Abstract
Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Inflammation after ICH contributes to clinical outcomes, but the relevant molecular mechanisms remain poorly understood. In studies of peripheral leukocyte counts and mRNA-sequencing (mRNA-seq), our group previously reported that monocytes and Interleukin-8 (IL-8) were important contributors to post-ICH inflammation. microRNA (miRNA) are powerful regulators of gene expression and promising therapeutic targets. We now report findings from an integrated analysis of miRNA-seq and mRNA-seq in peripheral blood mononuclear cells (PBMCs) from a swine ICH model. In 10 pigs, one PBMC sample was collected immediately prior to ICH induction and a second 6 h later; miRNA-seq and mRNA-seq were completed for each sample. An aggregate score calculation determined which miRNA regulated the differentially expressed mRNA. Networks of molecular interactions were generated for the combined miRNA/target mRNA. A total of 227 miRNA were identified, and 46 were differentially expressed after ICH (FDR < 0.05). The anti-inflammatory miR-181a was decreased post-ICH, and it was the most highly connected miRNA in the miRNA/mRNA bioinformatic network analysis. miR-181a has interconnected pathophysiology with IL-8 and monocytes; in prior studies, we found that IL-8 and monocytes contributed to post-ICH inflammation and ICH clinical outcome, respectively. miR-181a was a significant mediator of post-ICH inflammation and is promising for further study, including as a potential therapeutic target. This investigation also demonstrated feasible methodology for miRNA-seq/mRNA-seq analysis in swine that is innovative, and with unique challenges, compared with transcriptomics research in more established species.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The transcriptomics data for the submitted manuscript are publicly available through the National Center for Biotechnology Information Gene Expression Omnibus. mRNA-seq data: record number GSE124624. microRNA-seq data: record number GSE155242.
References
Adeoye O, Clark JF, Khatri P, Wagner KR, Zuccarello M, Pyne-Geithman GJ (2011) Do current animal models of intracerebral hemorrhage mirror the human pathology? Transl Stroke Res 2:17–25. https://doi.org/10.1007/s12975-010-0037-1
Adeoye O et al (2014) Peripheral monocyte count is associated with case fatality after intracerebral hemorrhage. J Stroke Cerebrovasc Dis 23:e107-111. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.09.006
Askenase MH, Sansing LH (2016) Stages of the inflammatory response in pathology and tissue repair after intracerebral hemorrhage seminars in neurology 36:288–297. https://doi.org/10.1055/s-0036-1582132
Bader GD, Hogue CW (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinf 4:2. https://doi.org/10.1186/1471-2105-4-2
Bidzhekov K et al (2012) microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thrombosis and haemostasis 107:619–625. https://doi.org/10.1160/th11-09-0607
Bruen R, Fitzsimons S, Belton O (2019) miR-155 in the resolution of atherosclerosis. Front Pharmacol 10:463. https://doi.org/10.3389/fphar.2019.00463
Casimir GJ, Duchateau J (2011) Gender differences in inflammatory processes could explain poorer prognosis for males. J Clin Microbiol 49:478; author reply 478–479. https://doi.org/10.1128/jcm.02096-10
Chen H, Jin Y, Chen H, Liao N, Wang Y, Chen J (2017) MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-kappaB pathway in human monocytes. Int J Mol Med 39:1525–1532. https://doi.org/10.3892/ijmm.2017.2951
Chen S, Yang Q, Chen G, Zhang JH (2015) An update on inflammation in the acute phase of intracerebral hemorrhage. Transl Stroke Res 6:4–8. https://doi.org/10.1007/s12975-014-0384-4
Cui Q et al (2018) Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma. Oncotarget 9:34644–34657. https://doi.org/10.18632/oncotarget.26141
Cunningham F et al (2019) Ensembl 2019. Nucleic Acids Res 47:D745-d751. https://doi.org/10.1093/nar/gky1113
Curtale G, Rubino M, Locati M (2019) MicroRNAs as molecular switches in macrophage activation. Front Immunol 10:799. https://doi.org/10.3389/fimmu.2019.00799
Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immun 8:1086–1094. https://doi.org/10.1038/ni1511
Duroux-Richard I, Robin M, Peillex C, Apparailly F (2019) MicroRNAs: fine tuners of monocyte heterogeneity. Front Immunol 10:2145. https://doi.org/10.3389/fimmu.2019.02145
Fairbairn L, Kapetanovic R, Sester DP, Hume DA (2011) The mononuclear phagocyte system of the pig as a model for understanding human innate immunity and disease. J Leukoc Biol 89:855–871. https://doi.org/10.1189/jlb.1110607
Fang Z, Du R, Edwards A, Flemington EK, Zhang K (2013) The sequence structures of human microRNA molecules and their implications PloS One 8:e54215. https://doi.org/10.1371/journal.pone.0054215
Fast QC: A quality control tool for high throughput sequence data. http://www.bioinformatics.babraham.ac.uk/projects/fastqc/. Accessed 2 June 2020
Fogel O et al (2019) Deregulation of microRNA expression in monocytes and CD4(+) T lymphocytes from patients with axial spondyloarthritis. Arthritis Res Ther 21:51. https://doi.org/10.1186/s13075-019-1829-7
Fu X, Niu T, Li X (2019) MicroRNA-126–3p Attenuates intracerebral hemorrhage-induced blood-brain barrier disruption by regulating VCAM-1 expression. Front Neurosci 13:866. https://doi.org/10.3389/fnins.2019.00866
Galicia JC, Naqvi AR, Ko CC, Nares S, Khan AA (2014) MiRNA-181a regulates Toll-like receptor agonist-induced inflammatory response in human fibroblasts. Genes Immun 15:333–337. https://doi.org/10.1038/gene.2014.24
Gallant-Behm CL et al (2019) A microRNA-29 mimic (Remlarsen) represses extracellular matrix expression and fibroplasia in the skin. J Invest Dermatol 139:1073–1081. https://doi.org/10.1016/j.jid.2018.11.007
Gareev I et al (2020) Circulating MicroRNAs as potential noninvasive biomarkers of spontaneous intracerebral hemorrhage. World Neurosurg 133:e369–e375. https://doi.org/10.1016/j.wneu.2019.09.016
Hammond MD, Ambler WG, Ai Y, Sansing LH (2014a) alpha4 integrin is a regulator of leukocyte recruitment after experimental intracerebral hemorrhage. Stroke 45:2485–2487. https://doi.org/10.1161/strokeaha.114.005551
Hammond MD et al (2014b) CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage. J Neurosci Off J Soc Neurosci 34:3901–3909. https://doi.org/10.1523/jneurosci.4070-13.2014
Haynes W (2013) Benjamini–Hochberg Method. Dubitzky W., Wolkenhauer O., Cho KH., Yokota H (editors). Encyclopedia of Systems Biology. Springer, New York, NY
Hu L, Zhang H, Wang B, Ao Q, Shi J, He Z (2019) MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase. Int Immunopharmacol 76:105887. https://doi.org/10.1016/j.intimp.2019.105887
Hu YL, Wang H, Huang Q, Wang G, Zhang HB (2018) MicroRNA-23a-3p promotes the perihematomal edema formation after intracerebral hemorrhage via ZO-1. Eur Rev Med Pharmacol Sci 22:2809–2816. https://doi.org/10.26355/eurrev_201805_14980
Huang Z, Xu H (2019) MicroRNA-181a-5p regulates inflammatory response of macrophages in sepsis. Open Med (Wars) 14:899–908. https://doi.org/10.1515/med-2019-0106
Hulsmans M, Sinnaeve P, Van der Schueren B, Mathieu C, Janssens S, Holvoet P (2012) Decreased miR-181a expression in monocytes of obese patients is associated with the occurrence of metabolic syndrome and coronary artery disease. J Clin Endocrinol Metab 97:E1213–1218. https://doi.org/10.1210/jc.2012-1008
Hutchison ER et al (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018–1028. https://doi.org/10.1002/glia.22483
Iwuchukwu I, Nguyen D, Sulaiman W (2016) MicroRNA profile in cerebrospinal fluid and plasma of patients with spontaneous intracerebral hemorrhage. CNS Neurosci Ther 22:1015–1018. https://doi.org/10.1111/cns.12656
Janssen HL et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694. https://doi.org/10.1056/NEJMoa1209026
Kapetanovic R, Fairbairn L, Beraldi D, Sester DP, Archibald AL, Tuggle CK, Hume DA (2012) Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide. J Immunol (Baltimore, Md : 1950) 188:3382–3394. https://doi.org/10.4049/jimmunol.1102649
Kim JM et al (2014) Inhibition of Let7c microRNA is neuroprotective in a rat intracerebral hemorrhage model. PloS One 9:e97946. https://doi.org/10.1371/journal.pone.0097946
Kissela B et al (2004) Stroke in a biracial population: the excess burden of stroke among blacks. Stroke 35:426–431. https://doi.org/10.1161/01.STR.0000110982.74967.3935/2/426 [pii]
Kozomara A, Birgaoanu M, Griffiths-Jones S (2019) miRBase: from microRNA sequences to function. Nucleic Acids Res 47:D155-d162. https://doi.org/10.1093/nar/gky1141
Kuhns DB, Priel DA, Gallin JI (2007) Induction of human monocyte interleukin (IL)-8 by fibrinogen through the toll-like receptor pathway. Inflammation 30:178–188. https://doi.org/10.1007/s10753-007-9035-1
Langevin S et al (2017) Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers. Oncotarget 8:82459–82474. https://doi.org/10.18632/oncotarget.19614
Langevin SM, Kuhnell D, Orr-Asman MA, Biesiada J, Zhang X, Medvedovic M, Thomas HE (2019) Balancing yield, purity and practicality: a modified differential ultracentrifugation protocol for efficient isolation of small extracellular vesicles from human serum. RNA Biol 16:5–12. https://doi.org/10.1080/15476286.2018.1564465
Langmead B, Trapnell C, Pop M, Salzberg SL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10:R25. https://doi.org/10.1186/gb-2009-10-3-r25
Lim CX et al (2020) miR-181a Modulation of ERK-MAPK signaling sustains DC-SIGN expression and limits activation of monocyte-derived dendritic cells. Cell Rep 30:3793–3805.e3795. https://doi.org/10.1016/j.celrep.2020.02.077
Liu G, Liu W, Guo J (2020) Clinical significance of miR-181a in patients with neonatal sepsis and its regulatory role in the lipopolysaccharide-induced inflammatory response. Exp Ther Med 19:1977–1983. https://doi.org/10.3892/etm.2020.8408
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8
Lu Q, Wu R, Zhao M, Garcia-Gomez A, Ballestar E (2019) miRNAs as therapeutic targets in inflammatory disease trends in pharmacological sciences 40:853–865. https://doi.org/10.1016/j.tips.2019.09.007
Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment F1000prime reports 6:13. https://doi.org/10.12703/p6-13
Matsumoto T, Ikeda K, Mukaida N, Harada A, Matsumoto Y, Yamashita J, Matsushima K (1997) Prevention of cerebral edema and infarct in cerebral reperfusion injury by an antibody to interleukin-8. Laboratory investigation; a journal of technical methods and pathology 77:119–125
miRBase: The microRNA database. http://mirbase.org/. Accessed 4 March 2020
Morotti A et al (2016) Leukocyte count and intracerebral hemorrhage expansion. Stroke 47:1473–1478. https://doi.org/10.1161/strokeaha.116.013176
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das S (2016) Heart disease and stroke statistics—2016 update: a report from the American Heart Association Circulation 133:e38–60
Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. https://doi.org/10.1038/nri3073
Ouyang Y et al (2019) MiR-21–5p/dual-specificity phosphatase 8 signalling mediates the anti-inflammatory effect of haem oxygenase 1 in aged intracerebral haemorrhage rats. Aging Cell 18:e13022. https://doi.org/10.1111/acel.13022
Ouyang YB et al (2012) miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiol Dis 45:555–563. https://doi.org/10.1016/j.nbd.2011.09.012
Qiagen ingenuity pathway analysis http://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis. Accessed 3 June 2020
Rathod KS et al (2017) Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans. J Clin Investig 127:169–182. https://doi.org/10.1172/jci89429
Rodriguez-Yanez M, Brea D, Arias S, Blanco M, Pumar JM, Castillo J, Sobrino T (2012) Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage. J Neuroimmunol 247:75–80. https://doi.org/10.1016/j.jneuroim.2012.03.019
Rouhi A, Mager DL, Humphries RK, Kuchenbauer F (2008) MiRNAs, epigenetics, and cancer Mamm Genome
Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787. https://doi.org/10.1038/nri3086
Sansing LH, Harris TH, Kasner SE, Hunter CA, Kariko K (2011a) Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage. Actaneurochirurgica Supplement 111:173–178. https://doi.org/10.1007/978-3-7091-0693-8_29
Sansing LH, Harris TH, Welsh FA, Kasner SE, Hunter CA, Kariko K (2011b) Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann Neurol 70:646–656. https://doi.org/10.1002/ana.22528
Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, Ottenhoff TH (2008) Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol (Baltimore, Md : 1950) 181:2220–2226
Schook L et al (2005) Swine in biomedical research: creating the building blocks of animal models. Anim Biotechnol 16:183–190
Schroder K et al (2012) Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proc Natl Acad Sci USA 109:E944–953. https://doi.org/10.1073/pnas.1110156109
Seto AG, Beatty X, Lynch JM, Hermreck M, Tetzlaff M, Duvic M, Jackson AL (2018) Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma. Br J Haematol 183:428–444. https://doi.org/10.1111/bjh.15547
Shimizu S et al (2015) Sensitization of H2O2-induced TRPM2 activation and subsequent interleukin-8 (CXCL8) production by intracellular Fe(2+) in human monocytic U937 cells. Int J Biochem Cell Biol 68:119–127. https://doi.org/10.1016/j.biocel.2015.09.005
Shu L, Wang Z, Wang Q, Wang Y, Zhang X (2018) Signature miRNAs in peripheral blood monocytes of patients with gastric or breast cancers. Open Biol 8. https://doi.org/10.1098/rsob.180051
Stary CM et al (2017) Inhibition of miR-181a protects female mice from transient focal cerebral ischemia by targeting astrocyte estrogen receptor-α. Mol Cell Neurosci 82:118–125. https://doi.org/10.1016/j.mcn.2017.05.004
Szklarczyk D et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607-d613. https://doi.org/10.1093/nar/gky1131
Taylor RA, Hammond MD, Ai Y, Sansing LH (2014) CX3CR1 signaling on monocytes is dispensable after intracerebral hemorrhage. PloS One 9:e114472. https://doi.org/10.1371/journal.pone.0114472
Villa P et al (2007) The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats. Mol Med (Cambridge, Mass) 13:125–133. https://doi.org/10.2119/2007-00008.Villa
Wagner KR (2007) Modeling intracerebral hemorrhage: glutamate, nuclear factor-kappa B signaling and cytokines. Stroke 38:753–758. https://doi.org/10.1161/01.STR.0000255033.02904.db
Wagner KR et al (1996) Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 27:490–497
Walsh KB et al (2015) Monocyte Count and 30-Day Case Fatality in Intracerebral Hemorrhage Stroke 46:2302–2304. https://doi.org/10.1161/strokeaha.115.009880
Walsh KB, Zhang X, Zhu X, Wohleb E, Woo D, Lu L, Adeoye O (2019a) Intracerebral hemorrhage induces inflammatory gene expression in peripheral blood: global transcriptional profiling in ICH patients. DNA Cell Biol 38:660–669
Walsh KB, Zhang X, Zhu X, Wohleb E, Woo D, Lu L, Adeoye O (2019b) Intracerebral hemorrhage induces monocyte-related gene expression within six hours: Global transcriptional profiling in swine ICH. Metab Brain Dis 34:763–774. https://doi.org/10.1007/s11011-019-00399-z
Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92:463–477. https://doi.org/10.1016/j.pneurobio.2010.08.001
Wang J, Zhu Y, Jin F, Tang L, He Z, He Z (2016a) Differential expression of circulating microRNAs in blood and haematoma samples from patients with intracerebralhaemorrhage. J Int Med Res 44:419–432. https://doi.org/10.1177/0300060516630852
Wang MD et al (2016b) High serum MiR-130a levels are associated with severe perihematomal edema and predict adverse outcome in acute ICH. Mol Neurobiol 53:1310–1321. https://doi.org/10.1007/s12035-015-9099-0
Wang XM et al (2016c) Expressions of serum inflammatory cytokines and their relationship with cerebral edema in patients with acute basal ganglia hemorrhage. Eur Rev Med Pharmacol Sci 20:2868–2871
Wang Z et al (2018) Plasma miR-124 is a promising candidate biomarker for human intracerebral hemorrhage stroke. Mol Neurobiol 55:5879–5888. https://doi.org/10.1007/s12035-017-0808-8
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics (Oxford, England) 26:2190–2191. https://doi.org/10.1093/bioinformatics/btq340
Xi T et al (2018) miR-27a-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting endothelial aquaporin-11. J Biol Chem 293:20041–20050. https://doi.org/10.1074/jbc.RA118.001858
Xie W, Li M, Xu N, Lv Q, Huang N, He J, Zhang Y (2013) MiR-181a regulates inflammation responses in monocytes and macrophages PloS One 8:e58639. https://doi.org/10.1371/journal.pone.0058639
Xu LJ, Ouyang YB, Xiong X, Stary CM, Giffard RG (2015) Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp Neurol 264:1–7. https://doi.org/10.1016/j.expneurol.2014.11.007
Xu W, Li F, Liu Z, Xu Z, Sun B, Cao J, Liu Y (2017) MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury. Oncotarget 8:70669–70684. https://doi.org/10.18632/oncotarget.19974
Yang N, Coukos G, Zhang L (2008) MicroRNA epigenetic alterations in human cancer: one step forward in diagnosis and treatment. Int J Cancer 122:963–968
Yang Z et al (2018) Let-7a promotes microglia M2 polarization by targeting CKIP-1 following ICH. Immunol Lett 202:1–7. https://doi.org/10.1016/j.imlet.2018.07.007
Yu A et al (2017) MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-alpha pathway in intracerebral hemorrhage. Immunol Lett 182:1–11. https://doi.org/10.1016/j.imlet.2016.12.003
Zhang H, Wang Y, Lv Q, Gao J, Hu L, He Z (2018a) MicroRNA-21 overexpression promotes the neuroprotective efficacy of mesenchymal stem cells for treatment of intracerebral hemorrhage. Front Neurol 9:931. https://doi.org/10.3389/fneur.2018.00931
Zhang XD, Fan QY, Qiu Z, Chen S (2018b) MiR-7 alleviates secondary inflammatory response of microglia caused by cerebral hemorrhage through inhibiting TLR4 expression. Eur Rev Med Pharmacol Sci 22:5597–5604. https://doi.org/10.26355/eurrev_201809_15824
Zhang Y, Shan Z, Zhao Y, Ai Y (2019) Sevoflurane prevents miR-181a-induced cerebral ischemia/reperfusion injury. Chem Biol Interact 308:332–338. https://doi.org/10.1016/j.cbi.2019.06.008
Zhao S et al (2017) QuickMIRSeq: a pipeline for quick and accurate quantification of both known miRNAs and isomiRs by jointly processing multiple samples from microRNA sequencing. BMC Bioinf 18:180. https://doi.org/10.1186/s12859-017-1601-4
Zhu Y, Wang JL, He ZY, Jin F, Tang L (2015) Association of altered serum microRNAs with perihematomal edema after acute intracerebral hemorrhage. PloS One 10:e0133783. https://doi.org/10.1371/journal.pone.0133783
Funding
The authors would like to acknowledge financial support for the reported research from the University of Cincinnati Gardner Neuroscience Institute (UCGNI). This provided funding for the blood sample collection, processing, RNA sequencing, and bioinformatic analysis. Financial support for other aspects of the swine experiments only was provided by Sense Diagnostics, LLC, Cincinnati, Ohio. The research reported in the submitted manuscript was performed as an ancillary study to a swine intracerebral hemorrhage study performed by Sense Diagnostics, LLC, for the testing of a non-invasive brain monitor. The reported results in this manuscript have no relationship with the development of this non-invasive brain monitoring device.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by K Walsh, K Zimmerman, X Zhang, and C Langefeld. The first draft of the manuscript was written by K Walsh, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics Approval
The study protocol was approved by the University of Cincinnati Institutional Animal Care and Use Committee, and all aspects of the study were conducted in accordance with the US Public Health Service’s Policy on Human Care and Use of Laboratory Animals.
Conflicts of Interest
The author O Adeoye discloses holding equity in Sense Diagnostics, LLC, a company indirectly related to the submitted manuscript as described above in “funding.”
All other authors report no relevant conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Walsh, K.B., Zimmerman, K.D., Zhang, X. et al. miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model. J Mol Neurosci 71, 1802–1814 (2021). https://doi.org/10.1007/s12031-021-01815-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-021-01815-9