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Mareckova K, Holland L, Marecek R, Andryskova L, Brazdil M, Dawson S, Nikolova YS. Dietary inflammatory index during pregnancy and its relationship with gyrification and IQ in young adult offspring. Prog Neuropsychopharmacol Biol Psychiatry 2025; 139:111373. [PMID: 40262673 DOI: 10.1016/j.pnpbp.2025.111373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 04/13/2025] [Accepted: 04/18/2025] [Indexed: 04/24/2025]
Abstract
Maternal diet during pregnancy has been associated with brain development and cognitive function in offspring, but the mechanisms mediating these relationships remain poorly understood. We conducted a longitudinal neuroimaging follow-up of a prenatal birth cohort and used Food Frequency Questionnaires completed by the mother in mid-pregnancy to calculate prenatal Dietary Inflammatory Index (DII) and tested its relationship with brain gyrification, an index of early brain development, and IQ in young adults (n = 179, age 28-30). The longitudinal gyrification data were available for a subset of these individuals (n = 77, age 23-24). A higher maternal pro-inflammatory diet during pregnancy, as represented by higher DII, was associated with worse verbal IQ but not performance IQ in young adulthood. These findings were independent of sex and remained significant after adjusting for maternal education, maternal stressful life events during pregnancy, maternal smoking during pregnancy, prenatal supplements (e.g. folic acid, iron, zinc, calcium, vitamins), and maternal age at birth. Moreover, higher DII was associated with altered cortical gyrification in the early as well as the late 20, particularly in men. Gyrification of the anterior middle and inferior frontal gyrus mediated the relationship between prenatal DII and verbal IQ in young adulthood. These findings support the use of cortical gyrification as a proxy marker of early brain development and suggest it may underlie the relationship between maternal diet during pregnancy and its long-term impact on cognitive skills in offspring. They also have important implications for pregnant women who might be able to optimize the brain development and verbal IQ of their children through an anti-inflammatory diet.
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Affiliation(s)
- Klara Mareckova
- Brain and Mind Research, Central European Institute of Technology, Masaryk University (CEITEC MU), Brno, Czech Republic; 1(st) Department of Neurology, St. Anne's Univ. Hospital and Faculty of Medicine, MU, Brno, Czech Republic.
| | - Lada Holland
- Florey Institute of Neuroscience and Mental Health, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia
| | - Radek Marecek
- Brain and Mind Research, Central European Institute of Technology, Masaryk University (CEITEC MU), Brno, Czech Republic
| | - Lenka Andryskova
- RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Milan Brazdil
- Brain and Mind Research, Central European Institute of Technology, Masaryk University (CEITEC MU), Brno, Czech Republic; 1(st) Department of Neurology, St. Anne's Univ. Hospital and Faculty of Medicine, MU, Brno, Czech Republic
| | - Samantha Dawson
- Food & Mood Centre, Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, Australia
| | - Yuliya S Nikolova
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Canada
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Jaiswal C, Singh AK. Particulate matter exposure and its consequences on hippocampal neurogenesis and cognitive function in experimental models. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 363:125275. [PMID: 39515570 DOI: 10.1016/j.envpol.2024.125275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/30/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Exposure to air pollution is thought to cause millions of deaths globally each year. According to the Who 2018, approximately 7 million deaths annually are caused predominantly by noncommunicable diseases due to air pollution. Exposure to air particulate matter 2.5 (PM2.5) has been strongly associated with increased mortality and has significant effects on brain health. Air pollution, particularly ultrafine particulate matter, has emerged as a serious environmental concern with profound implications for human health. Studies in animal models have indicated that exposure to these pollutants during gestational development impacts prenatal and postnatal brain development. In particular, air pollution has been increasingly identified as a potential causative factor, as it affects neurogenesis in the brain's hippocampal region. The hippocampus is highly vulnerable to PM exposure, and any alteration in the structure or function of this region leads to various neurodevelopmental defects and neurodegenerative disorders via oxidative stress, microglial activation, neuronal death, and differential expression of genes. The neurogenesis process involves several steps, such as proliferation, differentiation, migration, synaptogenesis, and neuritogenesis. If any step of the neurogenesis process is hampered by environmental exposure or other factors, it can lead to neurodevelopmental defects, neurodegenerative disorders, and cognitive decline. One significant contributor to these alterations is air pollution, which ranks as the leading environmental risk factor worldwide. Some of the most common effects include oxidative stress, neuroinflammation, depressive behavior, altered cognitive processes, and microglial activation. This review explores how prenatal and postnatal PM exposure affects the hippocampal regions of the brain and the defects associated with exposure.
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Affiliation(s)
- Charu Jaiswal
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India.
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Khoshnavay Foumani M, Amirshahrokhi K, Namjoo Z, Niapour A. Carvedilol attenuates inflammatory reactions of lipopolysaccharide-stimulated BV2 cells and modulates M1/M2 polarization of microglia via regulating NLRP3, Notch, and PPAR-γ signaling pathways. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4727-4736. [PMID: 38133658 DOI: 10.1007/s00210-023-02914-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/15/2023] [Indexed: 12/23/2023]
Abstract
Microglial cells coordinate immune responses in the central nervous system. Carvedilol (CVL) is a non-selective β-blocker with anti-inflammatory and anti-oxidant effects. This study aims to investigate the anti-inflammatory effects and the underlying mechanisms of CVL on lipopolysaccharide (LPS)-induced inflammation in microglial BV2 cells. BV2 cells were stimulated with LPS, and the protective effects of CVL were investigated via measurement of cell viability, reactive oxygen species (ROS), and interleukin (IL)-1β liberation. The protein levels of some inflammatory cascade, Notch, and peroxisome proliferator-activated receptor (PPAR)-γ pathways and relative markers of M1/M2 microglial phenotypes were assessed. Neuroblastoma SH-SY5Y cells were cultured with a BV2-conditioned medium (CM), and the capacity of CVL to protect cell viability was evaluated. CVL displayed a protective effect against LPS stress through reducing ROS and down-regulating of nuclear factor kappa B (NF-κB) p65, NLR family pyrin domain containing-3 (NLRP3), and IL-1β proteins. LPS treatment significantly increased the levels of the M1 microglial marker inducible nitric oxide synthase (iNOS) and M1-associated cleaved-NOTCH1 and hairy and enhancer of split-1 (HES1) proteins. Conversely, LPS treatment reduced the levels of the M2 marker arginase-1 (Arg-1) and PPAR-γ proteins. CVL pre-treatment reduced the protein levels of iNOS, cleaved-NOTCH1, and HES1, while increased Arg-1 and PPAR-γ. CM of CVL-primed BV2 cells significantly improved SH-SY5Y cell viability as compared with the LPS-induced cells. CVL suppressed ROS production and alleviated the expression of inflammatory markers in LPS-stimulated BV2 cells. Our results demonstrated that targeting Notch and PPAR-γ pathways as well as directing BV2 cell polarization toward the M2 phenotype may provide a therapeutic strategy to suppress neuroinflammation by CVL.
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Affiliation(s)
- Mohammadjavad Khoshnavay Foumani
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Keyvan Amirshahrokhi
- Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Zeinab Namjoo
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Ali Niapour
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
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Li J, Wang Z, Zhang Y, Li Y, Feng L, Wang J, Zhang J, Zhou Z, Zhang Y, Chang X. Effects of environmentally relevant concentration of short-chain chlorinated paraffins on BV2 microglia activation and lipid metabolism, implicating altered neurogenesis. ENVIRONMENTAL RESEARCH 2024; 251:118602. [PMID: 38431072 DOI: 10.1016/j.envres.2024.118602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/11/2024] [Accepted: 02/28/2024] [Indexed: 03/05/2024]
Abstract
Short-chain chlorinated paraffins (SCCPs), a class of persistent organic pollutants, have been found to cause diverse organ and systemic toxicity. However, little is known about their neurotoxic effects. In this study, we exposed BV2, a mouse microglia cell line, to environmentally relevant concentration of SCCPs (1 μg/L, 10 μg/L, 100 μg/L) for 24 h to investigate their impacts on the nervous system. Our observations revealed that SCCPs induced the activation of BV2 microglia, as indicated by altered morphology, stimulated cell proliferation, enhanced phagocytic and migratory capabilities. Analysis at the mRNA level confirmed the activation status, with the downregulation of TMEM119 and Tgfbr1, and upregulation of Iba1 and CD11b. The upregulated expression of genes such as cenpe, mki67, Axl, APOE and LPL also validated alterations in cell functions. Moreover, BV2 microglia presented an M2 alternative phenotype upon SCCPs exposure, substantiated by the reduction of NF-κB, TNF-α, IL-1β, and the elevation of TGF-β. Additionally, SCCPs caused lipid metabolic changes in BV2 microglia, characterized by the upregulations of long-chain fatty acids and acylcarnitines, reflecting an enhancement of β-oxidation. This aligns with our findings of increased ATP production upon SCCPs exposure. Intriguingly, cell activation coincided with elevated levels of omega-3 polyunsaturated fatty acids. Furthermore, activated microglial medium remarkably altered the proliferation and differentiation of mouse neural stem cells. Collectively, exposure to environmentally relevant concentrations of SCCPs resulted in activation and lipid metabolic alterations in BV2 microglia, potentially impacting neurogenesis. These findings provide valuable insights for further research on the neurotoxic effect of SCCPs.
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Affiliation(s)
- Jiayi Li
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Zheng Wang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yuwei Zhang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yixi Li
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Longfei Feng
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Jinglin Wang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Jiming Zhang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Zhijun Zhou
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Yunhui Zhang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China.
| | - Xiuli Chang
- School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai, 200032, China.
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Šimončičová E, Henderson Pekarik K, Vecchiarelli HA, Lauro C, Maggi L, Tremblay MÈ. Adult Neurogenesis, Learning and Memory. ADVANCES IN NEUROBIOLOGY 2024; 37:221-242. [PMID: 39207695 DOI: 10.1007/978-3-031-55529-9_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Neural plasticity can be defined as the ability of neural circuits to be shaped by external and internal factors. It provides the brain with a capacity for functional and morphological remodelling, with many lines of evidence indicating that these changes are vital for learning and memory formation. The basis of this brain plasticity resides in activity- and experience-driven modifications of synaptic strength, including synaptic formation, elimination or weakening, as well as of modulation of neuronal population, which drive the structural reorganization of neural networks. Recent evidence indicates that brain-resident glial cells actively participate in these processes, suggesting that mechanisms underlying plasticity in the brain are multifaceted. Establishing the 'tripartite' synapse, the role of astrocytes in modulating synaptic transmission in response to neuronal activity was recognized first. Further redefinition of the synapse as 'quad-partite' followed to acknowledge the contribution of microglia which were revealed to affect numerous brain functions via dynamic interactions with synapses, acting as 'synaptic sensors' that respond to neuronal activity and neurotransmitter release, as well as crosstalk with astrocytes. Early studies identified microglial ability to dynamically survey their local brain environment and established their integral role in the active interfacing of environmental stimuli (both internal and external), with brain plasticity and remodelling. Following the introduction to neurogenesis, this chapter details the role that microglia play in regulating neurogenesis in adulthood, specifically as it relates to learning and memory, as well as factors involved in modulation of microglia. Further, a microglial perspective is introduced for the context of environmental enrichment impact on neurogenesis, learning and memory across states of stress, ageing, disease and injury.
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Affiliation(s)
- Eva Šimončičová
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | | | | | - Clotilde Lauro
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Laura Maggi
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
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Diamanti T, Trobiani L, Mautone L, Serafini F, Gioia R, Ferrucci L, Lauro C, Bianchi S, Perfetto C, Guglielmo S, Sollazzo R, Giorda E, Setini A, Ragozzino D, Miranda E, Comoletti D, Di Angelantonio S, Cacci E, De Jaco A. Glucocorticoids rescue cell surface trafficking of R451C Neuroligin3 and enhance synapse formation. Traffic 2024; 25:e12930. [PMID: 38272450 DOI: 10.1111/tra.12930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/27/2024]
Abstract
Neuroligins are synaptic cell adhesion proteins with a role in synaptic function, implicated in neurodevelopmental disorders. The autism spectrum disorder-associated substitution Arg451Cys (R451C) in NLGN3 promotes a partial misfolding of the extracellular domain of the protein leading to retention in the endoplasmic reticulum (ER) and the induction of the unfolded protein response (UPR). The reduced trafficking of R451C NLGN3 to the cell surface leads to altered synaptic function and social behavior. A screening in HEK-293 cells overexpressing NLGN3 of 2662 compounds (FDA-approved small molecule drug library), led to the identification of several glucocorticoids such as alclometasone dipropionate, desonide, prednisolone sodium phosphate, and dexamethasone (DEX), with the ability to favor the exit of full-length R451C NLGN3 from the ER. DEX improved the stability of R451C NLGN3 and trafficking to the cell surface, reduced the activation of the UPR, and increased the formation of artificial synapses between HEK-293 and hippocampal primary neurons. The effect of DEX was validated on a novel model system represented by neural stem progenitor cells and differentiated neurons derived from the R451C NLGN3 knock-in mouse, expressing the endogenous protein. This work shows a potential rescue strategy for an autism-linked mutation affecting cell surface trafficking of a synaptic protein.
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Affiliation(s)
- Tamara Diamanti
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Laura Trobiani
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
| | - Lorenza Mautone
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University, Rome, Italy
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Federica Serafini
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Roberta Gioia
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Laura Ferrucci
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
| | - Clotilde Lauro
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
| | - Sara Bianchi
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Camilla Perfetto
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Stefano Guglielmo
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Raimondo Sollazzo
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Ezio Giorda
- Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Andrea Setini
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Davide Ragozzino
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
| | - Elena Miranda
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Davide Comoletti
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
- Child Health Institute of New Jersey, Rutgers University, New Brunswick, New Jersey, USA
| | - Silvia Di Angelantonio
- Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy
- D-tails s.r.l. Via di Torre Rossa, Rome, Italy
| | - Emanuele Cacci
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Antonella De Jaco
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
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Harry GJ. Microglia Colonization Associated with Angiogenesis and Neural Cell Development. ADVANCES IN NEUROBIOLOGY 2024; 37:163-178. [PMID: 39207692 DOI: 10.1007/978-3-031-55529-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
The temporal and spatial pattern of microglia colonization of the nervous system implies a role in early stages of organ development including cell proliferation, differentiation, and neurovascularization. As microglia colonize and establish within the developing nervous system, they assume a neural-specific identity and contribute to key developmental events. Their association around blood vessels implicates them in development of the vascular system or vice versa. A similar association has been reported for neural cell proliferation and associated phenotypic shifts and for cell fate differentiation to neuronal or glial phenotypes. These processes are accomplished by phagocytic activities, cell-cell contact relationships, and secretion of various factors. This chapter will present data currently available from studies evaluating the dynamic and interactive nature of these processes throughout the progression of nervous system development.
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Affiliation(s)
- G Jean Harry
- Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute Environmental Health Sciences, Research Triangle Park, NC, USA.
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Camacho-Concha N, Santana-Román ME, Sánchez NC, Velasco I, Pando-Robles V, Pedraza-Alva G, Pérez-Martínez L. Insights into Zika Virus Pathogenesis and Potential Therapeutic Strategies. Biomedicines 2023; 11:3316. [PMID: 38137537 PMCID: PMC10741857 DOI: 10.3390/biomedicines11123316] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 12/24/2023] Open
Abstract
Zika virus (ZIKV) has emerged as a significant public health threat, reaching pandemic levels in 2016. Human infection with ZIKV can manifest as either asymptomatic or as an acute illness characterized by symptoms such as fever and headache. Moreover, it has been associated with severe neurological complications in adults, including Guillain-Barre syndrome, and devastating fetal abnormalities, like microcephaly. The primary mode of transmission is through Aedes spp. mosquitoes, and with half of the world's population residing in regions where Aedes aegypti, the principal vector, thrives, the reemergence of ZIKV remains a concern. This comprehensive review provides insights into the pathogenesis of ZIKV and highlights the key cellular pathways activated upon ZIKV infection. Additionally, we explore the potential of utilizing microRNAs (miRNAs) and phytocompounds as promising strategies to combat ZIKV infection.
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Affiliation(s)
- Nohemi Camacho-Concha
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, Mexico; (N.C.-C.); (M.E.S.-R.); (N.C.S.); (G.P.-A.)
| | - María E. Santana-Román
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, Mexico; (N.C.-C.); (M.E.S.-R.); (N.C.S.); (G.P.-A.)
| | - Nilda C. Sánchez
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, Mexico; (N.C.-C.); (M.E.S.-R.); (N.C.S.); (G.P.-A.)
| | - Iván Velasco
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Ciudad de México 14269, Mexico
| | - Victoria Pando-Robles
- Centro de Investigación Sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca 62100, Morelos, Mexico;
| | - Gustavo Pedraza-Alva
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, Mexico; (N.C.-C.); (M.E.S.-R.); (N.C.S.); (G.P.-A.)
| | - Leonor Pérez-Martínez
- Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, Mexico; (N.C.-C.); (M.E.S.-R.); (N.C.S.); (G.P.-A.)
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9
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Morrison V, Houpert M, Trapani J, Brockman A, Kingsley P, Katdare K, Layden H, Nguena-Jones G, Trevisan A, Maguire-Zeiss K, Marnett L, Bix G, Ihrie R, Carter B. Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone. Cell Rep 2023; 42:113423. [PMID: 37952151 PMCID: PMC10842823 DOI: 10.1016/j.celrep.2023.113423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
Microglia are the primary phagocytes in the central nervous system and clear dead cells generated during development or disease. The phagocytic process shapes the microglia phenotype, which affects the local environment. A unique population of microglia resides in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence the neurogenic niche is not well understood. Here, we demonstrate that phagocytosis contributes to a pro-neurogenic microglial phenotype in the V-SVZ and that these microglia phagocytose apoptotic cells via the engulfment receptor Jedi-1. Deletion of Jedi-1 decreases apoptotic cell clearance, triggering a neuroinflammatory microglia phenotype that resembles dysfunctional microglia in neurodegeneration and aging and that reduces neural precursor proliferation via elevated interleukin-1β signaling; interleukin-1 receptor inhibition rescues precursor proliferation in vivo. Together, these results reveal a critical role for Jedi-1 in connecting microglial phagocytic activity to the maintenance of a pro-neurogenic phenotype in the developing V-SVZ.
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Affiliation(s)
- Vivianne Morrison
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA; Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA
| | - Matthew Houpert
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Jonathan Trapani
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Asa Brockman
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Philip Kingsley
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Ketaki Katdare
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Hillary Layden
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Gabriela Nguena-Jones
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Alexandra Trevisan
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | | | - Lawrence Marnett
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37235, USA; A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA
| | - Gregory Bix
- Center for Clinical Neuroscience Research, Tulane University, New Orleans, LA 70118, USA
| | - Rebecca Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37235, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA
| | - Bruce Carter
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37235, USA.
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10
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Almarhoumi R, Alvarez C, Harris T, Tognoni CM, Paster BJ, Carreras I, Dedeoglu A, Kantarci A. Microglial cell response to experimental periodontal disease. J Neuroinflammation 2023; 20:142. [PMID: 37316834 PMCID: PMC10265806 DOI: 10.1186/s12974-023-02821-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/29/2023] [Indexed: 06/16/2023] Open
Abstract
OBJECTIVES Microglial activation is critical for modulating the neuroinflammatory process and the pathological progression of neurodegenerative diseases, such as Alzheimer's disease (AD). Microglia are involved in forming barriers around extracellular neuritic plaques and the phagocytosis of β-amyloid peptide (Aβ). In this study, we tested the hypothesis that periodontal disease (PD) as a source of infection alters inflammatory activation and Aβ phagocytosis by the microglial cells. METHODS Experimental PD was induced using ligatures in C57BL/6 mice for 1, 10, 20, and 30 days to assess the progression of PD. Animals without ligatures were used as controls. Maxillary bone loss and local periodontal tissue inflammation associated with the development of PD were confirmed by morphometric bone analysis and cytokine expression, respectively. The frequency and the total number of activated microglia (CD45+ CD11b+ MHCII+) in the brain were analyzed by flow cytometry. Mouse microglial cells (1 × 105) were incubated with heat-inactivated bacterial biofilm isolated from the ligatures retrieved from the teeth or with Klebsiella variicola, a relevant PD-associated bacteria in mice. Expression of pro-inflammatory cytokines, toll-like receptors (TLR), and receptors for phagocytosis was measured by quantitative PCR. The phagocytic capacity of microglia to uptake β-amyloid was analyzed by flow cytometry. RESULTS Ligature placement caused progressive periodontal disease and bone resorption that was already significant on day 1 post-ligation (p < 0.05) and continued to increase until day 30 (p < 0.0001). The severity of periodontal disease increased the frequency of activated microglia in the brains on day 30 by 36%. In parallel, heat-inactivated PD-associated total bacteria and Klebsiella variicola increased the expression of TNFα, IL-1β, IL-6, TLR2, and TLR9 in microglial cells (1.6-, 83-, 3.2-, 1.5-, 1.5-fold, respectively p < 0.01). Incubation of microglia with Klebsiella variicola increased the Aβ-phagocytosis by 394% and the expression of the phagocytic receptor MSR1 by 33-fold compared to the non-activated cells (p < 0.0001). CONCLUSIONS We showed that inducing PD in mice results in microglia activation in vivo and that PD-associated bacteria directly promote a pro-inflammatory and phagocytic phenotype in microglia. These results support a direct role of PD-associated pathogens in neuroinflammation.
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Affiliation(s)
- Rawan Almarhoumi
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
- Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Carla Alvarez
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
| | - Theodore Harris
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
| | - Christina M. Tognoni
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
| | - Bruce J. Paster
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
| | - Isabel Carreras
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 USA
| | - Alpaslan Dedeoglu
- Department of Veterans Affairs, VA Boston Healthcare System, Research and Development Service, Building 1A-(151), 150 S. Huntington Avenue, Boston, MA 02130 USA
- Department of Neurology, Boston University School of Medicine, Boston, MA 02118 USA
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA
| | - Alpdogan Kantarci
- Forsyth Institute, 245 First Street, Cambridge, MA 02142 USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115 USA
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11
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Abbate C. The Adult Neurogenesis Theory of Alzheimer's Disease. J Alzheimers Dis 2023:JAD221279. [PMID: 37182879 DOI: 10.3233/jad-221279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.
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Affiliation(s)
- Carlo Abbate
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
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12
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Peng SJ, Feng Y, Li X, Wang XX, Wang Y, Zhou BT, Liu Y, Liu T, Wu YC. Thymopentin (TP-5) prevents lipopolysaccharide-induced neuroinflammation and dopaminergic neuron injury by inhibiting the NF-κB/NLRP3 signaling pathway. Int Immunopharmacol 2023; 119:110109. [PMID: 37121113 DOI: 10.1016/j.intimp.2023.110109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/03/2023] [Accepted: 03/24/2023] [Indexed: 05/02/2023]
Abstract
Neuroinflammation plays a pivotal role in neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and stroke, and is accompanied by excessive release of inflammatory cytokines and mediators by activated microglia. Microglial inflammatory response inhibition may be an effective strategy for preventing inflammatory disorders. However, the reciprocal connections between the central nervous system (CNS) and immune system have not been elucidated. Thus far, these links have been proven to mainly involve immuno- and neuropeptides. The pentapeptide thymopentin (TP-5) exerts a significant immunomodulatory effect; however, its antineuroinflammatory effects and underlying mechanism are still unclear. In this study, lipopolysaccharide (LPS) was used to establish an inflammation model, and the therapeutic effect of TP-5 was evaluated. Behavioral tests showed that TP-5 treatment could improve the performance of LPS-treated mice in the open field and pole test, but not hanging wire test. TP-5 also attenuated neuronal lesions in the brains of LPS-treated mice. TP-5 reduced cytotoxicity and morphological changes in activated microglia. Label-free quantitative analysis indicated that the expression of multiple proteins and the activation of associated signaling pathways were altered by TP-5. Moreover, TP-5 could inhibit LPS-induced neuroinflammation in the brain and BV2 microglia and the expression of major genes in the NF-κB/NLRP3 signaling pathway. Additionally, tyrosine hydroxylase (TH) expression downregulation was rescued in the LPS + TP-5 group compared with the LPS group. We conclude that TP-5 exerts neuroprotection by alleviating LPS-induced inflammatory damage and dopaminergic neurodegeneration. The protective effect of TP-5 may involve the NF-κB/NLRP3 signaling pathway.
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Affiliation(s)
- Si-Jia Peng
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Ya Feng
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Xuan Li
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Xi-Xi Wang
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Yu Wang
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Bu-Tian Zhou
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Ye Liu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China
| | - Te Liu
- Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
| | - Yun-Cheng Wu
- Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, PR China.
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13
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Song WP, Jin LY, Zhu MD, Wang H, Xia DS. Clinical trials using dental stem cells: 2022 update. World J Stem Cells 2023; 15:31-51. [PMID: 37007456 PMCID: PMC10052340 DOI: 10.4252/wjsc.v15.i3.31] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/20/2023] [Accepted: 03/08/2023] [Indexed: 03/23/2023] Open
Abstract
For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.
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Affiliation(s)
- Wen-Peng Song
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Lu-Yuan Jin
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
| | - Meng-Di Zhu
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
| | - Hao Wang
- Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Deng-Sheng Xia
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China.
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14
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Morrison VE, Houpert MG, Trapani JB, Brockman AA, Kingsley PJ, Katdare KA, Layden HM, Nguena-Jones G, Trevisan AJ, Maguire-Zeiss KA, Marnett LJ, Bix GJ, Ihrie RA, Carter BD. Jedi-1/MEGF12-mediated phagocytosis controls the pro-neurogenic properties of microglia in the ventricular-subventricular zone. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.03.531012. [PMID: 36945622 PMCID: PMC10028845 DOI: 10.1101/2023.03.03.531012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Microglia are the primary phagocytes in the central nervous system and are responsible for clearing dead cells generated during development or disease. The phagocytic process shapes the phenotype of the microglia, which affects the local environment. A unique population of microglia reside in the ventricular-subventricular zone (V-SVZ) of neonatal mice, but how they influence this neurogenic niche is not well-understood. Here, we demonstrate that phagocytosis creates a pro-neurogenic microglial phenotype in the V-SVZ and that these microglia phagocytose apoptotic cells via the engulfment receptor Jedi-1. Deletion of Jedi-1 decreases apoptotic cell clearance, triggering the development of a neuroinflammatory phenotype, reminiscent of neurodegenerative and-age-associated microglia, that reduces neural precursor proliferation via elevated interleukin (IL)-1β signaling; inhibition of IL-1 receptor rescues precursor proliferation in vivo. Together, these results reveal a critical role for Jedi-1 in connecting microglial phagocytic activity to a phenotype that promotes neurogenesis in the developing V-SVZ.
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Affiliation(s)
- Vivianne E Morrison
- Vanderbilt University Department of Biochemistry
- Vanderbilt Brain Institute
- Tulane University Center for Clinical Neuroscience Research
| | - Matthew G Houpert
- Vanderbilt University Department of Biochemistry
- Vanderbilt Brain Institute
| | - Jonathan B Trapani
- Vanderbilt University Department of Biochemistry
- Vanderbilt Brain Institute
| | - Asa A Brockman
- Vanderbilt University Department of Cell and Developmental Biology
- Vanderbilt Brain Institute
| | | | | | | | | | - Alexandra J Trevisan
- Vanderbilt University Department of Biochemistry
- St. Jude Children's Research Hospital
| | | | - Lawrence J Marnett
- Vanderbilt University Department of Biochemistry
- Vanderbilt University Department of Chemistry
- Vanderbilt University Department of Pharmacology
- A.B. Hancock Jr. Memorial Laboratory for Cancer Research
| | - Gregory J Bix
- Tulane University Center for Clinical Neuroscience Research
| | - Rebecca A Ihrie
- Vanderbilt University Department of Cell and Developmental Biology
- Vanderbilt Brain Institute
| | - Bruce D Carter
- Vanderbilt University Department of Biochemistry
- Vanderbilt Brain Institute
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15
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Stem Cells and Targeted Gene Therapy in Brain and Spinal Cord Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1394:137-152. [PMID: 36587386 DOI: 10.1007/978-3-031-14732-6_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The CNS tumors, in particular those with malignant characteristics, are prominent burdens around the world with high mortality and low cure rate. Given that, researchers were curious about novel treatments with promising effectiveness which resulted in shifting the dogmatism era of neurogenesis to the current concept of postnatal neurogenesis. Considering all existing stem cells, various strategies are available for treating CNS cancers, including hematopoietic stem cells transplantation, mesenchymal stem cells transplantation, neural stem cells (NSCs) transplantation, and using stem cells as genetic carriers called "suicide gene therapy". Despite some complications, this ongoing therapeutic method has succeeded in decreasing tumor volume, inhibiting tumor progression, and enhancing patients' survival. These approaches could lead to acceptable results, relatively better safety, and tolerable side effects compared to conventional chemo and radiotherapy. Accordingly, this treatment will be applicable to a wide range of CNS tumors in the near future. Furthermore, tumor genomic analysis and understanding of the underlying molecular mechanisms will help researchers determine patient selection criteria for targeted gene therapy.
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16
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Willis CM, Nicaise AM, Krzak G, Ionescu RB, Pappa V, D'Angelo A, Agarwal R, Repollés-de-Dalmau M, Peruzzotti-Jametti L, Pluchino S. Soluble factors influencing the neural stem cell niche in brain physiology, inflammation, and aging. Exp Neurol 2022; 355:114124. [DOI: 10.1016/j.expneurol.2022.114124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 05/16/2022] [Accepted: 05/21/2022] [Indexed: 11/27/2022]
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17
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Zuo C, Ma J, Pan Y, Zheng D, Chen C, Ruan N, Su Y, Nan H, Lian Q, Lin H. Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway. Neurotox Res 2022; 40:775-790. [PMID: 35471722 PMCID: PMC9098611 DOI: 10.1007/s12640-022-00511-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/26/2022] [Accepted: 04/12/2022] [Indexed: 12/30/2022]
Abstract
Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.
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Affiliation(s)
- Chunlong Zuo
- Department of Anesthesiology, The First Affiliated Hospital of AnHui Medical University, Hefei, 230022, PRC, China.,Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China
| | - Junmei Ma
- Department of Anesthesiology, Ningbo Medical Center Lihuili Hospital, Ningbo, 315040, PRC, China
| | - Yizhao Pan
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Shangcaicun, Wenzhou, 325000, PRC, China
| | - Dongxu Zheng
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China
| | - Chunjiang Chen
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China
| | - Naqi Ruan
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China
| | - Ying Su
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China
| | - Haihan Nan
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, 325035, PRC, China
| | - Qingquan Lian
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China.
| | - Han Lin
- Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PRC, Zhejiang Province Key Lab of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, PRC, China.
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18
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The secretome of microglia induced by IL-4 of IFN-γ differently regulate proliferation, differentiation and survival of adult neural stem/progenitor cell by targeting the PI3K-Akt pathway. Cytotechnology 2022; 74:407-420. [DOI: 10.1007/s10616-022-00534-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 04/04/2022] [Indexed: 01/04/2023] Open
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19
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Early Life Events and Maturation of the Dentate Gyrus: Implications for Neurons and Glial Cells. Int J Mol Sci 2022; 23:ijms23084261. [PMID: 35457079 PMCID: PMC9031216 DOI: 10.3390/ijms23084261] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/15/2022] Open
Abstract
The dentate gyrus (DG), an important part of the hippocampus, plays a significant role in learning, memory, and emotional behavior. Factors potentially influencing normal development of neurons and glial cells in the DG during its maturation can exert long-lasting effects on brain functions. Early life stress may modify maturation of the DG and induce lifelong alterations in its structure and functioning, underlying brain pathologies in adults. In this paper, maturation of neurons and glial cells (microglia and astrocytes) and the effects of early life events on maturation processes in the DG have been comprehensively reviewed. Early postnatal interventions affecting the DG eventually result in an altered number of granule neurons in the DG, ectopic location of neurons and changes in adult neurogenesis. Adverse events in early life provoke proinflammatory changes in hippocampal glia at cellular and molecular levels immediately after stress exposure. Later, the cellular changes may disappear, though alterations in gene expression pattern persist. Additional stressful events later in life contribute to manifestation of glial changes and behavioral deficits. Alterations in the maturation of neuronal and glial cells induced by early life stress are interdependent and influence the development of neural nets, thus predisposing the brain to the development of cognitive and psychiatric disorders.
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20
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Wu C, Pan Y, Wang L, Liu M, Wu M, Wang J, Yang G, Guo Y, Ma Y. A new method for primary culture of microglia in rats with spinal cord injury. Biochem Biophys Res Commun 2022; 599:63-68. [PMID: 35176626 DOI: 10.1016/j.bbrc.2022.02.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 11/29/2022]
Abstract
At present, the primary culture method of microglia is complicated, and the culture of spinal cord microglia is rare, so we will explore to establish a new and efficient primary culture method of microglia in rats with spinal cord injury (SCI). The SCI model of SD rats was established by modified A11en's method, and the model of SCI was performed on 1 d, 3 d, 7 d and 14 d respectively. Then the injured spinal cord was removed, mechanically separated and filtered. The morphology of microglia was observed the next day and its purity was identified by CD11b and Iba1 immunofluorescence labeling. According to the above results, the morphological changes of microglia after 3 d of SCI were observed at 1 d, 2 d and 4 d. The results showed that the purity of microglia was 98%. The number of microglia after 3 d of SCI was the most. After SCI, the migration ability of microglia was enhanced, the number of microglia in the injured area increased, and the number was the highest at 3 d, then gradually decreased. In addition, the microglia after SCI would gradually change from active state to resting state with the passage of time. Therefore, we can use a simple and efficient mechanical separation method to extract primary microglia, which provides the basis for the study of microglia.
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Affiliation(s)
- Chengjie Wu
- Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yalan Pan
- Laboratory of Chinese Medicine Nursing Intervention for Chronic Diseases, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lining Wang
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing, China
| | - Mengmin Liu
- School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing, China
| | - Mao Wu
- Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, China
| | - Jianwei Wang
- Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, China
| | - Guanglu Yang
- Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Guo
- Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Yong Ma
- Department of Traumatology and Orthopedics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, China; School of Chinese Medicine, School of Integrated Chinese and Western Medicine, Nanjing, China.
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21
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Zheng X, Mi T, Wang R, Zhang Z, Li W, Zhao J, Yang P, Xia H, Mao Q. Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury. Glia 2022; 70:1317-1336. [PMID: 35362178 DOI: 10.1002/glia.24175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/07/2022]
Abstract
Traumatic brain injury (TBI) can be progressive and can lead to the development of a long-term complication termed chronic traumatic encephalopathy. The mechanisms underlying the progressive changes are still unknown; however, studies have suggested that microglia-mediated neuroinflammation in response to TBI may play a fundamental role. This study aimed to determine whether progranulin (PGRN), a major modulator of microglial activity, plays a role in the progressive damage following TBI. PGRN-deficient and wild-type mice were subjected to controlled cortical impact and were observed neuropathologically after 3 days, 7 days, and 5 months. Compared to sham and wild-type mice, the PGRN-deficient mice showed overall stronger microgliosis and astrocytosis. The astrocytosis involved broader areas than the microgliosis and was more prominent in the basal ganglia, hippocampus, and internal capsule in PGRN-deficient mice. Ongoing neuronal death was uniquely observed in the hippocampal CA3 region of PGRN-deficient mice at 5 months after TBI, accompanying the regional chronic microgliosis and astrocytosis involving the CA3 commissural pathway. In addition, there was M1 microglial polarization in the pericontusional area with activated TLR4/MyD88/NF-κB signaling; however, the hippocampus showed only mild M1 polarization 7 days after TBI. Lastly, Morris water maze tests showed PGRN-deficient mice had poorer spatial learning and memory 5 months after TBI than wild-type or sham mice. The data indicated the PGRN deficiency caused TBI progression by promoting persistent microgliosis with microglial polarization and astrocytosis, as well as regional pathology in the hippocampus. The study suggests that PGRN should be evaluated as a potential therapy for TBI.
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Affiliation(s)
- Xiaojing Zheng
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Tiantian Mi
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Rong Wang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Zihan Zhang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Wenyan Li
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Junli Zhao
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Peiyan Yang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Haibin Xia
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Qinwen Mao
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
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22
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Ma Y, Yang S, He Q, Zhang D, Chang J. The Role of Immune Cells in Post-Stroke Angiogenesis and Neuronal Remodeling: The Known and the Unknown. Front Immunol 2022; 12:784098. [PMID: 34975872 PMCID: PMC8716409 DOI: 10.3389/fimmu.2021.784098] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Following a cerebral ischemic event, substantial alterations in both cellular and molecular activities occur due to ischemia-induced cerebral pathology. Mounting evidence indicates that the robust recruitment of immune cells plays a central role in the acute stage of stroke. Infiltrating peripheral immune cells and resident microglia mediate neuronal cell death and blood-brain barrier disruption by releasing inflammation-associated molecules. Nevertheless, profound immunological effects in the context of the subacute and chronic recovery phase of stroke have received little attention. Early attempts to curtail the infiltration of immune cells were effective in mitigating brain injury in experimental stroke studies but failed to exert beneficial effects in clinical trials. Neural tissue damage repair processes include angiogenesis, neurogenesis, and synaptic remodeling, etc. Post-stroke inflammatory cells can adopt divergent phenotypes that influence the aforementioned biological processes in both endothelial and neural stem cells by either alleviating acute inflammatory responses or secreting a variety of growth factors, which are substantially involved in the process of angiogenesis and neurogenesis. To better understand the multiple roles of immune cells in neural tissue repair processes post stroke, we review what is known and unknown regarding the role of immune cells in angiogenesis, neurogenesis, and neuronal remodeling. A comprehensive understanding of these inflammatory mechanisms may help identify potential targets for the development of novel immunoregulatory therapeutic strategies that ameliorate complications and improve functional rehabilitation after stroke.
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Affiliation(s)
- Yinzhong Ma
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Shilun Yang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Qianyan He
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Dianhui Zhang
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Junlei Chang
- Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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23
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Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery. Neural Plast 2022; 2022:9959044. [PMID: 35075360 PMCID: PMC8783751 DOI: 10.1155/2022/9959044] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/21/2021] [Accepted: 12/15/2021] [Indexed: 12/31/2022] Open
Abstract
The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer's disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.
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24
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Wang YC, Lu YB, Huang XL, Lao YF, Zhang L, Yang J, Shi M, Ma HL, Pan YW, Zhang YN. Myeloperoxidase: a new target for the treatment of stroke? Neural Regen Res 2022; 17:1711-1716. [PMID: 35017418 PMCID: PMC8820716 DOI: 10.4103/1673-5374.332130] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Myeloperoxidase is an important inflammatory factor in the myeloid system, primarily expressed in neutrophils and microglia. Myeloperoxidase and its active products participate in the occurrence and development of hemorrhagic and ischemic stroke, including damage to the blood-brain barrier and brain. As a specific inflammatory marker, myeloperoxidase can be used in the evaluation of vascular disease occurrence and development in stroke, and a large amount of experimental and clinical data has indicated that the inhibition or lack of myeloperoxidase has positive impacts on stroke prognosis. Many studies have also shown that there is a correlation between the overexpression of myeloperoxidase and the risk of stroke. The occurrence of stroke not only refers to the first occurrence but also includes recurrence. Therefore, myeloperoxidase is significant for the clinical evaluation and prognosis of stroke. This paper reviews the potential role played by myeloperoxidase in the development of vascular injury and secondary brain injury after stroke and explores the effects of inhibiting myeloperoxidase on stroke prognosis. This paper also analyzes the significance of myeloperoxidase etiology in the occurrence and development of stroke and discusses whether myeloperoxidase can be used as a target for the treatment and prediction of stroke.
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Affiliation(s)
- Yun-Chang Wang
- The Second Clinical Medical School, Lanzhou University; Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu Province; Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yu-Bao Lu
- The Second Clinical Medical School, Lanzhou University; Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu Province; Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao-Lan Huang
- University of Chinese Academy of Sciences, Beijing, China
| | - Yong-Feng Lao
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China
| | - Lu Zhang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China
| | - Jun Yang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China
| | - Mei Shi
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China
| | - Hai-Long Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China
| | - Ya-Wen Pan
- The Second Clinical Medical School, Lanzhou University; Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
| | - Yi-Nian Zhang
- The Second Clinical Medical School, Lanzhou University; Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
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25
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Minamisawa M, Sato Y, Ishiguro E, Taniai T, Sakamoto T, Kawai G, Saito T, Saido TC. Amelioration of Alzheimer's Disease by Gut-Pancreas-Liver-Brain Interaction in an App Knock-In Mouse Model. Life (Basel) 2021; 12:34. [PMID: 35054427 PMCID: PMC8778338 DOI: 10.3390/life12010034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/19/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023] Open
Abstract
In this study, we observed disease progression, changes in the gut microbiota, and interactions among the brain, liver, pancreas, and intestine in a mouse model of Alzheimer's disease (AD), in addition to attempting to inhibit disease progression through the dietary supplementation of L-arginine and limonoids. Wild-type mice (WC) and AD mice were fed a normal diet (AC), a diet supplemented with L-arginine and limonoids (ALA), or a diet containing only limonoids (AL) for 12-64 weeks. The normal diet-fed WC and AC mice showed a decrease in the diversity of the gut microbiota, with an increase in the Firmicutes/Bacteroidetes ratio, and bacterial translocation. Considerable bacterial translocation to the pancreas and intense inflammation of the pancreas, liver, brain, and intestinal tissues were observed in the AC mice from alterations in the gut microbiota. The ALA diet or AL diet-fed mice showed increased diversity of the bacterial flora and suppressed oxidative stress and inflammatory responses in hepatocytes and pancreatic cells, bacterial translocation, and neurodegeneration of the brain. These findings suggest that L-arginine and limonoids help in maintaining the homeostasis of the gut microbiota, pancreas, liver, brain, and gut in AD mice.
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Affiliation(s)
- Mayumi Minamisawa
- Department of Life Science, Chiba Institute of Technology, Graduate School of Advanced Engineering, Chiba 275-0016, Japan; (Y.S.); (T.S.); (G.K.)
- Education Center, Faculty of Advanced Engineering, Chiba Institute of Technology, Chiba 275-0023, Japan;
| | - Yuma Sato
- Department of Life Science, Chiba Institute of Technology, Graduate School of Advanced Engineering, Chiba 275-0016, Japan; (Y.S.); (T.S.); (G.K.)
| | | | - Tetsuyuki Taniai
- Education Center, Faculty of Advanced Engineering, Chiba Institute of Technology, Chiba 275-0023, Japan;
| | - Taiichi Sakamoto
- Department of Life Science, Chiba Institute of Technology, Graduate School of Advanced Engineering, Chiba 275-0016, Japan; (Y.S.); (T.S.); (G.K.)
| | - Gota Kawai
- Department of Life Science, Chiba Institute of Technology, Graduate School of Advanced Engineering, Chiba 275-0016, Japan; (Y.S.); (T.S.); (G.K.)
| | - Takashi Saito
- RIKEN Center for Brain Science, Laboratory for Proteolytic Neuroscience, Saitama 351-0198, Japan; (T.S.); (T.C.S.)
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Takaomi C. Saido
- RIKEN Center for Brain Science, Laboratory for Proteolytic Neuroscience, Saitama 351-0198, Japan; (T.S.); (T.C.S.)
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26
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Borrajo A, Spuch C, Penedo MA, Olivares JM, Agís-Balboa RC. Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis. Ann Med 2021; 53:43-69. [PMID: 32841065 PMCID: PMC7877929 DOI: 10.1080/07853890.2020.1814962] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. KEY MESSAGES Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND.
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Affiliation(s)
- A. Borrajo
- Department of Microbiology and Parasitology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Roma, Italy
| | - C. Spuch
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur)-Área Sanitaria de Vigo, SERGAS-UVigo, CIBERSAM, Vigo, Spain
| | - M. A. Penedo
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur)-Área Sanitaria de Vigo, SERGAS-UVigo, CIBERSAM, Vigo, Spain
| | - J. M. Olivares
- Department of Psychiatry, Área Sanitaria de Vigo, Vigo, Spain
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur)-Área Sanitaria de Vigo, SERGAS-UVigo, CIBERSAM, Vigo, Spain
| | - R. C. Agís-Balboa
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur)-Área Sanitaria de Vigo, SERGAS-UVigo, CIBERSAM, Vigo, Spain
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27
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Mizobuchi H, Soma GI. Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia. Neural Regen Res 2021; 16:1928-1934. [PMID: 33642362 PMCID: PMC8343302 DOI: 10.4103/1673-5374.308067] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/26/2020] [Accepted: 12/16/2020] [Indexed: 12/25/2022] Open
Abstract
Microglia, which are tissue-resident macrophages in the brain, play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis. Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria, and activates immune cells including microglia via Toll-like receptor 4 signaling. Lipopolysaccharide is generally known as an endotoxin, as administration of high-dose lipopolysaccharide induces potent systemic inflammation. Also, it has long been recognized that lipopolysaccharide exacerbates neuroinflammation. In contrast, our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer's disease pathology and suggested that neuroprotective microglia are involved in this phenomenon. Additionally, other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype. Therefore, lipopolysaccharide may not a mere inflammatory inducer, but an immunomodulator that can lead to neuroprotective effects in the brain. In this review, we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide. We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators, but instead must be described by their complex profile comprising various molecules related to inflammatory regulation, phagocytosis, neuroprotection, anti-apoptosis, and antioxidation. In addition, microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training. Immune training of neuroprotective microglia using low-dose lipopolysaccharide, especially through oral lipopolysaccharide administration, may represent an innovative prevention or treatment for neurological diseases; however more vigorous studies are still required to properly modulate these treatments.
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Affiliation(s)
- Haruka Mizobuchi
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan
| | - Gen-Ichiro Soma
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan
- Macrophi Inc., Kagawa, Japan
- Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
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28
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Mizobuchi H, Yamamoto K, Yamashita M, Inagawa H, Kohchi C, Soma GI. Prevention of streptozotocin‑induced Neuro‑2a cell death by C8‑B4 microglia transformed with repetitive low‑dose lipopolysaccharide. Mol Med Rep 2021; 24:687. [PMID: 34328201 DOI: 10.3892/mmr.2021.12328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/29/2021] [Indexed: 11/05/2022] Open
Abstract
Diabetes‑associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2‑deoxy‑2‑(3‑methy1‑3‑nitrosoureido) D‑glucopyranose; STZ] is one of the most well‑established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8‑B4 microglia transformed by the stimulus of repetitive low‑dose lipopolysaccharide (LPSx3‑microglia) prevent STZ‑induced Neuro‑2a neuronal cell death in vitro. The ELISA results showed that neurotrophin‑4/5 (NT‑4/5) secretion was promoted in LPSx3‑microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3‑microglia prevented STZ‑induced neuronal cell death. In addition, reverse transcription‑quantitative PCR showed that neurons treated with the culture supernatant of LPSx3‑microglia promoted the gene expression of B‑cell lymphoma‑extra large and glucose‑dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT‑4/5, suppressed the neuroprotective effect of LPSx3‑microglia. Taken together, the present study demonstrated that LPSx3‑microglia prevent STZ‑induced neuronal death and that NT‑4/5 may be involved in the neuroprotective mechanism of LPSx3‑microglia.
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Affiliation(s)
- Haruka Mizobuchi
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
| | - Kazushi Yamamoto
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
| | - Masashi Yamashita
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
| | - Hiroyuki Inagawa
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
| | - Chie Kohchi
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
| | - Gen-Ichiro Soma
- Control of Innate Immunity, Collaborative Innovation Partnership, Takamatsu‑shi, Kagawa 761‑0301, Japan
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29
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Turkin A, Tuchina O, Klempin F. Microglia Function on Precursor Cells in the Adult Hippocampus and Their Responsiveness to Serotonin Signaling. Front Cell Dev Biol 2021; 9:665739. [PMID: 34109176 PMCID: PMC8182052 DOI: 10.3389/fcell.2021.665739] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/12/2021] [Indexed: 12/18/2022] Open
Abstract
Microglia are the resident immune cells of the adult brain that become activated in response to pathogen- or damage-associated stimuli. The acute inflammatory response to injury, stress, or infection comprises the release of cytokines and phagocytosis of damaged cells. Accumulating evidence indicates chronic microglia-mediated inflammation in diseases of the central nervous system, most notably neurodegenerative disorders, that is associated with disease progression. To understand microglia function in pathology, knowledge of microglia communication with their surroundings during normal state and the release of neurotrophins and growth factors in order to maintain homeostasis of neural circuits is of importance. Recent evidence shows that microglia interact with serotonin, the neurotransmitter crucially involved in adult neurogenesis, and known for its role in antidepressant action. In this chapter, we illustrate how microglia contribute to neuroplasticity of the hippocampus and interact with local factors, e.g., BDNF, and external stimuli that promote neurogenesis. We summarize the recent findings on the role of various receptors in microglia-mediated neurotransmission and particularly focus on microglia’s response to serotonin signaling. We review microglia function in neuroinflammation and neurodegeneration and discuss their novel role in antidepressant mechanisms. This synopsis sheds light on microglia in healthy brain and pathology that involves serotonin and may be a potential therapeutic model by which microglia play a crucial role in the maintenance of mood.
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Affiliation(s)
- Andrei Turkin
- School of Life Sciences, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Oksana Tuchina
- School of Life Sciences, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Friederike Klempin
- Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Berlin, Germany
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30
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N-docosahexaenoylethanolamine reduces neuroinflammation and cognitive impairment after mild traumatic brain injury in rats. Sci Rep 2021; 11:756. [PMID: 33436960 PMCID: PMC7804312 DOI: 10.1038/s41598-020-80818-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/28/2020] [Indexed: 12/14/2022] Open
Abstract
At present, there is a growing interest in the study of the neurotropic activity of polyunsaturated fatty acids ethanolamides (N-acylethanolamines). N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analogue of anandamide, a widely studied endocannabinoid derived from arachidonic acid. The results of this study demonstrate that DHEA, when administered subcutaneously (10 mg/kg/day, 7 days), promotes cognitive recovery in rats subjected to mild traumatic brain injury (mTBI). In the cerebral cortex of experimental animals, we analyzed the dynamics of Iba-1-positive microglia activity changes and the expression of pro-inflammatory markers (IL1β, IL6, CD86). We used immortalized mouse microglial cells (SIM-A9) to assess the effects of DHEA on LPS-induced cytokines/ROS/NO/nitrite, as well as on CD206 (anti-inflammatory microglia) and the antioxidant enzyme superoxide dismutase (SOD) production. In vivo and in vitro experiments showed that DHEA: (1) improves indicators of anxiety and long-term memory; (2) inhibits the pro-inflammatory microglial cells activity; (3) decrease the level of pro-inflammatory cytokines/ROS/NO/nitrites; (4) increase CD206 and SOD production. In general, the results of this study indicate that DHEA has a complex effect on the neuroinflammation processes, which indicates its high therapeutic potential.
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31
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Zhang D, Cai G, Liu K, Zhuang Z, Jia K, Pei S, Wang X, Wang H, Xu S, Cui C, Sun M, Guo S, Song W, Cai G. Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1. Aging (Albany NY) 2021; 13:4079-4095. [PMID: 33461167 PMCID: PMC7906161 DOI: 10.18632/aging.202373] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.
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Affiliation(s)
- Dianquan Zhang
- Department of Rehabilitation Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Guoliang Cai
- Postdoctoral Research Workstation of Harbin Sport University, Harbin 150008, China.,Harbin Sport University, Harbin 150008, China
| | - Kai Liu
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Zhe Zhuang
- Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Kunping Jia
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Siying Pei
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Xiuzhen Wang
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Hong Wang
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
| | - Shengnan Xu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Cheng Cui
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Manchao Sun
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Sihui Guo
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Wenli Song
- Harbin Sport University, Harbin 150008, China
| | - Guofeng Cai
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China.,Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
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32
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Lorenzen K, Mathy NW, Whiteford ER, Eischeid A, Chen J, Behrens M, Chen XM, Shibata A. Microglia induce neurogenic protein expression in primary cortical cells by stimulating PI3K/AKT intracellular signaling in vitro. Mol Biol Rep 2021; 48:563-584. [PMID: 33387198 PMCID: PMC7884585 DOI: 10.1007/s11033-020-06092-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 12/15/2020] [Indexed: 12/23/2022]
Abstract
Emerging evidence suggests that microglia can support neurogenesis. Little is known about the mechanisms by which microglia regulate the cortical environment and stimulate cortical neurogenesis. We used an in vitro co-culture model system to investigate the hypothesis that microglia respond to soluble signals from cortical cells, particularly following mechanical injury, to alter the cortical environment and promote cortical cell proliferation, differentiation, and survival. Analyses of cortical cell proliferation, cell death, neurogenic protein expression, and intracellular signaling were performed on uninjured and injured cortical cells in co-culture with microglial cell lines. Microglia soluble cues enhanced cortical cell viability and proliferation cortical cells. Co-culture of injured cortical cells with microglia significantly reduced cell death of cortical cells. Microglial co-culture significantly increased Nestin + and α-internexin + cortical cells. Multiplex ELISA and RT-PCR showed decreased pro-inflammatory cytokine production by microglia co-cultured with injured cortical cells. Inhibition of AKT phosphorylation in cortical cells blocked microglial-enhanced cortical cell viability and expression of neurogenic markers in vitro. This in vitro model system allows for assessment of the effect of microglial-derived soluble signals on cortical cell viability, proliferation, and stages of differentiation during homeostasis or following mechanical injury. These data suggest that microglia cells can downregulate inflammatory cytokine production following activation by mechanical injury to enhance proliferation of new cells capable of neurogenesis via activation of AKT intracellular signaling. Increasing our understanding of the mechanisms that drive microglial-enhanced cortical neurogenesis during homeostasis and following injury in vitro will provide useful information for future primary cell and in vivo studies.
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Affiliation(s)
- Kristi Lorenzen
- Biology Department, Creighton University, Omaha, NE, USA
- University of Nebraska Medical Center, Omaha, NE, USA
| | - Nicholas W Mathy
- Biology Department, Creighton University, Omaha, NE, USA
- Pediatric Medicine, St. Joseph Heritage Healthcare, Chino Hills, CA, USA
| | - Erin R Whiteford
- Biology Department, Creighton University, Omaha, NE, USA
- Pediatric Medicine, St. Joseph Heritage Healthcare, Chino Hills, CA, USA
| | - Alex Eischeid
- Biology Department, Creighton University, Omaha, NE, USA
- Stanford Hospital and Clinics, 300 Pasteur Dr, Stanford, CA, USA
| | - Jing Chen
- Biology Department, Creighton University, Omaha, NE, USA
- Pediatric Medicine, St. Joseph Heritage Healthcare, Chino Hills, CA, USA
| | - Matthew Behrens
- Biology Department, Creighton University, Omaha, NE, USA
- University of Nebraska College of Medicine, Omaha, NE, USA
| | - Xian-Ming Chen
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Creighton University, Omaha, NE, USA
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Wen SJ, Zheng XM, Liu LF, Li NN, Mao HA, Huang L, Yuan QL. Effects of primary microglia and astrocytes on neural stem cells in in vitro and in vivo models of ischemic stroke. Neural Regen Res 2021; 16:1677-1685. [PMID: 33510055 PMCID: PMC8328755 DOI: 10.4103/1673-5374.306093] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Transplantation of neural stem cells (NSCs) can protect neurons in animal stroke models; however, their low rates of survival and neuronal differentiation limit their clinical application. Glial niches, an important location of neural stem cells, regulate survival, proliferation and differentiation of neural stem cells. However, the effects of activated glial cells on neural stem cells remain unclear. In the present study, we explored the effects of activated astrocytes and microglia on neural stem cells in vitro stroke models. We also investigated the effects of combined transplantation of neural stem cells and glial cells after stroke in rats. In a Transwell co-culture system, primary cultured astrocytes, microglia or mixed glial cells were exposed to glutamate or H2O2 and then seeded in the upper inserts, while primary neural stem cells were seeded in the lower uncoated wells and cultured for 7 days. Our results showed that microglia were conducive to neurosphere formation and had no effects on apoptosis within neurospheres, while astrocytes and mixed glial cells were conducive to neurosphere differentiation and reduced apoptosis within neurospheres, regardless of their pretreatment. In contrast, microglia and astrocytes induced neuronal differentiation of neural stem cells in differentiation medium, regardless of their pretreatment, with an exception of astrocytes pretreated with H2O2. Rat models of ischemic stroke were established by occlusion of the middle cerebral artery. Three days later, 5 × 105 neural stem cells with microglia or astrocytes were injected into the right lateral ventricle. Neural stem cell/astrocyte-treated rats displayed better improvement of neurological deficits than neural stem cell only-treated rats at 4 days after cell transplantation. Moreover, neural stem cell/microglia-, and neural stem cell/astrocyte-treated rats showed a significant decrease in ischemic volume compared with neural stem cell-treated rats. These findings indicate that microglia and astrocytes exert different effects on neural stem cells, and that co-transplantation of neural stem cells and astrocytes is more conducive to the recovery of neurological impairment in rats with ischemic stroke. The study was approved by the Animal Ethics Committee of Tongji University School of Medicine, China (approval No. 2010-TJAA08220401) in 2010.
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Affiliation(s)
- Sheng-Jun Wen
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xi-Min Zheng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li-Fen Liu
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Na-Na Li
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hai-An Mao
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liang Huang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiong-Lan Yuan
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Role of Microglia in Modulating Adult Neurogenesis in Health and Neurodegeneration. Int J Mol Sci 2020; 21:ijms21186875. [PMID: 32961703 PMCID: PMC7555074 DOI: 10.3390/ijms21186875] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023] Open
Abstract
Microglia are the resident immune cells of the brain, constituting the powerhouse of brain innate immunity. They originate from hematopoietic precursors that infiltrate the developing brain during different stages of embryogenesis, acquiring a phenotype characterized by the presence of dense ramifications. Microglial cells play key roles in maintaining brain homeostasis and regulating brain immune responses. They continuously scan and sense the brain environment to detect any occurring changes. Upon detection of a signal related to physiological or pathological processes, the cells are activated and transform to an amoeboid-like phenotype, mounting adequate responses that range from phagocytosis to secretion of inflammatory and trophic factors. The overwhelming evidence suggests that microglia are crucially implicated in influencing neuronal proliferation and differentiation, as well as synaptic connections, and thereby cognitive and behavioral functions. Here, we review the role of microglia in adult neurogenesis under physiological conditions, and how this role is affected in neurodegenerative diseases.
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Gray SC, Kinghorn KJ, Woodling NS. Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis. Neural Regen Res 2020; 15:1208-1219. [PMID: 31960800 PMCID: PMC7047786 DOI: 10.4103/1673-5374.272571] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/02/2019] [Accepted: 10/22/2019] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer's disease is necessary. Recent studies have revealed increasing evidence for the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-established roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines produced by microglia in Alzheimer's disease. A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation may play a key role in the pathogenesis of Alzheimer's disease. Here we review recent findings on the roles played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer's disease. In each case, landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases, the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium, in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer's disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of the pathogenic mechanisms underlying Alzheimer's disease, and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer's disease brain.
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Affiliation(s)
- Sophie C. Gray
- Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK
| | - Kerri J. Kinghorn
- Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK
| | - Nathaniel S. Woodling
- Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK
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Mizobuchi H, Yamamoto K, Tsutsui S, Yamashita M, Nakata Y, Inagawa H, Kohchi C, Soma GI. A unique hybrid characteristic having both pro- and anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in C8-B4 microglia. Sci Rep 2020; 10:8945. [PMID: 32488176 PMCID: PMC7265460 DOI: 10.1038/s41598-020-65998-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 05/13/2020] [Indexed: 12/11/2022] Open
Abstract
Although lipopolysaccharide (LPS) is regarded as an inducer of inflammation, previous studies have suggested that repetitive low-dose LPS has neuroprotective effects via immunomodulation of microglia, resident macrophages of brain. However, microglia transformed by the stimulus of repetitive low-dose LPS (REPELL-microglia) are not well characterized, whereas microglia transformed by repetitive high-dose LPS are well studied as an endotoxin tolerance model in which the induction of pro-inflammatory molecules is suppressed. In this study, to characterize REPELL-microglia, the gene expression and phagocytic activity of REPELL-microglia were analyzed with the murine C8-B4 microglia cell line. The REPELL-microglia were characterized by a high expression of pro-inflammatory molecules (Nos2, Ccl1, IL-12B, and CD86), anti-inflammatory molecules (IL-10, Arg1, Il13ra2, and Mrc1), and neuroprotective molecules (Ntf5, Ccl7, and Gipr). In addition, the phagocytic activity of REPELL-microglia was promoted as high as that of microglia transformed by single low-dose LPS. These results suggest the potential of REPELL-microglia for inflammatory regulation, neuroprotection, and phagocytic clearance. Moreover, this study revealed that gene expression of REPELL-microglia was distinct from that of microglia transformed by repetitive high-dose LPS treatment, suggesting the diversity of microglia transformation by different doses of LPS.
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Affiliation(s)
- Haruka Mizobuchi
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan
| | - Kazushi Yamamoto
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan
| | | | - Masafumi Yamashita
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan
| | | | - Hiroyuki Inagawa
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan.,Macrophi Inc., Kagawa, Japan.,Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
| | | | - Gen-Ichiro Soma
- Control of Innate Immunity, Technology Research Association, Kagawa, Japan. .,Macrophi Inc., Kagawa, Japan. .,Research Institute for Healthy Living, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
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Ward H, West SJ. Microglia: sculptors of neuropathic pain? ROYAL SOCIETY OPEN SCIENCE 2020; 7:200260. [PMID: 32742693 PMCID: PMC7353970 DOI: 10.1098/rsos.200260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/01/2020] [Indexed: 05/02/2023]
Abstract
Neuropathic pain presents a huge societal and individual burden. The limited efficacy of current analgesics, diagnostic markers and clinical trial outcome measures arises from an incomplete understanding of the underlying mechanisms. A large and growing body of evidence has established the important role of microglia in the onset and possible maintenance of neuropathic pain, and these cells may represent an important target for future therapy. Microglial research has further revealed their important role in structural remodelling of the nervous system. In this review, we aim to explore the evidence for microglia in sculpting nervous system structure and function, as well as their important role in neuropathic pain, and finally integrate these studies to synthesize a new model for microglia in somatosensory circuit remodelling, composed of six key and inter-related mechanisms. Summarizing the mechanisms through which microglia modulate nervous system structure and function helps to frame a better understanding of neuropathic pain, and provide a clear roadmap for future research.
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Affiliation(s)
- Harry Ward
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Steven J. West
- Sainsbury Wellcome Centre, University College London, 25 Howland St, London WC1E 6BT, UK
- Author for correspondence: Steven J. West e-mail:
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Sharma S, Ifergan I, Kurz JE, Linsenmeier RA, Xu D, Cooper JG, Miller SD, Kessler JA. Intravenous Immunomodulatory Nanoparticle Treatment for Traumatic Brain Injury. Ann Neurol 2020; 87:442-455. [PMID: 31925846 PMCID: PMC7296512 DOI: 10.1002/ana.25675] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 12/29/2019] [Accepted: 01/05/2020] [Indexed: 01/06/2023]
Abstract
OBJECTIVE There are currently no definitive disease-modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function. METHODS IMPs, composed of US Food and Drug Administration-approved 500nm carboxylated-poly(lactic-co-glycolic) acid, were infused intravenously into wild-type C57BL/6 mice following 2 different models of experimental TBI, controlled cortical impact (CCI), and closed head injury (CHI). RESULTS IMP administration resulted in remarkable preservation of both tissue and neurological function in both CCI and CHI TBI models in mice. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiologic visual function, improved long-term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination. INTERPRETATION Our findings suggest that IMPs are a clinically translatable acute intervention for TBI with a well-defined mechanism of action and beneficial anatomic and physiologic preservation and recovery. Ann Neurol 2020;87:442-455.
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Affiliation(s)
- Sripadh Sharma
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago
| | - Igal Ifergan
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago
| | - Jonathan E Kurz
- Davee Pediatric Neurocritical Care Program, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago
| | - Robert A Linsenmeier
- Department of Biomedical Engineering, Northwestern University, Evanston, IL
- Department of Neurobiology, Northwestern University, Evanston, IL
| | - Dan Xu
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago
| | - John G Cooper
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago
| | - Stephen D Miller
- Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago
| | - John A Kessler
- Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago
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Fisch U, Brégère C, Geier F, Chicha L, Guzman R. Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia. J Neuroinflammation 2020; 17:26. [PMID: 31954397 PMCID: PMC6969423 DOI: 10.1186/s12974-020-1706-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 01/08/2020] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Recent findings describe microglia as modulators of neurogenesis in the subventricular zone (SVZ). SVZ microglia in the adult rat are thought to adopt a neurotrophic phenotype after ischemic stroke. Early postnatal microglia are endogenously activated and may therefore exhibit an increased sensitivity to neonatal hypoxia-ischemia (HI). The goal of this study was to investigate the impact of cortico-striatal HI on the microglial phenotype, function, and gene expression in the early postnatal SVZ. METHODS Postnatal day (P)7 rats underwent sham or right-hemispheric HI surgery. Microglia in the SVZ, the uninjured cortex, and corpus callosum were immunohistochemically analyzed at P10, P20, and P40. The transcriptome of microdissected SVZ and cortical microglia was analyzed at P10 and P20, and the effect of P10 SVZ microglia on neurosphere generation in vitro was studied. RESULTS The microglial response to HI was region-specific. In the SVZ, a microglial accumulation, prolonged activation and phagocytosis was noted that was not observed in the cortex and corpus callosum. The transcriptome of SVZ microglia and cortical microglia were distinct, and after HI, SVZ microglia concurrently upregulated pro- and anti-inflammatory as well as neurotrophic genes. In vitro, microglia isolated from the SVZ supported neurosphere generation in a concentration-dependent manner. CONCLUSIONS Microglia are an inherent cellular component of the early postnatal SVZ and undergo developmental changes that are affected on many aspects by neonatal HI injury. Our results demonstrate that early postnatal SVZ microglia are sensitive to HI injury and display a long-lasting region-specific response including neurotrophic features.
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Affiliation(s)
- Urs Fisch
- Department of Neurology, University Hospital Basel, University Basel, Basel, Switzerland.
- Brain ischemia and regeneration, Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland.
| | - Catherine Brégère
- Brain ischemia and regeneration, Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
| | - Florian Geier
- Bioinformatics Core Facility, Department of Biomedicine, University Basel, Basel, Switzerland
- Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Laurie Chicha
- Brain ischemia and regeneration, Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
| | - Raphael Guzman
- Brain ischemia and regeneration, Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
- Department of Neurosurgery, University Hospital Basel, University Basel, Basel, Switzerland
- Faculty of Medicine, University Basel, Basel, Switzerland
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40
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Kaalund SS, Johansen A, Fabricius K, Pakkenberg B. Untreated Patients Dying With AIDS Have Loss of Neocortical Neurons and Glia Cells. Front Neurosci 2020; 13:1398. [PMID: 32009881 PMCID: PMC6974793 DOI: 10.3389/fnins.2019.01398] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/12/2019] [Indexed: 11/13/2022] Open
Abstract
Untreated human immunodeficiency virus (HIV) depletes its host CD4 cells, ultimately leading to acquired immunodeficiency syndrome (AIDS). In brain, the HIV confines itself to astrocytes and microglia, the resident brain macrophages, but does not infect oligodendrocytes and neurons. Nonetheless, cognitive symptoms associated with HIV and AIDS are attributed to loss of axons and white matter damage. We used design-based stereology to estimate the numbers of neocortical neurons and glial cells (astrocytes, oligodendrocytes, and microglia), in a series of 12 patients dying with AIDS before the era of retroviral treatments, and in 13 age-matched control brains. Relative to the control material, there was a 19% loss of neocortical neuron (p = 0.04) and a 29% reduction of oligodendrocytes (p = 0.003) in the patients with AIDS, whereas astrocyte and microglia numbers did not differ between patients and controls. Furthermore, we saw a 17% reduction in mean hemispheric volume in the AIDS group (p = 0.0015), which was driven by neocortical and white matter loss (p < 0.05), while the archicortex, subcortical gray matter, and ventricular volumes were within normal limits. Our results confirm previous reports of neuronal loss in AIDS. The new finding of oligodendrocyte loss supports the proposal that HIV in the brain provokes demyelination and axonal dysfunction and suggests that remyelination treatment strategies may be beneficial to patients suffering from HIV-associated neurocognitive deficits.
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Affiliation(s)
- Sanne Simone Kaalund
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Annette Johansen
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Katrine Fabricius
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Gubra, Hørsholm, Denmark
| | - Bente Pakkenberg
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Bacigaluppi M, Sferruzza G, Butti E, Ottoboni L, Martino G. Endogenous neural precursor cells in health and disease. Brain Res 2019; 1730:146619. [PMID: 31874148 DOI: 10.1016/j.brainres.2019.146619] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/25/2019] [Accepted: 12/19/2019] [Indexed: 12/15/2022]
Abstract
Neurogenesis persists in the adult brain of mammals in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG). The complex interactions between intrinsic and extrinsic signals provided by cells in the niche but also from distant sources regulate the fate of neural stem/progenitor cells (NPCs) in these sites. This fine regulation is perturbed in aging and in pathological conditions leading to a different NPC behavior, tailored to the specific physio-pathological features. Indeed, NPCs exert in physiological and pathological conditions important neurogenic and non-neurogenic regulatory functions and participate in maintaining and protecting brain tissue homeostasis. In this review, we discuss intrinsic and extrinsic signals that regulate NPC activation and NPC functional role in various homeostatic and non-homeostatic conditions.
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Affiliation(s)
- Marco Bacigaluppi
- Neuroimmunology Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital and Università Vita- Salute San Raffaele, Via Olgettina 60, 20132 Milano, Italy.
| | - Giacomo Sferruzza
- Neuroimmunology Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital and Università Vita- Salute San Raffaele, Via Olgettina 60, 20132 Milano, Italy
| | - Erica Butti
- Neuroimmunology Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital and Università Vita- Salute San Raffaele, Via Olgettina 60, 20132 Milano, Italy
| | - Linda Ottoboni
- Neuroimmunology Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital and Università Vita- Salute San Raffaele, Via Olgettina 60, 20132 Milano, Italy
| | - Gianvito Martino
- Neuroimmunology Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Hospital and Università Vita- Salute San Raffaele, Via Olgettina 60, 20132 Milano, Italy
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Li A, Zhao J, Fan C, Zhu L, Huang C, Li Q, Gan D, Wen C, Chen M, Lu D. Delivery of exogenous proteins by mesenchymal stem cells attenuates early memory deficits in a murine model of Alzheimer's disease. Neurobiol Aging 2019; 86:81-91. [PMID: 31837910 DOI: 10.1016/j.neurobiolaging.2019.10.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/18/2019] [Accepted: 10/20/2019] [Indexed: 01/04/2023]
Abstract
A promising intervention for Alzheimer's disease (AD) would ideally target key pathological factors that are involved in AD pathogenesis. Soluble factors produced by engrafted mesenchymal stem cells (MSCs) mediate potential therapeutic effects in AD. However, these therapeutic benefits are largely hampered by the limited paracrine capacity of MSCs. In this study, we used adenovirus-mediated gene transduction of bone marrow MSCs to deliver exogenous proteins into the brain of APPswe/PSEN1dE9 (APP/PS1) mice in the early stage of impairment. We observed that engrafted MSCs carrying exogenous (C-X3-C motif) ligand 1 (CX3CL1) alone reduced the production of the inflammatory cytokine TNF-ɑ and improved synapse-related protein expression but not cognitive function. Transplantation of MSCs carrying CX3CL1 and Wnt3a (CX3CL1-Wnt3a-MSC) significantly attenuated the learning and memory impairment when compared with a control group. The improvement of neurobehavioral functions in APP/PS1 mice treated with CX3CL1-Wnt3a-MSC was related to the inhibition of microglial neurotoxicity and promotion of hippocampal neurogenesis. Transplantation of CX3CL1-Wnt3a-MSC also regulated phosphoinositide 3-kinase/activated protein kinase B (PI3K/AKT) signaling to inhibit the activity of glycogen synthase kinase 3 beta (GSK3β). Taken together, these results indicate that the delivery of exogenous proteins via MSCs can modulate microglial function and enhance neurogenesis, thereby providing new insights into AD intervention.
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Affiliation(s)
- An Li
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Jiayi Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Chongzhu Fan
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Lihong Zhu
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Cuiqin Huang
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Qin Li
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Danhui Gan
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Caiyan Wen
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Daxiang Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Jinan University, Guangzhou, Guangdong, China.
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Peng S, Jia J, Sun J, Xie Q, Zhang X, Deng Y, Yi L. LXW7 attenuates inflammation via suppressing Akt/nuclear factor kappa B and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated BV2 microglial cells. Int Immunopharmacol 2019; 77:105963. [DOI: 10.1016/j.intimp.2019.105963] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/07/2019] [Accepted: 10/03/2019] [Indexed: 02/06/2023]
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Liu Z, Wang X, Jiang K, Ji X, Zhang YA, Chen Z. TNFα-induced Up-regulation of Ascl2 Affects the Differentiation and Proliferation of Neural Stem Cells. Aging Dis 2019; 10:1207-1220. [PMID: 31788333 PMCID: PMC6844591 DOI: 10.14336/ad.2018.1028] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/28/2018] [Indexed: 01/11/2023] Open
Abstract
The molecular mediators underlying the effects of inflammation on neural stem cells (NSCs) are not fully characterized. In this study, we identified Ascl2 as a downstream basic helix-loop-helix (bHLH) transcription factor in NSCs following exposure to TNFα. Under normal conditions, Ascl2 expression is inhibited at post-transcriptional levels by miR-26a, which targets the 3’ untranslated region (UTR) of Ascl2. Upon exposure to TNFα, miR-26a expression is reduced, which leads to up-regulation of Ascl2. Overexpression of Ascl2 promotes neuronal differentiation, reduces proliferation, and increases the level of cleaved CASPASE 3 in NSCs, as observed in the in vitro and in ovo experiments. Ascl2 may serve in NSCs as a standby factor that readily responds to TNFα, which is often induced in inflammatory situations. In a chronic inflammatory condition with consistent up-regulation of TNFα, overexpression of Ascl2 may inhibit neurogenesis as a net result.
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Affiliation(s)
- Zhongfeng Liu
- 1Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China.,2Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.,3Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Xuan Wang
- 1Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China.,2Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.,3Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Kewen Jiang
- 4Department of Neurology, the Children's Hospital School of Medicine, Zhejiang University, Hangzhou, China
| | - Xunming Ji
- 5Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Y Alex Zhang
- 1Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Zhiguo Chen
- 1Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China.,2Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.,3Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
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45
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D'Angelo B, Astarita C, Boffo S, Massaro-Giordano M, Antonella Ianuzzi C, Caporaso A, Macaluso M, Giordano A. LPS-induced inflammatory response triggers cell cycle reactivation in murine neuronal cells through retinoblastoma proteins induction. Cell Cycle 2019; 16:2330-2336. [PMID: 28820328 DOI: 10.1080/15384101.2017.1363943] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Cell cycle reactivation in adult neurons is an early hallmark of neurodegeneration. The lipopolysaccharide (LPS) is a well-known pro-inflammatory factor that provokes neuronal cell death via glial cells activation. The retinoblastoma (RB) family includes RB1/p105, retinoblastoma-like 1 (RBL1/p107), and retinoblastoma-like 2 (Rb2/p130). Several studies have indicated that RB proteins exhibit tumor suppressor activities, and play a central role in cell cycle regulation. In this study, we assessed LPS-mediated inflammatory effect on cell cycle reactivation and apoptosis of neuronally differentiated cells. Also, we investigated whether the LPS-mediated inflammatory response can influence the function and expression of RB proteins. Our results showed that LPS challenges triggered cell cycle reactivation of differentiated neuronal cells, indicated by an accumulation of cells in S and G2/M phase. Furthermore, we found that LPS treatment also induced apoptotic death of neurons. Interestingly, we observed that LPS-mediated inflammatory effect on cell cycle re-entry and apoptosis was concomitant with the aberrant expression of RBL1/p107 and RB1/p105. To the best of our knowledge, our study is the first to indicate a role of LPS in inducing cell cycle re-entry and/or apoptosis of differentiated neuronal cells, perhaps through mechanisms altering the expression of specific members of RB family proteins. This study provides novel information on the biology of post-mitotic neurons and could help in identifying novel therapeutic targets to prevent de novo cell cycle reactivation and/or apoptosis of neurons undergoing neurodegenerative processes.
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Affiliation(s)
- Barbara D'Angelo
- a Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology , Temple University , Philadelphia , PA , USA
| | - Carlo Astarita
- a Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology , Temple University , Philadelphia , PA , USA.,b Department of Medicine, Surgery, and Neuroscience , University of Siena , Siena , Italy
| | - Silvia Boffo
- a Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology , Temple University , Philadelphia , PA , USA
| | - Mina Massaro-Giordano
- c Department of Ophthalmology, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA
| | | | - Antonella Caporaso
- d Oncology Research Center of Mercogliano (CROM) , Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale , Naples , Italy
| | - Marcella Macaluso
- a Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology , Temple University , Philadelphia , PA , USA
| | - Antonio Giordano
- a Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology , Temple University , Philadelphia , PA , USA.,b Department of Medicine, Surgery, and Neuroscience , University of Siena , Siena , Italy
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46
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Kong X, Gong Z, Zhang L, Sun X, Ou Z, Xu B, Huang J, Long D, He X, Lin X, Li Q, Xu L, Xuan A. JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation. Brain Behav Immun 2019; 79:159-173. [PMID: 30763768 DOI: 10.1016/j.bbi.2019.01.027] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 01/10/2019] [Accepted: 01/30/2019] [Indexed: 10/27/2022] Open
Abstract
Neuroinflammation, considered as a pathological hallmark of Alzheimer's disease (AD), has been demonstrated to affect hippocampal neurogenesis and cognitive function. Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. However, the mechanisms are still largely unknown. Here, we reported that IL-6 suppressed neurogenesis via a JAK2/STAT3 signaling in neural stem cells (NSCs). Importantly, we found that NeuroD1 (Neurogenic differentiation 1) gene expression, which drives NSCs neurodifferentiation, was regulated by TET3 and DNMT1 in a JAK2/STAT3-dependent manner. We further found that JAK2/STAT3 inhibition enhanced demethylation of NeuroD1 regulatory elements in IL-6-treated cells, which is related to the significant upregulation of TET3 expression as well as the decreased expression of DNMT1. Furthermore, Inhibiting JAK2/STAT3 significantly rescued the memory deficits and hippocampal neurogenesis dysfunction in APP/PS1 mice. Our data suggest that JAK2/STAT3 signaling plays a vital role in suppressing neurogenesis of NSCs exposed to IL-6 at the epigenetic level, by regulating DNA methylation/demethylation.
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Affiliation(s)
- Xuejian Kong
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China; Department of Neurology of the Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511518, China
| | - Zhuo Gong
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Le Zhang
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Xiangdong Sun
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Zhenri Ou
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Biao Xu
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Jingyi Huang
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Dahong Long
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Xiaosong He
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Xiaohong Lin
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Qingqing Li
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Liping Xu
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Aiguo Xuan
- Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
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47
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Lin Q, Shen F, Zhou Q, Huang P, Lin L, Chen M, Chen X, Jiang S, He S, Zeng H, Deng Y. Interleukin-1β Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide. ACS Chem Neurosci 2019; 10:2560-2575. [PMID: 30817119 DOI: 10.1021/acschemneuro.9b00051] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1β (IL-1β) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1β and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP+) astrocytes and decreased numbers of neuronal nuclei positive (NeuN+) cells. The numbers of sex-determining region Y-box 2 positive (SOX2+) and doublecortin positive (DCX+) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2+ cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1β administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1β for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1β administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1β in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.
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Affiliation(s)
- Qiongyu Lin
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Jieyang People's Hospital, Jieyang Affiliated Hospital , Sun Yat-sen University , Jieyang 522000 , China
| | - Fengcai Shen
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Department of Rheumatology, the First Affiliated Hospital , Shantou University Medical College , Shantou 515063 , China
| | - Qiuping Zhou
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
| | - Peixian Huang
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Shantou University Medical College , Shantou 515063 , China
| | - Lanfen Lin
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Southern Medical University , Guangzhou 510515 , China
| | - Mengmeng Chen
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Shantou University Medical College , Shantou 515063 , China
| | - Xuan Chen
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Shantou University Medical College , Shantou 515063 , China
| | - Shuqi Jiang
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
- Southern Medical University , Guangzhou 510515 , China
| | - Shaoru He
- Department of Neonatology , Guangzhou General Hospital , Guangzhou 510080 , China
| | - Hongke Zeng
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
| | - Yiyu Deng
- Department of Critical Care and Emergency, Guangdong Provincial People' Hospital , Guangdong Academy of Medical Sciences , Guangzhou 510080 , China
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48
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Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death. Sci Rep 2019; 9:4572. [PMID: 30872738 PMCID: PMC6418113 DOI: 10.1038/s41598-019-41040-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 02/25/2019] [Indexed: 12/12/2022] Open
Abstract
Mutations of Fused in sarcoma (FUS), a ribonucleoprotein involved in RNA metabolism, have been found associated with both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). Notably, besides mutations in the coding sequence, also mutations into the 3′ untranslated region, leading to increased levels of the wild-type protein, have been associated with neuronal death and ALS pathology, in ALS models and patients. The mechanistic link between altered FUS levels and ALS-related neurodegeneration is far to be elucidated, as well as the consequences of elevated FUS levels in the modulation of the inflammatory response sustained by glial cells, a well-recognized player in ALS progression. Here, we studied the effect of wild-type FUS overexpression on the responsiveness of mouse and human neural progenitor-derived astrocytes to a pro-inflammatory stimulus (IL1β) used to mimic an inflammatory environment. We found that astrocytes with increased FUS levels were more sensitive to IL1β, as shown by their enhanced expression of inflammatory genes, compared with control astrocytes. Moreover, astrocytes overexpressing FUS promoted neuronal cell death and pro-inflammatory microglia activation. We conclude that overexpression of wild-type FUS intrinsically affects astrocyte reactivity and drives their properties toward pro-inflammatory and neurotoxic functions, suggesting that a non-cell autonomous mechanism can support neurodegeneration in FUS-mutated animals and patients.
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49
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Lupo G, Gioia R, Nisi PS, Biagioni S, Cacci E. Molecular Mechanisms of Neurogenic Aging in the Adult Mouse Subventricular Zone. J Exp Neurosci 2019; 13:1179069519829040. [PMID: 30814846 PMCID: PMC6381424 DOI: 10.1177/1179069519829040] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 01/10/2019] [Indexed: 12/31/2022] Open
Abstract
In the adult rodent brain, the continuous production of new neurons by neural stem/progenitor cells (NSPCs) residing in specialized neurogenic niches and their subsequent integration into pre-existing cerebral circuitries supports odour discrimination, spatial learning, and contextual memory capabilities. Aging is recognized as the most potent negative regulator of adult neurogenesis. The neurogenic process markedly declines in the aged brain, due to the reduction of the NSPC pool and the functional impairment of the remaining NSPCs. This decline has been linked to the progressive cognitive deficits of elderly individuals and it may also be involved in the onset/progression of neurological disorders. Since the human lifespan has been dramatically extended, the incidence of age-associated neuropsychiatric conditions in the human population has increased. This has prompted efforts to shed light on the mechanisms underpinning the age-related decline of adult neurogenesis, whose knowledge may foster therapeutic approaches to prevent or delay cognitive alterations in elderly patients. In this review, we summarize recent progress in elucidating the molecular causes of neurogenic aging in the most abundant NSPC niche of the adult mouse brain: the subventricular zone (SVZ). We discuss the age-associated changes occurring both in the intrinsic NSPC molecular networks and in the extrinsic signalling pathways acting in the complex environment of the SVZ niche, and how all these changes may steer young NSPCs towards an aged phenotype.
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Affiliation(s)
- Giuseppe Lupo
- Department of Chemistry, Sapienza University of Rome, Rome, Italy
| | - Roberta Gioia
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Paola Serena Nisi
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Stefano Biagioni
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Emanuele Cacci
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Rome, Italy
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50
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Lin R, Cai J, Kenyon L, Iozzo R, Rosenwasser R, Iacovitti L. Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain. Stem Cells 2018; 37:395-406. [PMID: 30431198 PMCID: PMC7028145 DOI: 10.1002/stem.2947] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 10/19/2018] [Accepted: 10/25/2018] [Indexed: 01/10/2023]
Abstract
It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury‐related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche cells, known as the neurovascular unit (NVU), has attracted interest. Further facilitating communication between blood and NSCs is a permeable blood‐brain‐barrier (BBB) present in most niches, making vascular cells a potential conduit between systemic signals, such as vascular endothelial growth factor (VEGF), and NSCs in the niche, which could play an important role in regulating neurogenesis. We show that the leaky BBB in stem cell niches of the intact and stroke brain can respond to circulating VEGF165 to drive induction of the Notch ligand DLL4 (one of the most important cues in angiogenesis) in endothelial cells (ECs), pericytes, and further induce significant proliferation and neurogenesis of stem cells. Stem Cells2019;37:395–406
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Affiliation(s)
- Ruihe Lin
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Jingli Cai
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Lawrence Kenyon
- Department of Pathology, Anatomy, & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Renato Iozzo
- Department of Pathology, Anatomy, & Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Robert Rosenwasser
- The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Lorraine Iacovitti
- Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,The Joseph and Marie Field Cerebrovascular Research Laboratory, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Vickie & Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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