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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Research

Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys

Authors: Yuxin Zhou, Hrishti Bhatt, Chromewell A. Mojica, Hongqi Xin, Monica A. Pessina, Douglas L. Rosene, Tara L. Moore, Maria Medalla

Published in: Journal of Neuroinflammation | Issue 1/2023

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Abstract

Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke or traumatic brain injury. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys following injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. A focal lesion was induced via surgical ablation of pial blood vessels over lying the cortical hand representation of M1 of aged female rhesus monkeys, that received intravenous infusions of either vehicle (veh) or EVs 24 h and again 14 days post-injury. The current study used this same cohort to address how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC). We compared this lesion cohort to age-matched non-lesion controls (ctr). Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EVs on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglia–spine contacts. Our results suggest that EV treatment may enhance synaptic plasticity via clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic function to support functional recovery after injury.
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Literature
1.
Winship IR, Murphy TH. Remapping the somatosensory cortex after stroke: insight from imaging the synapse to network. Neuroscientist. 2009;15:507–24.PubMedCrossRef
2.
Edwards I, Singh I, Rose’meyer R. The role of cortisol in the development of post-stroke dementia: a narrative review. Heart Mind. 2022;6:151.CrossRef
3.
Carmichael ST. Brain excitability in stroke: the Yin and Yang of stroke progression. Arch Neurol. 2012;69:161–7.PubMedCrossRef
4.
Patel AR, Ritzel R, McCullough LD, Liu F. Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol. 2013;5:73.PubMedPubMedCentral
5.
6.
Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. J Immunol Res. 2013;2013: e746068.
7.
Go V, Sarikaya D, Zhou Y, Bowley BGE, Pessina MA, Rosene DL, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys. Exp Neurol. 2021;337: 113540.PubMedCrossRef
8.
Perego C, Fumagalli S, De Simoni M-G. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation. 2011;8:174.PubMedPubMedCentralCrossRef
9.
Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122:856–67.PubMedPubMedCentralCrossRef
10.
Zhang Y, Chopp M, Liu XS, Katakowski M, Wang X, Tian X, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol. 2017;54:2659–73.PubMedCrossRef
11.
12.
Moore TL, Bowley BGE, Pessina MA, Calderazzo SM, Medalla M, Go V, et al. Mesenchymal derived exosomes enhance recovery of motor function in a monkey model of cortical injury. Restor Neurol Neurosci. 2019;37:347–62.PubMedPubMedCentral
13.
Go V, Bowley BGE, Pessina MA, Zhang ZG, Chopp M, Finklestein SP, et al. Extracellular vesicles from mesenchymal stem cells reduce microglial-mediated neuroinflammation after cortical injury in aged Rhesus monkeys. GeroScience. 2020;42:1–17.PubMedCrossRef
14.
Medalla M, Chang W, Calderazzo SM, Go V, Tsolias A, Goodliffe JW, et al. Treatment with mesenchymal-derived extracellular vesicles reduces injury-related pathology in pyramidal neurons of monkey perilesional ventral premotor cortex. J Neurosci. 2020;40:3385–407.PubMedPubMedCentralCrossRef
15.
Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: Identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157–88.PubMedCrossRef
16.
17.
Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res. 1992;581:156–60.PubMedCrossRef
18.
Li S, Carmichael ST. Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke. Neurobiol Dis. 2006;23:362–73.PubMedCrossRef
19.
Benowitz LI, Carmichael ST. Promoting axonal rewiring to improve outcome after stroke. Neurobiol Dis. 2010;37:259–66.PubMedCrossRef
20.
Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with d-amphetamine therapy after neocortical infarction in rats. Stroke. 1998;29:2381–95.PubMedCrossRef
21.
Ward NS. Functional reorganization of the cerebral motor system after stroke. Curr Opin Neurol. 2004;17:725.PubMedCrossRef
22.
Jang SH, Kim Y-H, Cho S-H, Chang Y, Lee ZI, Ha JS. Cortical reorganization associated with motor recovery in hemiparetic stroke patients. NeuroReport. 2003;14:1305.PubMed
23.
24.
Miyai I, Yagura H, Oda I, Konishi I, Eda H, Suzuki T, et al. Premotor cortex is involved in restoration of gait in stroke. Ann Neurol. 2002;52:188–94.PubMedCrossRef
25.
Johansen-Berg H, Rushworth MFS, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci. 2002;99:14518–23.PubMedPubMedCentralCrossRef
26.
Fonseca MI, Chu S-H, Hernandez MX, Fang MJ, Modarresi L, Selvan P, et al. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation. 2017;14:48.PubMedPubMedCentralCrossRef
27.
Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun. 2018;9:1228.PubMedPubMedCentralCrossRef
28.
29.
Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol. 1997;158:4525–8.PubMedCrossRef
30.
Wang J, Xing H, Wan L, Jiang X, Wang C, Wu Y. Treatment targets for M2 microglia polarization in ischemic stroke. Biomed Pharmacother. 2018;105:518–25.PubMedCrossRef
31.
32.
Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43:3063–70.PubMedCrossRef
33.
Orczykowski ME, Calderazzo SM, Shobin E, Pessina MA, Oblak AL, Finklestein SP, et al. Cell based therapy reduces secondary damage and increases extent of microglial activation following cortical injury. Brain Res. 2019;1717:147–59.PubMedPubMedCentralCrossRef
34.
Medalla M, Luebke JI. Diversity of glutamatergic synaptic strength in lateral prefrontal versus primary visual cortices in the Rhesus monkey. J Neurosci. 2015;35:112–27.PubMedPubMedCentralCrossRef
35.
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan W-B, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006;9:1512–9.PubMedCrossRef
36.
Walker DG, Lue L-F. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther. 2015;7:56.PubMedPubMedCentralCrossRef
37.
Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, et al. A dramatic increase of C1q protein in the CNS during normal aging. J Neurosci. 2013;33:13460–74.PubMedPubMedCentralCrossRef
38.
Ikezu S, Yeh H, Delpech J-C, Woodbury ME, Van Enoo AA, Ruan Z, et al. Inhibition of colony stimulating factor 1 receptor corrects maternal inflammation-induced microglial and synaptic dysfunction and behavioral abnormalities. Mol Psychiatry. 2021;26:1808–31.PubMedCrossRef
39.
40.
Pessina MA, Bowley BGE, Rosene DL, Moore TL. A method for assessing recovery of fine motor function of the hand in a rhesus monkey model of cortical injury: an adaptation of the Fugl-Meyer Scale and Eshkol-Wachman Movement Notation. Somatosens Mot Res. 2019;36:69–77.PubMedPubMedCentralCrossRef
41.
Moechars D, Weston MC, Leo S, Callaerts-Vegh Z, Goris I, Daneels G, et al. Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain. J Neurosci. 2006;26:12055–66.PubMedPubMedCentralCrossRef
42.
Chang PK-Y, Verbich D, McKinney RA. AMPA receptors as drug targets in neurological disease—advantages, caveats, and future outlook. Eur J Neurosci. 2012;35:1908–16.PubMedCrossRef
43.
Milenkovic I, Vasiljevic M, Maurer D, Höger H, Klausberger T, Sieghart W. The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits alpha1, beta2, and delta along their extrasynaptic cell membrane. Neuroscience. 2013;254:80–96.PubMedCrossRef
44.
Kullmann DM, Ruiz A, Rusakov DM, Scott R, Semyanov A, Walker MC. Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why? Prog Biophys Mol Biol. 2005;87:33–46.PubMedPubMedCentralCrossRef
45.
Mott DD, Lewis DV. The pharmacology and function of central GabaB receptors. Int Rev Neurobiol. 1994;36:97–223.PubMedCrossRef
46.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.PubMedCrossRef
47.
Bohlson SS, O’Conner SD, Hulsebus HJ, Ho M-M, Fraser DA. Complement, C1q, and C1q-related molecules regulate macrophage polarization. Front Immunol. 2014;5:402.PubMedPubMedCentralCrossRef
48.
Zanier ER, Fumagalli S, Perego C, Pischiutta F, De Simoni M-G. Shape descriptors of the “never resting” microglia in three different acute brain injury models in mice. Intensive Care Med Exp. 2015;3:7.PubMedPubMedCentralCrossRef
49.
Medalla M, Gilman JP, Wang J-Y, Luebke JI. Strength and diversity of inhibitory signaling differentiates primate anterior cingulate from lateral prefrontal cortex. J Neurosci. 2017;37:4717–34.PubMedPubMedCentralCrossRef
50.
Calderazzo S, Covert M, Alba DD, Bowley BE, Pessina MA, Rosene DL, et al. Neural recovery after cortical injury: effects of MSC derived extracellular vesicles on motor circuit remodeling in rhesus monkeys. IBRO Neurosci Rep. 2022;13:243–54.PubMedPubMedCentralCrossRef
51.
Herzog E, Takamori S, Jahn R, Brose N, Wojcik SM. Synaptic and vesicular co-localization of the glutamate transporters VGLUT1 and VGLUT2 in the mouse hippocampus. J Neurochem. 2006;99:1011–8.PubMedCrossRef
52.
Fremeau RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron. 2001;31:247–60.PubMedCrossRef
53.
Fremeau RT, Voglmaier S, Seal RP, Edwards RH. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 2004;27:98–103.PubMedCrossRef
54.
Meng Y, Zhang Y, Jia Z. Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3. Neuron. 2003;39:163–76.PubMedCrossRef
55.
Bassani S, Valnegri P, Beretta F, Passafaro M. The GLUR2 subunit of AMPA receptors: synaptic role. Neuroscience. 2009;158:55–61.PubMedCrossRef
56.
Saglietti L, Dequidt C, Kamieniarz K, Rousset M-C, Valnegri P, Thoumine O, et al. Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron. 2007;54:461–77.PubMedCrossRef
57.
Orlandi C, Via LL, Bonini D, Mora C, Russo I, Barbon A, et al. AMPA receptor regulation at the mRNA and protein level in rat primary cortical cultures. PLoS ONE. 2011;6: e25350.PubMedPubMedCentralCrossRef
58.
Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABAa and GABAb receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience. 2005;134:691–704.PubMedCrossRef
59.
Clarkson AN, Huang BS, MacIsaac SE, Mody I, Carmichael ST. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305–9.PubMedPubMedCentralCrossRef
60.
Hiu T, Farzampour Z, Paz JT, Wang EHJ, Badgely C, Olson A, et al. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target. Brain. 2016;139:468–80.PubMedCrossRef
61.
62.
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.PubMedPubMedCentralCrossRef
63.
64.
65.
66.
67.
Jamjoom AAB, Rhodes J, Andrews PJD, Grant SGN. The synapse in traumatic brain injury. Brain. 2021;144:18–31.PubMedCrossRef
68.
Krukowski K, Nolan A, Becker M, Picard K, Vernoux N, Frias ES, et al. Novel microglia-mediated mechanisms underlying synaptic loss and cognitive impairment after traumatic brain injury. Brain Behav Immun. 2021;98:122–35.PubMedPubMedCentralCrossRef
69.
Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89.PubMedCrossRef
70.
Ramaglia V, Hughes TR, Donev RM, Ruseva MM, Wu X, Huitinga I, et al. C3-dependent mechanism of microglial priming relevant to multiple sclerosis. Proc Natl Acad Sci USA. 2012;109:965–70.PubMedPubMedCentralCrossRef
71.
Gouweleeuw L, Pol C, Simonides W, de Kleijn V, Schoemaker R. Evidence for neuroinflammation after myocardial infarction in a mouse model. Heart Mind. 2017;1:134.CrossRef
72.
Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ. C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-β neurotoxicity. J Biol Chem. 2013;288:654–65.PubMedCrossRef
73.
Masuda T, Sankowski R, Staszewski O, Prinz M. Microglia heterogeneity in the single-cell era. Cell Rep. 2020;30:1271–81.PubMedCrossRef
74.
Li Y, Li Z, Yang M, Wang F, Zhang Y, Li R, et al. Decoding the temporal and regional specification of microglia in the developing human brain. Cell Stem Cell. 2022;29:620-634.e6.PubMedCrossRef
75.
76.
Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–70.PubMedCrossRef
77.
García-Cabezas MÁ, Joyce MKP, John YJ, Zikopoulos B, Barbas H. Mirror trends of plasticity and stability indicators in primate prefrontal cortex. Eur J Neurosci. 2017;46:2392–405.PubMedPubMedCentralCrossRef
78.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8.PubMedCrossRef
79.
Shobin E, Bowley MP, Estrada LI, Heyworth NC, Orczykowski ME, Eldridge SA, et al. Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. GeroScience. 2017;39:199–220.PubMedPubMedCentralCrossRef
80.
Bottenfield KR, Bowley BGE, Pessina MA, Medalla M, Rosene DL, Moore TL. Sex differences in recovery of motor function in a rhesus monkey model of cortical injury. Biol Sex Differ. 2021;12:54.PubMedPubMedCentralCrossRef
81.
82.
83.
Bordt EA, Ceasrine AM, Bilbo SD. Microglia and sexual differentiation of the developing brain: a focus on ontogeny and intrinsic factors. Glia. 2020;68:1085–99.PubMedCrossRef
84.
Chen R-L, Balami JS, Esiri MM, Chen L-K, Buchan AM. Ischemic stroke in the elderly: an overview of evidence. Nat Rev Neurol. 2010;6:256–65.PubMedCrossRef
85.
86.
Davalos D, Lee JK, Smith WB, Brinkman B, Ellisman MH, Zheng B, et al. Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods. 2008;169:1–7.PubMedCrossRef
87.
88.
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016;90:724–39.PubMedPubMedCentralCrossRef
89.
Luebke JI, Weaver CM, Rocher AB, Rodriguez A, Crimins JL, Dickstein DL, et al. Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models. Brain Struct Funct. 2010;214:181–99.PubMedPubMedCentralCrossRef
90.
Abercrombie M. Estimation of nuclear population from microtome sections. Anat Rec. 1946;94:239–47.PubMedCrossRef
91.
92.
Seitz RJ, Höflich P, Binkofski F, Tellmann L, Herzog H, Freund H-J. Role of the premotor cortex in recovery from middle cerebral artery infarction. Arch Neurol. 1998;55:1081–8.PubMedCrossRef
93.
Yamamoto T, Hayashi T, Murata Y, Ose T, Higo N. Premotor cortical-cerebellar reorganization in a macaque model of primary motor cortical lesion and recovery. J Neurosci. 2019;39:8484–96.PubMedPubMedCentralCrossRef
Metadata
Title
Mesenchymal-derived extracellular vesicles enhance microglia-mediated synapse remodeling after cortical injury in aging Rhesus monkeys
Authors
Yuxin Zhou
Hrishti Bhatt
Chromewell A. Mojica
Hongqi Xin
Monica A. Pessina
Douglas L. Rosene
Tara L. Moore
Maria Medalla
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02880-0

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