New role of astrocytes in neuroprotective mechanisms after ischemic stroke

Abstract

Astrocytes are the most abundant cell subtypes in the central nervous system. Previous studies believed that astrocytes are supporting cells in the brain, which only provide nutrients for neurons. However, recent studies have found that astrocytes have more crucial and complex functions in the brain, such as neurogenesis, phagocytosis, and ischemic tolerance. After an ischemic stroke, the activated astrocytes can exert neuroprotective or neurotoxic effects through a variety of pathways. In this review, we will discuss the neuroprotective mechanisms of astrocytes in cerebral ischemia, and mainly focus on reactive astrocytosis or glial scar, neurogenesis, phagocytosis, and cerebral ischemic tolerance, for providing new strategies for the clinical treatment of stroke.

Resumo

Os astrócitos são os subtipos de células mais abundantes no sistema nervoso central. Estudos anteriores acreditavam que os astrócitos são células de suporte no cérebro, que apenas fornecem nutrientes para os neurônios. No entanto, estudos recentes descobriram que os astrócitos têm funções mais cruciais e complexas no cérebro, como neurogênese, fagocitose e tolerância isquêmica. Após um acidente vascular cerebral isquêmico, os astrócitos ativados podem exercer efeitos neuroprotetores ou neurotóxicos através de uma variedade de vias. Nesta revisão, discutiremos os mecanismos neuroprotetores dos astrócitos na isquemia cerebral, e focaremos principalmente na astrocitose reativa ou cicatriz glial, neurogênese, fagocitose e tolerância isquêmica cerebral, para fornecer novas estratégias para o tratamento clínico do acidente vascular cerebral.

Keywords

Astrocytes - Ischemic Stroke - Neurogenesis - Phagocytosis - Ischemic Preconditioning - Neuroprotective Agents

Palavras-chave

Astrócitos - AVC Isquêmico - Neurogênese - Fagocitose - Precondicionamento Isquêmico - Fármacos Neuroprotetores

Authors' Contributions

XX: conceptualization, writing the original draft; JL: supervision, writing, reviewing & editing.

Publikationsverlauf

Eingereicht: 11. September 2022

Angenommen: 15. Januar 2023

Artikel online veröffentlicht:
30. August 2023

• References

• 1 Wu S, Wu B, Liu M. et al; China Stroke Study Collaboration. Stroke in China: advances and challenges in epidemiology, prevention, and management. Lancet Neurol 2019; 18 (04) 394-405
• 2 Zerna C, Thomalla G, Campbell BCV, Rha JH, Hill MD. Current practice and future directions in the diagnosis and acute treatment of ischaemic stroke. Lancet 2018; 392 (10154): 1247-1256
• 3 Zhao SC, Ma LS, Chu ZH, Xu H, Wu WQ, Liu F. Regulation of microglial activation in stroke. Acta Pharmacol Sin 2017; 38 (04) 445-458
• 4 Turlova E, Feng ZP, Sun HS. The role of TRPM2 channels in neurons, glial cells and the blood-brain barrier in cerebral ischemia and hypoxia. Acta Pharmacol Sin 2018; 39 (05) 713-721
• 5 O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006; 59 (03) 467-477
• 6 Schmidt-Pogoda A, Bonberg N, Koecke MHM. et al. Why Most Acute Stroke Studies Are Positive in Animals but Not in Patients: A Systematic Comparison of Preclinical, Early Phase, and Phase 3 Clinical Trials of Neuroprotective Agents. Ann Neurol 2020; 87 (01) 40-51
• 7 Zhou B, Zuo YX, Jiang RT. Astrocyte morphology: Diversity, plasticity, and role in neurological diseases. CNS Neurosci Ther 2019; 25 (06) 665-673
• 8 Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 2016; 144: 103-120
• 9 Cohen-Salmon M, Slaoui L, Mazaré N. et al. Astrocytes in the regulation of cerebrovascular functions. Glia 2021; 69 (04) 817-841
• 10 Vasile F, Dossi E, Rouach N. Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct 2017; 222 (05) 2017-2029
• 11 Zhou H, Liu J, Zhou C. et al. In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice. Nat Neurosci 2018; 21 (03) 440-446
• 12 Zamanian JL, Xu L, Foo LC. et al. Genomic analysis of reactive astrogliosis. J Neurosci 2012; 32 (18) 6391-6410
• 13 Linnerbauer M, Rothhammer V. Protective Functions of Reactive Astrocytes Following Central Nervous System Insult. Front Immunol 2020; 11: 573256
• 14 Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 2009; 32 (12) 638-647
• 15 Xu S, Lu J, Shao A, Zhang JH, Zhang J. Glial Cells: Role of the Immune Response in Ischemic Stroke. Front Immunol 2020; 11: 294
• 16 Boccazzi M, Ceruti S. Where do you come from and what are you going to become, reactive astrocyte?. Stem Cell Investig 2016; 3: 15
• 17 Anderson MA, Burda JE, Ren Y. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 2016; 532 (7598): 195-200
• 18 Liauw J, Hoang S, Choi M. et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab 2008; 28 (10) 1722-1732
• 19 Lively S, Moxon-Emre I, Schlichter LC. SC1/hevin and reactive gliosis after transient ischemic stroke in young and aged rats. J Neuropathol Exp Neurol 2011; 70 (10) 913-929
• 20 Jones EV, Bernardinelli Y, Zarruk JG, Chierzi S, Murai KK. SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury. Front Cell Neurosci 2018; 12: 22
• 21 Sofroniew MV. Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity. Trends Immunol 2020; 41 (09) 758-770
• 22 Cai H, Ma Y, Jiang L. et al. Hypoxia Response Element-Regulated MMP-9 Promotes Neurological Recovery via Glial Scar Degradation and Angiogenesis in Delayed Stroke. Mol Ther 2017; 25 (06) 1448-1459
• 23 Kieran NW, Suresh R, Dorion MF. et al. MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes. J Neuroinflammation 2022; 19 (01) 10
• 24 de Pablo Y, Nilsson M, Pekna M, Pekny M. Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion. Histochem Cell Biol 2013; 140 (01) 81-91
• 25 Bao Y, Qin L, Kim E. et al. CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 2012; 32 (08) 1567-1577
• 26 Wilhelmsson U, Li L, Pekna M. et al. Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 2004; 24 (21) 5016-5021
• 27 Shen XY, Gao ZK, Han Y, Yuan M, Guo YS, Bi X. Activation and Role of Astrocytes in Ischemic Stroke. Front Cell Neurosci 2021; 15: 755955
• 28 Schäfer MKE, Tegeder I. NG2/CSPG4 and progranulin in the posttraumatic glial scar. Matrix Biol 2018; 68-69: 571-588
• 29 Liu Z, Li Y, Cui Y. et al. Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia 2014; 62 (12) 2022-2033
• 30 Williamson MR, Fuertes CJA, Dunn AK, Drew MR, Jones TA. Reactive astrocytes facilitate vascular repair and remodeling after stroke. Cell Rep 2021; 35 (04) 109048
• 31 He T, Yang GY, Zhang Z. Crosstalk of Astrocytes and Other Cells during Ischemic Stroke. Life (Basel) 2022; 12 (06) 910
• 32 Santopolo G, Magnusson JP, Lindvall O, Kokaia Z, Frisén J. Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke. Cells 2020; 9 (07) 1732
• 33 Magnusson JP, Göritz C, Tatarishvili J. et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 2014; 346 (6206): 237-241
• 34 Götz M, Sirko S, Beckers J, Irmler M. Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome-wide expression analysis. Glia 2015; 63 (08) 1452-1468
• 35 Cai Q, Chen Z, Song P. et al. Co-transplantation of hippocampal neural stem cells and astrocytes and microvascular endothelial cells improve the memory in ischemic stroke rat. Int J Clin Exp Med 2015; 8 (08) 13109-13117
• 36 Popa-Wagner A, Hermann D, Gresita A. Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain?. Geroscience 2019; 41 (04) 363-368
• 37 Jiang MQ, Yu SP, Wei ZZ. et al. Conversion of Reactive Astrocytes to Induced Neurons Enhances Neuronal Repair and Functional Recovery After Ischemic Stroke. Front Aging Neurosci 2021; 13: 612856
• 38 Zhang L, Yin JC, Yeh H. et al. Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons. Cell Stem Cell 2015; 17 (06) 735-747
• 39 Magnusson JP, Zamboni M, Santopolo G. et al. Activation of a neural stem cell transcriptional program in parenchymal astrocytes. eLife 2020; 9: 9
• 40 Corti S, Nizzardo M, Simone C. et al. Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 2012; 318 (13) 1528-1541
• 41 Gao L, Guan W, Wang M. et al. Direct Generation of Human Neuronal Cells from Adult Astrocytes by Small Molecules. Stem Cell Reports 2017; 8 (03) 538-547
• 42 Pereira M, Birtele M, Rylander Ottosson D. Direct reprogramming into interneurons: potential for brain repair. Cell Mol Life Sci 2019; 76 (20) 3953-3967
• 43 Lin Y, Zhang JC, Yao CY. et al. Critical role of astrocytic interleukin-17 A in post-stroke survival and neuronal differentiation of neural precursor cells in adult mice. Cell Death Dis 2016; 7 (06) e2273
• 44 Shen SW, Duan CL, Chen XH. et al. Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke. Neuropharmacology 2016; 108: 451-461
• 45 Mo JL, Liu Q, Kou ZW. et al. MicroRNA-365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6. Glia 2018; 66 (07) 1346-1362
• 46 Mattugini N, Bocchi R, Scheuss V. et al. Inducing Different Neuronal Subtypes from Astrocytes in the Injured Mouse Cerebral Cortex. Neuron 2019; 103 (06) 1086-1095.e5
• 47 Chen YC, Ma NX, Pei ZF. et al. A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion. Mol Ther 2020; 28 (01) 217-234
• 48 Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 2014; 14 (02) 188-202
• 49 Zhang L, Lei Z, Guo Z. et al. Development of Neuroregenerative Gene Therapy to Reverse Glial Scar Tissue Back to Neuron-Enriched Tissue. Front Cell Neurosci 2020; 14: 594170
• 50 Grubman A, Choo XY, Chew G. et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nat Commun 2021; 12 (01) 3015
• 51 Galloway DA, Phillips AEM, Owen DRJ, Moore CS. Phagocytosis in the Brain: Homeostasis and Disease. Front Immunol 2019; 10: 790
• 52 Konishi H, Okamoto T, Hara Y. et al. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction. EMBO J 2020; 39 (22) e104464
• 53 Lee JH, Kim JY, Noh S. et al. Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature 2021; 590 (7847): 612-617
• 54 Ritzel RM, Patel AR, Grenier JM. et al. Functional differences between microglia and monocytes after ischemic stroke. J Neuroinflammation 2015; 12: 106
• 55 Lee SY, Chung WS. The roles of astrocytic phagocytosis in maintaining homeostasis of brains. J Pharmacol Sci 2021; 145 (03) 223-227
• 56 Iram T, Ramirez-Ortiz Z, Byrne MH. et al. Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes. J Neurosci 2016; 36 (19) 5185-5192
• 57 Sloan SA, Darmanis S, Huber N. et al. Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells. Neuron 2017; 95 (04) 779-790.e6
• 58 Cahoy JD, Emery B, Kaushal A. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 2008; 28 (01) 264-278
• 59 Chung WS, Clarke LE, Wang GX. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 2013; 504 (7480): 394-400
• 60 Wan T, Zhu W, Zhao Y. et al. Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice. Nat Commun 2022; 13 (01) 1134
• 61 Morizawa YM, Hirayama Y, Ohno N. et al. Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun 2017; 8 (01) 28
• 62 Lööv C, Mitchell CH, Simonsson M, Erlandsson A. Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification. Glia 2015; 63 (11) 1997-2009
• 63 Scott MC, Bedi SS, Olson SD, Sears CM, Cox CS. Microglia as therapeutic targets after neurological injury: strategy for cell therapy. Expert Opin Ther Targets 2021; 25 (05) 365-380
• 64 Koizumi S, Hirayama Y, Morizawa YM. New roles of reactive astrocytes in the brain; an organizer of cerebral ischemia. Neurochem Int 2018; 119: 107-114
• 65 Hirayama Y, Koizumi S. Astrocytes and ischemic tolerance. Neurosci Res 2018; 126: 53-59
• 66 Li S, Hafeez A, Noorulla F. et al. Preconditioning in neuroprotection: From hypoxia to ischemia. Prog Neurobiol 2017; 157: 79-91
• 67 Hirayama Y, Anzai N, Kinouchi H, Koizumi S. P2X7 Receptors in Astrocytes: A Switch for Ischemic Tolerance. Molecules 2022; 27 (12) 3655
• 68 Lee JS, Hong JM, Yoon BS. et al. Expression of Cellular Receptors in the Ischemic Hemisphere of Mice with Increased Glucose Uptake. Exp Neurobiol 2020; 29 (01) 70-79
• 69 Herrero-Mendez A, Almeida A, Fernández E, Maestre C, Moncada S, Bolaños JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 2009; 11 (06) 747-752
• 70 Calì C, Tauffenberger A, Magistretti P. The Strategic Location of Glycogen and Lactate: From Body Energy Reserve to Brain Plasticity. Front Cell Neurosci 2019; 13: 82
• 71 Gundersen V, Storm-Mathisen J, Bergersen LH. Neuroglial Transmission. Physiol Rev 2015; 95 (03) 695-726
• 72 Martín-Jiménez CA, Salazar-Barreto D, Barreto GE, González J. Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network. Front Aging Neurosci 2017; 9: 23
• 73 Narayanan SV, Perez-Pinzon MA. Ischemic preconditioning treatment of astrocytes transfers ischemic tolerance to neurons. Cond Med 2017; 1 (01) 2-8
• 74 Stevens SL, Ciesielski TM, Marsh BJ. et al. Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2008; 28 (05) 1040-1047
• 75 McDonough A, Weinstein JR. Neuroimmune Response in Ischemic Preconditioning. Neurotherapeutics 2016; 13 (04) 748-761
• 76 Narayanan SV, Dave KR, Perez-Pinzon MA. Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Factor 2 Pathway. Transl Stroke Res 2018; 9 (02) 99-109
• 77 Pang Y, Chai CR, Gao K. et al. Ischemia preconditioning protects astrocytes from ischemic injury through 14-3-3γ. J Neurosci Res 2015; 93 (10) 1507-1518
• 78 Shinozaki Y, Nomura M, Iwatsuki K, Moriyama Y, Gachet C, Koizumi S. Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission. Sci Rep 2014; 4: 4329
• 79 Shinozaki Y, Shibata K, Yoshida K. et al. Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y₁ Receptor Downregulation. Cell Rep 2017; 19 (06) 1151-1164
• 80 Vlachaki Walker JM, Robb JL, Cruz AM. et al. AMP-activated protein kinase (AMPK) activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner. Diabetes Obes Metab 2017; 19 (07) 997-1005
• 81 Hirayama Y, Anzai N, Koizumi S. Mechanisms underlying sensitization of P2X7 receptors in astrocytes for induction of ischemic tolerance. Glia 2021; 69 (09) 2100-2110
• 82 Li L, Lundkvist A, Andersson D. et al. Protective role of reactive astrocytes in brain ischemia. J Cereb Blood Flow Metab 2008; 28 (03) 468-481
• 83 Li S, Zhang L, Lin J. et al. LncRNA BIRF Promotes Brain Ischemic Tolerance Induced By Cerebral Ischemic Preconditioning Through Upregulating GLT-1 via Sponging miR-330-5p. Mol Neurobiol 2022; 59 (07) 3996-4014
• 84 Zhang M, Gong JX, Wang JL. et al. p38 MAPK Participates in the Mediation of GLT-1 Up-regulation During the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning. Mol Neurobiol 2017; 54 (01) 58-71
• 85 Hirayama Y, Koizumi S. Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning. Glia 2017; 65 (03) 523-530
• 86 Ruscher K, Freyer D, Karsch M. et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 2002; 22 (23) 10291-10301