine Learning
3.6. Technical Validation of Regulated rno-miR-9a-3p, rno-miR-153-3p, rno-miR-15a-3p, rno-miR-136-3p, and rno-miR-434-3p Levels in Samples Used for miR-Seq
3.6.1. miR-9a-3p
3.6.2. miR-136-3p
3.6.3. miR-434-3p
3.7. Validation of Regulated rno-miR-9a-3p, rno-miR-136-3p, and rno-miR-434-3p Plasma Levels in Whole Animal Cohort
3.7.1. Hemolysis
3.7.2. Plasma Levels of miR-9a-3p, miR-136-3p, and miR-434-3p Assessed with RT-qPCR
3.7.3. Absolute Copy Numbers of miR-9a-3p, miR-136-3p, and miR-434-3p in Plasma Assessed with ddPCR
3.8. ddPCR of hsa-miR-9-3p and hsa-miR-136-3p in Human TBI Plasma
3.8.1. Hemolysis
3.8.2. Effect of Sex, Age, and Injury-Sampling Interval on Plasma miR-9-3p and miR-136 Levels
3.8.3. Absolute Copy Numbers for miR-9-3p and miR-136-3p in Plasma Assessed with ddPCR
3.8.4. Association of miR-9-3p and miR-136 Levels with Plasma S100B Concentrations
4. Discussion
4.1. mTBI Led to an Acute Increase in Plasma miR-9a-3p, miR-136-3p, and miR-434-3p Levels
4.2. An Impact Severity -Dependent Increase was Observed in the Plasma miRNA Signature
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Characteristics | Controls (n = 14) | mTBI (n = 15) | sTBI (n = 2) |
---|---|---|---|
Age (mean ± SD) | 63 ± 6 | 68 ± 12 | 63 ± 3 |
Female (n (%)) | 4 (29) | 5 (33) | 0 (0) |
GCS (mean ± SD) | - | 14.8 ± 0.6 | 3.5 ± 0.7 |
Post-traumatic amnesia (n (%)) | - | 12 (80) | - |
Hours from injury to plasma sampling (mean ± SD) | - | 11 ± 12 | - |
Plasma S100B (µg/L) (mean ± SD) | - | 0.2 ± 0.1 | - |
Plasma S100B > 0.1 µg/L (n (%)) | - | 11 (73) | - |
Alcohol consumed (n (%)) | - | 3 (20) | 1 (50) |
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Das Gupta, S.; Ciszek, R.; Heiskanen, M.; Lapinlampi, N.; Kukkonen, J.; Leinonen, V.; Puhakka, N.; Pitkänen, A. Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury. Int. J. Mol. Sci. 2021, 22, 1563. https://doi.org/10.3390/ijms22041563
Das Gupta S, Ciszek R, Heiskanen M, Lapinlampi N, Kukkonen J, Leinonen V, Puhakka N, Pitkänen A. Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury. International Journal of Molecular Sciences. 2021; 22(4):1563. https://doi.org/10.3390/ijms22041563
Chicago/Turabian StyleDas Gupta, Shalini, Robert Ciszek, Mette Heiskanen, Niina Lapinlampi, Janne Kukkonen, Ville Leinonen, Noora Puhakka, and Asla Pitkänen. 2021. "Plasma miR-9-3p and miR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury" International Journal of Molecular Sciences 22, no. 4: 1563. https://doi.org/10.3390/ijms22041563