Abstract
Traumatic brain injury (TBI) can result in axonal loss and demyelination, leading to persistent damage in the white matter. Demyelinated axons are vulnerable to pathologies related to an abnormal myelin structure that expose neurons to further damage. Oligodendrocyte progenitor cells (OPCs) mediate remyelination after recruitment to the injury site. Often this process is inefficient due to inadequate OPC proliferation. To date, no effective treatments are currently available to stimulate OPC proliferation in TBI. Recombinant human erythropoietin (rhEPO) is a pleiotropic neuroprotective cytokine, and its receptor is present in all stages of oligodendroglial lineage cell differentiation. Therefore, we hypothesized that rhEPO administration would enhance remyelination after TBI through the modulation of OPC response. Utilizing a murine model of controlled cortical impact and a primary OPC culture in vitro model, we characterized the impact of rhEPO on remyelination and proliferation of oligodendrocyte lineage cells. Myelin black gold II staining of the peri-contusional corpus callosum revealed an increase in myelinated area in association with an increase in BrdU-positive oligodendrocytes in injured mice treated with rhEPO. Furthermore, morphological analysis of OPCs showed a decrease in process length in rhEPO-treated animals. RhEPO treatment increased OPC proliferation after in vitro CSPG exposure. Erythropoietin receptor (EPOr) gene knockdown using siRNA prevented rhEPO-induced OPC proliferation, demonstrating that the rhEPO effect on OPC response is EPOr activation dependent. Together, our findings demonstrate that rhEPO administration may promote myelination by increasing oligodendrocyte lineage cell proliferation after TBI.
Similar content being viewed by others
Data Availability
All data is available on request from the authors.
References
Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9(4):231–6.
Filley CM, Kelly JP. White matter and cognition in traumatic brain injury. J Alzheimers Dis. 2018;65(2):345–62.
Marklund N, Bellander BM, Godbolt AK, Levin H, McCrory P, Thelin EP. Treatments and rehabilitation in the acute and chronic state of traumatic brain injury. J Intern Med. 2019;285(6):608–23.
James SL, Theadom A, Ellenbogen RG, Bannick MS, Mountjoy-Venning WC, Lucchesi LR, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):56–87.
Lipton ML, Gellella E, Lo C, Gold T, Ardekani BA, Shifteh K, et al. Multifocal white matter ultrastructural abnormalities in mild traumatic brain injury with cognitive disability: a voxel-wise analysis of diffusion tensor imaging. J Neurotrauma. 2008;25(11):1335–42.
Armstrong RC, Mierzwa AJ, Marion CM, Sullivan GM. White matter involvement after TBI: clues to axon and myelin repair capacity. Exp Neurol. 2016;275(Pt 3):328–33.
Chung S, Fieremans E, Wang X, Kucukboyaci NE, Morton CJ, Babb J, et al. White matter tract integrity: an indicator of axonal pathology after mild traumatic brain injury. J Neurotrauma. 2018;35(8):1015–20.
Dent KA, Christie KJ, Bye N, Basrai HS, Turbic A, Habgood M, et al. Oligodendrocyte birth and death following traumatic brain injury in adult mice. PLoS ONE. 2015;10(3):e0121541.
Mierzwa AJ, Marion CM, Sullivan GM, McDaniel DP, Armstrong RC. Components of myelin damage and repair in the progression of white matter pathology after mild traumatic brain injury. J Neuropathol Exp Neurol. 2015;74(3):218–32.
Reeves TM, Smith TL, Williamson JC, Phillips LL. Unmyelinated axons show selective rostrocaudal pathology in the corpus callosum after traumatic brain injury. J Neuropathol Exp Neurol. 2012;71(3):198–210.
Flygt J, Clausen F, Marklund N. Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts. Restor Neurol Neurosci. 2017;35(2):251–63.
Huntemer-Silveira A, Patil N, Brickner MA, Parr AM. Strategies for oligodendrocyte and myelin repair in traumatic CNS injury. Front Cell Neurosci. 2020;14:619707.
Song S, Hasan MN, Yu L, Paruchuri SS, Bielanin JP, Metwally S, et al. Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury. J Neuroinflammation. 2022;19(1):246.
Torup L. Neuroprotection with or without erythropoiesis; sometimes less is more. Brit J Pharmacol. 2007;151(8):1141–2.
Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol. 2004;207(Pt 18):3233–42.
Rabie T, Marti HH. Brain protection by erythropoietin: a manifold task. Physiology (Bethesda). 2008;23:263–74.
Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, et al. Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial. Lancet. 2015;386(10012):2499–506.
Gantner DC, Bailey M, Presneill J, French CJ, Nichol A, Little L, et al. Erythropoietin to reduce mortality in traumatic brain injury: a post-hoc dose-effect analysis. Ann Surg. 2018;267(3):585–9.
Skrifvars MB, French C, Bailey M, Presneill J, Nichol A, Little L, et al. Cause and timing of death and subgroup differential effects of erythropoietin in the EPO-TBI study. J Neurotrauma. 2018;35(2):333–40.
Hellewell SC, Yan EB, Alwis DS, Bye N, Morganti-Kossmann MC. Erythropoietin improves motor and cognitive deficit, axonal pathology, and neuroinflammation in a combined model of diffuse traumatic brain injury and hypoxia, in association with upregulation of the erythropoietin receptor. J Neuroinflamm. 2013;10.
Celorrio M, Rhodes J, Shumilov K, Moritz J, Xiao S, Anabayan I, et al. Recombinant human erythropoietin induces neuroprotection, activates MAPK/CREB pathway, and rescues fear memory after traumatic brain injury with delayed hypoxemia in mice. Brain Res. 2022;1795:148074.
Mazur M, Miller RH, Robinson S. Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury. J Neurosurg Pediatr. 2010;6(3):206–21.
Cho YK, Kim G, Park S, Sim JH, Won YJ, Hwang CH, et al. Erythropoietin promotes oligodendrogenesis and myelin repair following lysolecithin-induced injury in spinal cord slice culture. Biochem Biophys Res Commun. 2012;417(2):753–9.
Iwai M, Stetler RA, Xing J, Hu X, Gao Y, Zhang W, et al. Enhanced oligodendrogenesis and recovery of neurological function by erythropoietin after neonatal hypoxic/ischemic brain injury. Stroke. 2010;41(5):1032–7.
Parikh U, Williams M, Jacobs A, Pineda JA, Brody DL, Friess SH. Delayed hypoxemia following traumatic brain injury exacerbates white matter injury. J Neuropathol Exp Neurol. 2016;75(8):731–47.
Davis DP, Meade W, Sise MJ, Kennedy F, Simon F, Tominaga G, et al. Both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury. J Neurotrauma. 2009;26(12):2217–23.
Chi JH, Knudson MM, Vassar MJ, McCarthy MC, Shapiro MB, Mallet S, et al. Prehospital hypoxia affects outcome in patients with traumatic brain injury: a prospective multicenter study. J Trauma Injury Infect Crit Care. 2006;61(5):1134–41.
Fang R, Markandaya M, DuBose JJ, Cancio LC, Shackelford S, Blackbourne LH. Early in-theater management of combat-related traumatic brain injury: a prospective, observational study to identify opportunities for performance improvement. J Trauma Acute Care Surg. 2015;79(4 Suppl 2):S181–7.
Celorrio M, Shumilov K, Payne C, Vadivelu S, Friess SH. Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury. Acta Neuropathol Commun. 2022;10(1):10.
Zhou ZW, Li F, Zheng ZT, Li YD, Chen TH, Gao WW, et al. Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury. Brain Behav. 2017;7(11).
Chauhan NB, Gatto R. Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury. Brain Res. 2010;1360:177–92.
Robertson CS, Hannay HJ, Yamal JM, Gopinath S, Goodman JC, Tilley BC, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312(1):36–47.
Yang HJ, Vainshtein A, Maik-Rachline G, Peles E. G protein-coupled receptor 37 is a negative regulator of oligodendrocyte differentiation and myelination. Nat Commun. 2016;7:10884.
Castaneyra-Ruiz L, McAllister JP 2nd, Morales DM, Brody SL, Isaacs AM, Limbrick DD Jr. Preterm intraventricular hemorrhage in vitro: modeling the cytopathology of the ventricular zone. Fluids and barriers of the CNS. 2020;17(1):46.
Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S, et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol. 2012;72(3):419–32.
Siebert JR, Osterhout DJ. The inhibitory effects of chondroitin sulfate proteoglycans on oligodendrocytes. J Neurochem. 2011;119(1):176–88.
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.
Zhang L, Chopp M, Zhang RL, Wang L, Zhang J, Wang Y, et al. Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat. PLoS ONE. 2010;5(6):e11016.
Dai JX, Bercury KK, Ahrendsen JT, Macklin WB. Olig1 function is required for oligodendrocyte differentiation in the mouse brain. J Neurosci. 2015;35(10):4386–402.
Spitzer SO, Sitnikov S, Kamen Y, Evans KA, Kronenberg-Versteeg D, Dietmann S, et al. Oligodendrocyte progenitor cells become regionally diverse and heterogeneous with age. Neuron. 2019;101(3):459-+.
Vigano F, Mobius W, Gotz M, Dimou L. Transplantation reveals regional differences in oligodendrocyte differentiation in the adult brain. Nature neuroscience. 2013;16(10):1370-+.
Matsumoto Y, Tsunekawa Y, Nomura T, Suto F, Matsumata M, Tsuchiya S, et al. Differential proliferation rhythm of neural progenitor and oligodendrocyte precursor cells in the young adult hippocampus. Plos One. 2011;6(11).
Richardson WD, Young KM, Tripathi RB, McKenzie I. NG2-glia as multipotent neural stem cells: fact or fantasy? Neuron. 2011;70(4):661–73.
Guo FZ, Ma J, McCauley E, Bannerman P, Pleasure D. Early postnatal proteolipid promoter-expressing progenitors produce multilineage cells in vivo. J Neurosci. 2009;29(22):7256–70.
Kato S, Aoyama M, Kakita H, Hida H, Kato I, Ito T, et al. Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury. J Neurosci Res. 2011;89(10):1566–74.
Harris NG, Carmichael ST, Hovda DA, Sutton RL. Traumatic brain injury results in disparate regions of chondroitin sulfate proteoglycan expression that are temporally limited. J Neurosci Res. 2009;87(13):2937–50.
Yi JH, Katagiri Y, Susarla B, Figge D, Symes AJ, Geller HM. Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice. J Comp Neurol. 2012;520(15):3295–313.
Keough MB, Rogers JA, Zhang P, Jensen SK, Stephenson EL, Chen T, et al. An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nat Commun. 2016;7:11312.
Stephenson EL, Zhang P, Ghorbani S, Wang AX, Gu JM, Keough MB, et al. Targeting the chondroitin sulfate proteoglycans: evaluating fluorinated glucosamines and xylosides in screens pertinent to multiple sclerosis. Acs Central Sci. 2019;5(7):1223–34.
Wang RD, Zhou RB, Chen ZY, Gao S, Zhou F. The glial cells respond to spinal cord injury. Front Neurol. 2022;13.
Robinson AP, Rodgers JM, Goings GE, Miller SD. Characterization of oligodendroglial populations in mouse demyelinating disease using flow cytometry: clues for MS pathogenesis. Plos One. 2014;9(9).
Brown TI, Carr VA, LaRocque KF, Favila SE, Gordon AM, Bowles B, et al. Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science. 2016;352(6291):1323–6.
Hughes EG, Stockton ME. Premyelinating oligodendrocytes: mechanisms underlying cell survival and integration. Front Cell Dev Biol. 2021;9.
Yu T, Li L, Chen TH, Liu Z, Liu HX, Li ZZ. Erythropoietin attenuates advanced glycation endproducts-induced toxicity of Schwann cells in vitro. Neurochem Res. 2015;40(4):698–712.
Armstrong RC, Mierzwa AJ, Sullivan GM, Sanchez MA. Myelin and oligodendrocyte lineage cells in white matter pathology and plasticity after traumatic brain injury. Neuropharmacology. 2016;110:654–9.
Takase H, Washida K, Hayakawa K, Arai K, Wang XY, Lo EH, et al. Oligodendrogenesis after traumatic brain injury. Behav Brain Res. 2018;340:205–11.
Maki T, Liang AC, Miyamoto N, Lo EH, Arai K. Mechanisms of oligodendrocyte regeneration from ventricular-subventricular zone-derived progenitor cells in white matter diseases. Front Cell Neurosci. 2013;7.
Chen D, Huang YC, Shi ZY, Li JY, Zhang Y, Wang K, et al. Demyelinating processes in aging and stroke in the central nervous system and the prospect of treatment strategy. Cns Neurosci Ther. 2020;26(12):1219–29.
Jantzie LL, Miller RH, Robinson S. Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury. Pediatr Res. 2013;74(6):658–67.
Sundem L, Chris Tseng KC, Li H, Ketz J, Noble M, Elfar J. Erythropoietin enhanced recovery after traumatic nerve injury: myelination and localized effects. J Hand Surg Am. 2016;41(10):999–1010.
Joseph MJE, Caliaperumal J, Schlichter LC. After intracerebral hemorrhage, oligodendrocyte precursors proliferate and differentiate inside white-matter tracts in the rat striatum. Transl Stroke Res. 2016;7(3):192–208.
Wang S, Bates J, Li XJ, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell. 2013;12(2):252–64.
Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25(19):4694–705.
Gyetvai G, Hughes T, Wedmore F, Roe C, Heikal L, Ghezzi P, et al. Erythropoietin increases myelination in oligodendrocytes: gene expression profiling reveals early induction of genes involved in lipid transport and metabolism. Front Immunol. 2017;8.
Desu HL, Illiano P, Choi JS, Ascona MC, Gao H, Lee JK, et al. TNFR2 signaling regulates the immunomodulatory function of oligodendrocyte precursor cells. Cells. 2021;10(7).
Fernandez-Castaneda A, Chappell MS, Rosen DA, Seki SM, Beiter RM, Johanson DM, et al. The active contribution of OPCs to neuroinflammation is mediated by LRP1. Acta Neuropathol. 2020;139(2):365–82.
Wang RL, Zhang SJ, Yang ZH, Zheng YM, Yan F, Tao Z, et al. Mutant erythropoietin enhances white matter repair via the JAK2/STAT3 and C/EBP beta pathway in middle-aged mice following cerebral ischemia and reperfusion. Exp Neurol. 2021;337.
Laouafa S, Iturri P, Arias-Reyes C, Marcouiller F, Gonzales M, Joseph V, et al. Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: apnea of prematurity and sex dimorphism. Exp Neurol. 2019;320:112985.
Wen TC, Rogido M, Peng H, Genetta T, Moore J, Sola A. Gender differences in long-term beneficial effects of erythropoietin given after neonatal stroke in postnatal day-7 rats. Neuroscience. 2006;139(3):803–11.
Funding
This study was supported by a NINDS R01NS097721 fund.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics Approval
All procedures were approved by the Washington University Animal Studies Committee (Protocol 19–0864) and are consistent with the National Institutes of Health guidelines for the care and use of animals.
Conflict of Interest
The authors have no conflict of interests.
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
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Shumilov, K., Xiao, S., Ni, A. et al. Recombinant Erythropoietin Induces Oligodendrocyte Progenitor Cell Proliferation After Traumatic Brain Injury and Delayed Hypoxemia. Neurotherapeutics 20, 1859–1874 (2023). https://doi.org/10.1007/s13311-023-01443-8
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13311-023-01443-8