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Nabeel Mustafa A, Salih Mahdi M, Ballal S, Chahar M, Verma R, Ali Al-Nuaimi AM, Kumar MR, Kadhim A Al-Hussein R, Adil M, Jasem Jawad M. Netrin-1: Key insights in neural development and disorders. Tissue Cell 2025; 93:102678. [PMID: 39719818 DOI: 10.1016/j.tice.2024.102678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 12/26/2024]
Abstract
Netrin-1, an essential extracellular protein, has gained significant attention due to its pivotal role in guiding axon and cell migration during embryonic development. The fundamental significance of netrin-1 in developmental biology is reflected in its high conservation across different species as a part of the netrin family. The bifunctional nature of netrin-1 demonstrates its functional versatility, as it can function as either a repellent or an attractant according to the context and the expressed receptors on the target cells including the deleted in colorectal cancer (DCC), the uncoordinated-5 (UNC5), DSCAM, Neogenin-1, Adenosine A2b and Draxin receptors. By directing axonal growth cones toward the appropriate targets, netrin-1 is a critical actor in the formation of the intricate architecture of the nervous system. Netrin-1 is believed to be involved in additional biological and pathological processes in addition to its traditional function in neural development. The behavior of a diverse array of cell types is influenced by controlling cell adhesion and movement, which is impacted by netrin-1. It is a molecule of interest in both developmental biology and clinical research because of its involvement in angiogenesis, tumorigenesis, inflammation, and tissue regeneration, as confirmed by recent studies. The therapeutic capability of netrin-1 in disorders such as cancer, neurodegenerative disorders, and cardiovascular diseases warrants significant attention.
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Affiliation(s)
| | | | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bengaluru, Karnataka, India
| | - Mamata Chahar
- Department of Chemistry, NIMS University, Jaipur, Rajasthan, India
| | - Rajni Verma
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Punjab 140307, India
| | | | - M Ravi Kumar
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
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Hernandez-Morato I, Koss S, Honzel E, Pitman MJ. Netrin-1 as A neural guidance protein in development and reinnervation of the larynx. Ann Anat 2024; 254:152247. [PMID: 38458575 DOI: 10.1016/j.aanat.2024.152247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 02/01/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
Neural guidance proteins participate in motor neuron migration, axonal projection, and muscle fiber innervation during development. One of the guidance proteins that participates in axonal pathfinding is Netrin-1. Despite the well-known role of Netrin-1 in embryogenesis of central nervous tissue, it is still unclear how the expression of this guidance protein contributes to primary innervation of the periphery, as well as reinnervation. This is especially true in the larynx where Netrin-1 is upregulated within the intrinsic laryngeal muscles after nerve injury and where blocking of Netrin-1 alters the pattern of reinnervation of the intrinsic laryngeal muscles. Despite this consistent finding, it is unknown how Netrin-1 expression contributes to guidance of the axons towards the larynx. Improved knowledge of Netrin-1's role in nerve regeneration and reinnervation post-injury in comparison to its role in primary innervation during embryological development, may provide insights in the search for therapeutics to treat nerve injury. This paper reviews the known functions of Netrin-1 during the formation of the central nervous system and during cranial nerve primary innervation. It also describes the role of Netrin-1 in the formation of the larynx and during recurrent laryngeal reinnervation following nerve injury in the adult.
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Affiliation(s)
- Ignacio Hernandez-Morato
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States; Department of Anatomy and Embryology, School of Medicine, Complutense University of Madrid, Madrid, Madrid, Spain.
| | - Shira Koss
- ENT Associates of Nassau County, Levittown, NY, United States
| | - Emily Honzel
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States
| | - Michael J Pitman
- Department of Otolaryngology-Head & Neck Surgery, The Center for Voice and Swallowing, Columbia University College of Physicians and Surgeons, New York, NY, United States
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3
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Cashion JM, Young KM, Sutherland BA. How does neurovascular unit dysfunction contribute to multiple sclerosis? Neurobiol Dis 2023; 178:106028. [PMID: 36736923 DOI: 10.1016/j.nbd.2023.106028] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 01/17/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS) and the most common non-traumatic cause of neurological disability in young adults. Multiple sclerosis clinical care has improved considerably due to the development of disease-modifying therapies that effectively modulate the peripheral immune response and reduce relapse frequency. However, current treatments do not prevent neurodegeneration and disease progression, and efforts to prevent multiple sclerosis will be hampered so long as the cause of this disease remains unknown. Risk factors for multiple sclerosis development or severity include vitamin D deficiency, cigarette smoking and youth obesity, which also impact vascular health. People with multiple sclerosis frequently experience blood-brain barrier breakdown, microbleeds, reduced cerebral blood flow and diminished neurovascular reactivity, and it is possible that these vascular pathologies are tied to multiple sclerosis development. The neurovascular unit is a cellular network that controls neuroinflammation, maintains blood-brain barrier integrity, and tightly regulates cerebral blood flow, matching energy supply to neuronal demand. The neurovascular unit is composed of vessel-associated cells such as endothelial cells, pericytes and astrocytes, however neuronal and other glial cell types also comprise the neurovascular niche. Recent single-cell transcriptomics data, indicate that neurovascular cells, particular cells of the microvasculature, are compromised within multiple sclerosis lesions. Large-scale genetic and small-scale cell biology studies also suggest that neurovascular dysfunction could be a primary pathology contributing to multiple sclerosis development. Herein we revisit multiple sclerosis risk factors and multiple sclerosis pathophysiology and highlight the known and potential roles of neurovascular unit dysfunction in multiple sclerosis development and disease progression. We also evaluate the suitability of the neurovascular unit as a potential target for future disease modifying therapies for multiple sclerosis.
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Affiliation(s)
- Jake M Cashion
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia
| | - Kaylene M Young
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia
| | - Brad A Sutherland
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia.
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Lohrasbi F, Ghasemi-Kasman M, Soghli N, Ghazvini S, Vaziri Z, Abdi S, Darban YM. The Journey of iPSC-derived OPCs in Demyelinating Disorders: From In vitro Generation to In vivo Transplantation. Curr Neuropharmacol 2023; 21:1980-1991. [PMID: 36825702 PMCID: PMC10514531 DOI: 10.2174/1570159x21666230220150010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/22/2022] [Accepted: 10/31/2022] [Indexed: 02/22/2023] Open
Abstract
Loss of myelination is common among neurological diseases. It causes significant disability, even death, if it is not treated instantly. Different mechanisms involve the pathophysiology of demyelinating diseases, such as genetic background, infectious, and autoimmune inflammation. Recently, regenerative medicine and stem cell therapy have shown to be promising for the treatment of demyelinating disorders. Stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells (ASCs), can differentiate into oligodendrocyte progenitor cells (OPCs), which may convert to oligodendrocytes (OLs) and recover myelination. IPSCs provide an endless source for OPCs generation. However, the restricted capacity of proliferation, differentiation, migration, and myelination of iPSC-derived OPCs is a notable gap for future studies. In this article, we have first reviewed stem cell therapy in demyelinating diseases. Secondly, methods of different protocols have been discussed among in vitro and in vivo studies on iPSC-derived OPCs to contrast OPCs' transplantation efficacy. Lastly, we have reviewed the results of iPSCs-derived OLs production in each demyelination model.
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Affiliation(s)
- Fatemeh Lohrasbi
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
- Department of Physiology, School of Medical Sciences, Babol University of Medical Science, Babol, Iran
| | - Negar Soghli
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sobhan Ghazvini
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Zahra Vaziri
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sadaf Abdi
- Student Research Committee, Babol University of Medical Science, Babol, Iran
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El Waly B, Bertet C, Paris M, Falque M, Milpied P, Magalon K, Cayre M, Durbec P. Neuroblasts contribute to oligodendrocytes generation upon demyelination in the adult mouse brain. iScience 2022; 25:105102. [PMID: 36185360 PMCID: PMC9519617 DOI: 10.1016/j.isci.2022.105102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 04/06/2022] [Accepted: 09/05/2022] [Indexed: 11/21/2022] Open
Abstract
After demyelinating insult, the neuronal progenitors of the adult mouse sub-ventricular zone (SVZ) called neuroblasts convert into oligodendrocytes that participate to the remyelination process. We use this rare example of spontaneous fate conversion to identify the molecular mechanisms governing these processes. Using in vivo cell lineage and single cell RNA-sequencing, we demonstrate that SVZ neuroblasts fate conversion proceeds through formation of a non-proliferating transient cellular state co-expressing markers of both neuronal and oligodendrocyte identities. Transition between the two identities starts immediately after demyelination and occurs gradually, by a stepwise upregulation/downregulation of key TFs and chromatin modifiers. Each step of this fate conversion involves fine adjustments of the transcription and translation machineries as well as tight regulation of metabolism and migratory behaviors. Together, these data constitute the first in-depth analysis of a spontaneous cell fate conversion in the adult mammalian CNS.
NB can contribute to myelin repair by converting into oligodendrocytes NB fate conversion occurs gradually, through formation of an intermediate cell type NB fate conversion does not involve reversion toward a pluripotent state NB fate conversion seems to involve EMT-related mechanisms and metabolic changes
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Gao Y, Xie D, Wang Y, Niu L, Jiang H. Short-Chain Fatty Acids Reduce Oligodendrocyte Precursor Cells Loss by Inhibiting the Activation of Astrocytes via the SGK1/IL-6 Signalling Pathway. Neurochem Res 2022; 47:3476-3489. [PMID: 36098889 PMCID: PMC9546972 DOI: 10.1007/s11064-022-03710-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 12/09/2022]
Abstract
Short-chain fatty acids (SCFAs) are known to be actively involved in neurological diseases, but their roles in hypoxic-ischaemic brain injury (HIBI) are unclear. In this study, a rat model of HIBI was established, and this study measured the changes in IL-6 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), in addition to proliferation and apoptosis indicators of oligodendrocyte precursor cells (OPCs). The mechanism of action of SCFA on astrocytes was also investigated. Astrocytes were subjected to hypoxia in vitro, and OPCs were treated with IL-6. The results showed that SCFAs significantly alleviated HIBI-induced activation of astrocytes and loss of OPCs. SCFA pretreatment (1) downregulated the expression of NLRP3, IL-6, CCL2, and IP-10; (2) had no effect on the proliferation of OPCs; (3) ameliorated the abnormal expression of Bax and Bcl-2; and (4) regulated IL-6 expression via the SGK1-related pathway in astrocytes. Our findings revealed that SCFAs alleviated the loss of OPCs by regulating astrocyte activation through the SGK1/IL-6 signalling pathway.
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Affiliation(s)
- Yanmin Gao
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Jimo Road, Pudong New District, Shanghai, 200120, China.,Department of General Practice, Kongjiang Community Health Service Center, No. 100, Yanji West Road, Yangpu District, Shanghai, 200093, China
| | - Di Xie
- Emergency Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Yang Wang
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Jimo Road, Pudong New District, Shanghai, 200120, China.,Emergency Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Lei Niu
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Jimo Road, Pudong New District, Shanghai, 200120, China.,Emergency Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Hua Jiang
- Department of General Practice, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Jimo Road, Pudong New District, Shanghai, 200120, China. .,Emergency Department, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
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Xia W, Fancy SPJ. Mechanisms of oligodendrocyte progenitor developmental migration. Dev Neurobiol 2021; 81:985-996. [PMID: 34643996 DOI: 10.1002/dneu.22856] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/25/2021] [Accepted: 09/08/2021] [Indexed: 01/01/2023]
Abstract
Oligodendrocytes, the myelinating cells of the central nervous system (CNS), develop from oligodendrocyte progenitor cells (OPCs) that must first migrate extensively throughout the developing brain and spinal cord. Specified at particular times from discrete regions in the developing CNS, OPCs are one of the most migratory of cell types and disperse rapidly. A variety of factors act on OPCs to trigger intracellular changes that regulate their migration. We will discuss factors that act as long-range guidance cues, those that act to regulate cellular motility, and those that are critical in determining the final positioning of OPCs. In addition, recent evidence has identified the vasculature as the physical substrate used by OPCs for their migration. Several new findings relating to this oligodendroglial-vascular signaling axis reveal new insight on the relationship between OPCs and blood vessels in the developing and adult brain.
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Affiliation(s)
- Wenlong Xia
- Department of Neurology, University of California, San Francisco, San Francisco, California, USA.,Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.,Division of Neuroimmunology and Glial Biology, University of California, San Francisco, San Francisco, California, USA.,Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California, USA
| | - Stephen P J Fancy
- Department of Neurology, University of California, San Francisco, San Francisco, California, USA.,Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.,Division of Neuroimmunology and Glial Biology, University of California, San Francisco, San Francisco, California, USA.,Newborn Brain Research Institute, University of California, San Francisco, San Francisco, California, USA
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8
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Vásquez X, Sánchez-Gómez P, Palma V. Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime? Int J Mol Sci 2021; 22:8248. [PMID: 34361013 PMCID: PMC8348949 DOI: 10.3390/ijms22158248] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.
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Affiliation(s)
- Ximena Vásquez
- Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago 7800003, Chile;
| | - Pilar Sánchez-Gómez
- Neurooncology Unit, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain
| | - Verónica Palma
- Laboratory of Stem Cells and Developmental Biology, Faculty of Sciences, Universidad de Chile, Santiago 7800003, Chile;
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9
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Cayre M, Falque M, Mercier O, Magalon K, Durbec P. Myelin Repair: From Animal Models to Humans. Front Cell Neurosci 2021; 15:604865. [PMID: 33935649 PMCID: PMC8079744 DOI: 10.3389/fncel.2021.604865] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/15/2021] [Indexed: 12/20/2022] Open
Abstract
It is widely thought that brain repair does not occur, but myelin regeneration provides clear evidence to the contrary. Spontaneous remyelination may occur after injury or in multiple sclerosis (MS). However, the efficiency of remyelination varies considerably between MS patients and between the lesions of each patient. Myelin repair is essential for optimal functional recovery, so a profound understanding of the cells and mechanisms involved in this process is required for the development of new therapeutic strategies. In this review, we describe how animal models and modern cell tracing and imaging methods have helped to identify the cell types involved in myelin regeneration. In addition to the oligodendrocyte progenitor cells identified in the 1990s as the principal source of remyelinating cells in the central nervous system (CNS), other cell populations, including subventricular zone-derived neural progenitors, Schwann cells, and even spared mature oligodendrocytes, have more recently emerged as potential contributors to CNS remyelination. We will also highlight the conditions known to limit endogenous repair, such as aging, chronic inflammation, and the production of extracellular matrix proteins, and the role of astrocytes and microglia in these processes. Finally, we will present the discrepancies between observations in humans and in rodents, discussing the relationship of findings in experimental models to myelin repair in humans. These considerations are particularly important from a therapeutic standpoint.
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Affiliation(s)
- Myriam Cayre
- Aix Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM-UMR 7288), Marseille, France
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10
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Deboux C, Spigoni G, Caillava C, Garcia-Diaz B, Ypsilanti A, Sarrazin N, Bachelin C, Chédotal A, Baron-Van Evercooren A. Slit1 Protein Regulates SVZ-Derived Precursor Mobilization in the Adult Demyelinated CNS. Front Cell Neurosci 2020; 14:168. [PMID: 32670024 PMCID: PMC7332780 DOI: 10.3389/fncel.2020.00168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 05/19/2020] [Indexed: 01/03/2023] Open
Abstract
Slit1 is a secreted axon guidance molecule, also involved in adult neurogenesis. In physiological conditions, Slit1 loss promotes ectopic dispersal of SVZ-derived neural precursors (SVZ-NPCs) into periventricular structures such as the corpus callosum. Demyelination of the corpus callosum triggers SVZ-NPC migration to ectopic locations and their recruitment by the lesion, suggesting a possible role for Slit1 in SVZ-NPCs ectopic dispersal regulation in pathological conditions. Here, we have investigated the function of Slit1 protein in the recruitment of SVZ-NPCs after CNS demyelination. We find that the dynamics of oligodendrogenesis and temporal profile of developmental myelination in Slit1–/– mice are similar to Slit1+/− controls. SVZ micro-dissection and RT-PCR from wild-type mice, show that Slits and Robos are physiologically regulated at the transcriptional level in response to corpus callosum demyelination suggesting their role in the process of SVZ-NPC ectopic migration in demyelinating conditions. Moreover, we find that the number of SVZ-NPCs recruited by the lesion increases in Sli1–/– mice compared to Slit1+/− mice, leading to higher numbers of Olig2+ cells within the lesion. Time-lapse video-microscopy of immuno-purified NPCs shows that Slit1-deficient cells migrate faster and make more frequent directional changes than control NPCs, supporting a cell-autonomous mechanism of action of Slit1 in NPC migration. In conclusion, while Slit1 does not affect the normal developmental process of oligodendrogenesis and myelination, it regulates adult SVZ-NPC ectopic migration in response to demyelination, and consequently oligodendrocyte renewal within the lesion.
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Affiliation(s)
- C Deboux
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - G Spigoni
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - C Caillava
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - B Garcia-Diaz
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - A Ypsilanti
- Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France
| | - N Sarrazin
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - C Bachelin
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
| | - A Chédotal
- Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France
| | - A Baron-Van Evercooren
- Institut du Cerveau et de la Moelle épinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM U1127, CNRS, UMR 7225, Sorbonne Université, UM75, Paris, France
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11
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Macchi M, Magalon K, Zimmer C, Peeva E, El Waly B, Brousse B, Jaekel S, Grobe K, Kiefer F, Williams A, Cayre M, Durbec P. Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulfate production. eLife 2020; 9:51735. [PMID: 32515730 PMCID: PMC7308090 DOI: 10.7554/elife.51735] [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: 09/17/2019] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
Myelin destruction is followed by resident glia activation and mobilization of endogenous progenitors (OPC) which participate in myelin repair. Here we show that in response to demyelination, mature oligodendrocytes (OLG) bordering the lesion express Ndst1, a key enzyme for heparan sulfates (HS) synthesis. Ndst1+ OLG form a belt that demarcates lesioned from intact white matter. Mice with selective inactivation of Ndst1 in the OLG lineage display increased lesion size, sustained microglia and OPC reactivity. HS production around the lesion allows Sonic hedgehog (Shh) binding and favors the local enrichment of this morphogen involved in myelin regeneration. In MS patients, Ndst1 is also found overexpressed in oligodendroglia and the number of Ndst1-expressing oligodendroglia is inversely correlated with lesion size and positively correlated with remyelination potential. Our study suggests that mature OLG surrounding demyelinated lesions are not passive witnesses but contribute to protection and regeneration by producing HS.
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Affiliation(s)
| | | | | | - Elitsa Peeva
- MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh, Edinburgh, United Kingdom
| | | | | | - Sarah Jaekel
- MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Kay Grobe
- Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Münster, Germany
| | | | - Anna Williams
- MRC Centre for Regenerative Medicine, Multiple Sclerosis Society Centre for Translational Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Myriam Cayre
- Aix Marseille Univ, CNRS, IBDM, Marseille, France
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12
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Kang M, Yao Y. Oligodendrocytes in intracerebral hemorrhage. CNS Neurosci Ther 2019; 25:1075-1084. [PMID: 31410988 PMCID: PMC6776757 DOI: 10.1111/cns.13193] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/23/2019] [Accepted: 06/26/2019] [Indexed: 12/22/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a cerebrovascular disorder with high mortality and disability rates. Although a lot of effort has been put in ICH, there is still no effective treatment for this devastating disease. Recent studies suggest that oligodendrocytes play an important role in brain repair after ICH and thus may be targeted for the therapies of ICH. Here in this review, we first introduce the origin, migration, proliferation, differentiation, and myelination of oligodendrocytes under physiological condition. Second, recent findings on how ICH affects oligodendrocyte biology and function are reviewed. Third, potential crosstalk between oligodendrocytes and other cells in the brain is also summarized. Last, we discuss the therapeutic potential of oligodendrocyte‐based treatments in ICH. Our goal is to provide a comprehensive review on the biology and function of oligodendrocytes under both physiological and ICH conditions.
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Affiliation(s)
- Minkyung Kang
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA
| | - Yao Yao
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA
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13
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Adult Neurogenesis in the Subventricular Zone and Its Regulation After Ischemic Stroke: Implications for Therapeutic Approaches. Transl Stroke Res 2019; 11:60-79. [DOI: 10.1007/s12975-019-00717-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/13/2019] [Accepted: 06/27/2019] [Indexed: 12/21/2022]
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14
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Rajizadeh MA, Sheibani V, Bejeshk MA, Mohtashami Borzadaran F, Saghari H, Esmaeilpour K. The effects of high intensity exercise on learning and memory impairments followed by combination of sleep deprivation and demyelination induced by etidium bromide. Int J Neurosci 2019; 129:1166-1178. [DOI: 10.1080/00207454.2019.1640695] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Mohammad Amin Rajizadeh
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Vahid Sheibani
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Abbas Bejeshk
- Department of Physiology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Hasan Saghari
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Khadijeh Esmaeilpour
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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15
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Fujioka T, Kaneko N, Sawamoto K. Blood vessels as a scaffold for neuronal migration. Neurochem Int 2019; 126:69-73. [PMID: 30851365 DOI: 10.1016/j.neuint.2019.03.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/27/2019] [Accepted: 03/02/2019] [Indexed: 12/19/2022]
Abstract
Neurogenesis and angiogenesis share regulatory factors that contribute to the formation of vascular networks and neuronal circuits in the brain. While crosstalk mechanisms between neural stem cells (NSCs) and the vasculature have been extensively investigated, recent studies have provided evidence that blood vessels also play an essential role in neuronal migration in the brain during development and regeneration. The mechanisms of the neuronal migration along blood vessels, referred to as "vascular-guided migration," are now being elucidated. The vascular endothelial cells secrete soluble factors that attract and promote neuronal migration in collaboration with astrocytes that enwrap the blood vessels. In addition, especially in the adult brain, the blood vessels serve as a migration scaffold for adult-born immature neurons generated in the ventricular-subventricular zone (V-SVZ), a germinal zone surrounding the lateral ventricles. The V-SVZ-derived immature neurons use the vascular scaffold to assist their migration toward an injured area after ischemic stroke, and contribute to neuronal regeneration. Here we review the current knowledge about the role of vasculature in neuronal migration and the molecular mechanisms controlling this process. While most of this research has been done in rodents, a comprehensive understanding of vasculature-guided neuronal migration could contribute to new therapeutic approaches for increasing new neurons in the brain after injury.
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Affiliation(s)
- Teppei Fujioka
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan; Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Naoko Kaneko
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan; Division of Neural Development and Regeneration, National Institute for Physiological Sciences, Okazaki, Aichi, 444-8585, Japan.
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16
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Chen Z, Hu Q, Xie Q, Wu S, Pang Q, Liu M, Zhao Y, Tu F, Liu C, Chen X. Effects of Treadmill Exercise on Motor and Cognitive Function Recovery of MCAO Mice Through the Caveolin-1/VEGF Signaling Pathway in Ischemic Penumbra. Neurochem Res 2019; 44:930-946. [DOI: 10.1007/s11064-019-02728-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/09/2019] [Accepted: 01/10/2019] [Indexed: 11/29/2022]
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17
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Serwanski DR, Rasmussen AL, Brunquell CB, Perkins SS, Nishiyama A. Sequential Contribution of Parenchymal and Neural Stem Cell-Derived Oligodendrocyte Precursor Cells toward Remyelination. NEUROGLIA (BASEL, SWITZERLAND) 2018; 1:91-105. [PMID: 30662979 PMCID: PMC6335037 DOI: 10.3390/neuroglia1010008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In the adult mammalian forebrain, oligodendrocyte precursor cells (OPCs), also known as NG2 glia are distributed ubiquitously throughout the gray and white matter. They remain proliferative and continuously generate myelinating oligodendrocytes throughout life. In response to a demyelinating insult, OPCs proliferate rapidly and differentiate into oligodendrocytes which contribute to myelin repair. In addition to OPCs, neural stem cells (NSCs) in the subventricular zone (SVZ) also contribute to remyelinating oligodendrocytes, particularly in demyelinated lesions in the vicinity of the SVZ, such as the corpus callosum. To determine the relative contribution of local OPCs and NSC-derived cells toward myelin repair, we performed genetic fate mapping of OPCs and NSCs and compared their ability to generate oligodendrocytes after acute demyelination in the corpus callosum created by local injection of α-lysophosphatidylcholine (LPC). We have found that local OPCs responded rapidly to acute demyelination, expanded in the lesion within seven days, and produced oligodendrocytes by two weeks after lesioning. By contrast, NSC-derived NG2 cells did not significantly increase in the lesion until four weeks after demyelination and generated fewer oligodendrocytes than parenchymal OPCs. These observations suggest that local OPCs could function as the primary responders to repair acutely demyelinated lesion, and that NSCs in the SVZ contribute to repopulating OPCs following their depletion due to oligodendrocyte differentiation.
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Affiliation(s)
- David R Serwanski
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Andrew L Rasmussen
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Christopher B Brunquell
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Scott S Perkins
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
| | - Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, Storrs, CT 06269-3156, USA; (D.R.S.); (A.L.R.); (C.B.B.); (S.S.P.)
- Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA
- Institute for Brain and Cognitive Science, University of Connecticut, Storrs, CT 06269, USA
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18
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Santos AK, Vieira MS, Vasconcellos R, Goulart VAM, Kihara AH, Resende RR. Decoding cell signalling and regulation of oligodendrocyte differentiation. Semin Cell Dev Biol 2018; 95:54-73. [PMID: 29782926 DOI: 10.1016/j.semcdb.2018.05.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/15/2018] [Accepted: 05/17/2018] [Indexed: 12/20/2022]
Abstract
Oligodendrocytes are fundamental for the functioning of the nervous system; they participate in several cellular processes, including axonal myelination and metabolic maintenance for astrocytes and neurons. In the mammalian nervous system, they are produced through waves of proliferation and differentiation, which occur during embryogenesis. However, oligodendrocytes and their precursors continue to be generated during adulthood from specific niches of stem cells that were not recruited during development. Deficiencies in the formation and maturation of these cells can generate pathologies mainly related to myelination. Understanding the mechanisms involved in oligodendrocyte development, from the precursor to mature cell level, will allow inferring therapies and treatments for associated pathologies and disorders. Such mechanisms include cell signalling pathways that involve many growth factors, small metabolic molecules, non-coding RNAs, and transcription factors, as well as specific elements of the extracellular matrix, which act in a coordinated temporal and spatial manner according to a given stimulus. Deciphering those aspects will allow researchers to replicate them in vitro in a controlled environment and thus mimic oligodendrocyte maturation to understand the role of oligodendrocytes in myelination in pathologies and normal conditions. In this study, we review these aspects, based on the most recent in vivo and in vitro data on oligodendrocyte generation and differentiation.
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Affiliation(s)
- A K Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - M S Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil; Instituto Nanocell, Rua Santo Antônio, 420, 35500-041 Divinópolis, MG, Brazil
| | - R Vasconcellos
- Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil; Instituto Nanocell, Rua Santo Antônio, 420, 35500-041 Divinópolis, MG, Brazil
| | - V A M Goulart
- Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil
| | - A H Kihara
- Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil
| | - R R Resende
- Departamento de Bioquímica e Imunologia, Instituto de Ciência Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31270-901 Belo Horizonte, MG, Brazil; Instituto Nanocell, Rua Santo Antônio, 420, 35500-041 Divinópolis, MG, Brazil.
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19
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Andreopoulou E, Arampatzis A, Patsoni M, Kazanis I. Being a Neural Stem Cell: A Matter of Character But Defined by the Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1041:81-118. [PMID: 29204830 DOI: 10.1007/978-3-319-69194-7_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The cells that build the nervous system, either this is a small network of ganglia or a complicated primate brain, are called neural stem and progenitor cells. Even though the very primitive and the very recent neural stem cells (NSCs) share common basic characteristics that are hard-wired within their character, such as the expression of transcription factors of the SoxB family, their capacity to give rise to extremely different neural tissues depends significantly on instructions from the microenvironment. In this chapter we explore the nature of the NSC microenvironment, looking through evolution, embryonic development, maturity and even disease. Experimental work undertaken over the last 20 years has revealed exciting insight into the NSC microcosmos. NSCs are very capable in producing their own extracellular matrix and in regulating their behaviour in an autocrine and paracrine manner. Nevertheless, accumulating evidence indicates an important role for the vasculature, especially within the NSC niches of the postnatal brain; while novel results reveal direct links between the metabolic state of the organism and the function of NSCs.
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Affiliation(s)
- Evangelia Andreopoulou
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras, Greece
| | - Asterios Arampatzis
- Wellcome Trust- MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge, UK
- School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Melina Patsoni
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras, Greece
| | - Ilias Kazanis
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras, Greece.
- Wellcome Trust- MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge, UK.
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20
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El Waly B, Cayre M, Durbec P. Promoting Myelin Repair through In Vivo Neuroblast Reprogramming. Stem Cell Reports 2018; 10:1492-1504. [PMID: 29606615 PMCID: PMC5995160 DOI: 10.1016/j.stemcr.2018.02.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 11/28/2022] Open
Abstract
Demyelination is frequently observed in a variety of CNS insults and neurodegenerative diseases. In rodents, adult neural stem cells can generate oligodendrocytes and participate to myelin repair. However, these cells mainly produce migratory neuroblasts that differentiate in the olfactory bulb. Here, we show that, in the demyelination context, a small subset of these neuroblasts can spontaneously convert into myelinating oligodendrocytes. Furthermore, we demonstrate that the contribution of neuroblasts to myelin repair can be improved by in vivo forced expression of two transcription factors: OLIG2 and SOX10. These factors promote directed fate conversion of endogenous subventricular zone neuroblasts into mature functional oligodendrocytes, leading to enhanced remyelination in a cuprizone-induced mouse model of demyelination. These findings highlight the unexpected plasticity of committed neuroblasts and provide proof of concept that they could be targeted for the treatment of demyelinated lesions in the adult brain.
Sox10 and Olig2 convert endogenous neuroblasts into myelinating oligodendrocytes Converted cells migrate to the corpus callosum, striatum, and cortex Converted cells produce myelin and participate to the formation of node of Ranvier Forced neuroblast conversion improves myelin regeneration
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Affiliation(s)
- Bilal El Waly
- 1-Aix Marseille University, CNRS, IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, campus de Luminy, 13288 Marseille, Cedex 09, France
| | - Myriam Cayre
- 1-Aix Marseille University, CNRS, IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, campus de Luminy, 13288 Marseille, Cedex 09, France
| | - Pascale Durbec
- 1-Aix Marseille University, CNRS, IBDM-UMR 7288, Case 907, Parc Scientifique de Luminy, campus de Luminy, 13288 Marseille, Cedex 09, France.
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21
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Voortman MM, Pekar T, Bachmayer D, Archelos JJ, Stojakovic T, Scharnagl H, Ropele S, Pichler A, Enzinger C, Fuchs S, Fazekas F, Seifert-Held T, Khalil M. Serum netrin-1 in relation to gadolinium-enhanced magnetic resonance imaging in early multiple sclerosis. Mult Scler J Exp Transl Clin 2017; 3:2055217317727294. [PMID: 28856010 PMCID: PMC5571769 DOI: 10.1177/2055217317727294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 07/28/2017] [Indexed: 11/17/2022] Open
Abstract
Background Netrin-1, a secreted laminin-related protein, is known to regulate not only axonal guidance and neuronal cell migration, but also blood–brain barrier integrity and inflammation. Two preliminary studies reported altered serum netrin-1 levels in multiple sclerosis; however, associations with longitudinal clinical and magnetic resonance imaging activity have not been investigated. Objectives We aimed to assess serum netrin-1 in multiple sclerosis and controls with respect to disease activity and its temporal dynamics. Methods Serum netrin-1 was assessed by enzyme-linked immunosorbent assay in 79 patients with clinically isolated syndrome or multiple sclerosis, and 30 non-inflammatory neurological disease controls. In patients, serum samples were collected immediately prior to gadolinium-enhanced 3 T magnetic resonance imaging at two time points (initial contrast-enhancing gadolinium+ n = 47, non-enhancing gadolinium– n = 32; reference gadolinium– n = 70; median time-lag 1.4, interquartile range 1.0–2.3 years). Results Serum netrin-1 levels were similar in clinically isolated syndrome, multiple sclerosis and controls, and gadolinium+ and gadolinium– patients. Among gadolinium+ patients, serum netrin-1 was decreased in clinically active (n = 8) vs non-active patients (n = 39; p = 0.041). Serum netrin-1 showed no temporal dynamics in multiple sclerosis and was unrelated to clinical data. Conclusions Serum netrin-1 levels show no multiple sclerosis specific changes and are not sensitive for detection of subclinical disease activity. Netrin-1 changes during relapses may deserve further examination.
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Affiliation(s)
- M M Voortman
- Department of Neurology, Medical University of Graz, Austria
| | - T Pekar
- University of Applied Sciences Wiener Neustadt, Austria
| | | | - J-J Archelos
- Department of Neurology, Medical University of Graz, Austria
| | - T Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | - H Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | - S Ropele
- Department of Neurology, Medical University of Graz, Austria
| | - A Pichler
- Department of Neurology, Medical University of Graz, Austria
| | - C Enzinger
- Department of Neurology, Medical University of Graz, Austria
| | - S Fuchs
- Department of Neurology, Medical University of Graz, Austria
| | - F Fazekas
- Department of Neurology, Medical University of Graz, Austria
| | - T Seifert-Held
- Department of Neurology, Medical University of Graz, Austria
| | - M Khalil
- Department of Neurology, Medical University of Graz, Austria
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22
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Endothelial cell-oligodendrocyte interactions in small vessel disease and aging. Clin Sci (Lond) 2017; 131:369-379. [PMID: 28202749 PMCID: PMC5310718 DOI: 10.1042/cs20160618] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/28/2016] [Accepted: 12/14/2016] [Indexed: 12/11/2022]
Abstract
Cerebral small vessel disease (SVD) is a prevalent, neurological disease that significantly increases the risk of stroke and dementia. The main pathological changes are vascular, in the form of lipohyalinosis and arteriosclerosis, and in the white matter (WM), in the form of WM lesions. Despite this, it is unclear to what extent the key cell types involved–the endothelial cells (ECs) of the vasculature and the oligodendrocytes of the WM–interact. Here, we describe the work that has so far been carried out suggesting an interaction between ECs and oligodendrocytes in SVD. As these interactions have been studied in more detail in other disease states and in development, we explore these systems and discuss the role these mechanisms may play in SVD.
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23
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Yamahara K, Nakagawa T, Ito J, Kinoshita K, Omori K, Yamamoto N. Netrin 1 mediates protective effects exerted by insulin-like growth factor 1 on cochlear hair cells. Neuropharmacology 2017; 119:26-39. [PMID: 28373074 DOI: 10.1016/j.neuropharm.2017.03.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Revised: 03/15/2017] [Accepted: 03/29/2017] [Indexed: 01/17/2023]
Abstract
Sensorineural hearing loss (SNHL) is mainly caused by the damage of cochlear hair cells (HCs). As HCs and supporting cells (SCs) do not proliferate in postnatal mammals, the loss of HCs and SCs is irreversible, emphasizing the importance of preserving their numbers to prevent SNHL. It is known that insulin-like growth factor 1 (IGF1) is instrumental in the treatment of SNHL. Our previous study indicates that IGF1 protects HCs against aminoglycoside by activating IGF1 receptor and its two major downstream pathways, PI3K/AKT and MEK/ERK, in SCs, which results in the upregulation of the expression of the Netrin1-encoding gene (Ntn1). However, the mechanisms underlying IGF1-induced protection of HCs via SC activation as well as the role of NTN1 in this process have not been elucidated. Here, we demonstrated that NTN1, similar to IGF1, promoted HC survival. NTN1 blocking antibody attenuated IGF1-induced HC protection from aminoglycoside, indicating that NTN1 is the effector molecule of IGF1 signaling during HC protection. In situ hybridization demonstrated that IGF1 potently induced Ntn1 expression in SCs. NTN1 receptors were abundantly expressed in the cochlea; among them, UNC5B mediated IGF1 protective effects on HCs, as NTN1 binding to UNC5B inhibited HC apoptosis. These results provide new insights into the mechanisms underlying IGF1 protection of cochlear HCs, suggesting a possibility of using NTN1 as a new treatment for SNHL.
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Affiliation(s)
- Kohei Yamahara
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan
| | - Takayuki Nakagawa
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan
| | - Juichi Ito
- Shiga Medical Center Research Institute, Moriyama, Shiga 524-8523, Japan
| | - Kazuo Kinoshita
- Shiga Medical Center Research Institute, Moriyama, Shiga 524-8523, Japan
| | - Koichi Omori
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan
| | - Norio Yamamoto
- Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
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24
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He X, Lu Y, Lin X, Jiang L, Tang Y, Tang G, Chen X, Zhang Z, Wang Y, Yang GY. Optical inhibition of striatal neurons promotes focal neurogenesis and neurobehavioral recovery in mice after middle cerebral artery occlusion. J Cereb Blood Flow Metab 2017; 37:837-847. [PMID: 27055780 PMCID: PMC5363463 DOI: 10.1177/0271678x16642242] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Striatal neurons regulate the activity of neural progenitor cells in the subventricular zone, but the effect of striatal neuronal activity on neurogenesis after ischemic stroke is unclear. In this study, we used optogenetic tools to investigate the impact of striatal neuronal activity on the neurogenesis and functional recovery after cerebral ischemia. We transfected striatal neurons with channelrhodopsin-2 or halorhodopsin from Natronomonas so that they can be excited by 473 nm laser or inhibited by 594 nm laser, respectively. Neural inhibition but not excitation at 4-7 days after middle cerebral artery occlusion resulted in reduced atrophy volume (6.8 ± 0.7 vs 8.5 ± 1.2 mm3, p < 0.05) and better performance represented by longer sustaining time on rotarod (99.3 ± 9 vs 80.1 ± 11 s, p < 0.01) and faster moving speed (7.7 ± 2 vs 5.7 ± 1.1 cm/s, p < 0.05) in open field tests. Furthermore, neural inhibition increased the number of nestin+, BrdU+/doublecortin+ and BrdU+/NeuN+ cells ( p < 0.001) in the subventricular zone and peri-focal region, and the expression level of axon guidance factor Netrin-1 (0.39 ± 0.16 vs 0.16 ± 0.02, p < 0.05) in the peri-focal region. These data suggest that striatal neuronal activity plays an important role in regulating neurogenesis and neural-behavioral outcomes, and that inhibiting striatal neurons by optogenetics promotes the recovery after ischemic stroke in mice.
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Affiliation(s)
- Xiaosong He
- 1 Department of Human Anatomy, Guangzhou Medical University, Guangzhou, China.,2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yifan Lu
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaojie Lin
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Jiang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yaohui Tang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Guanghui Tang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoyan Chen
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zhijun Zhang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yongting Wang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,3 Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Yuan Yang
- 2 Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,4 Shanghai Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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25
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Leonetti C, Macrez R, Pruvost M, Hommet Y, Bronsard J, Fournier A, Perrigault M, Machin I, Vivien D, Clemente D, De Castro F, Maubert E, Docagne F. Tissue-type plasminogen activator exerts EGF-like chemokinetic effects on oligodendrocytes in white matter (re)myelination. Mol Neurodegener 2017; 12:20. [PMID: 28231842 PMCID: PMC5322587 DOI: 10.1186/s13024-017-0160-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 02/10/2017] [Indexed: 01/12/2023] Open
Abstract
Background The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion. Methods OPC migration was estimated by immunohistological analysis in spinal cord and corpus callosum during development in mice embryos (E13 to P0) and after white matter lesion induced by the stereotactic injection of lysolecithin in adult mice (1 to 21 days post injection). Migration was compared in these conditions between wild type and tPA knock-out animals. The action of tPA was further investigated in an in vitro chemokinesis assay. Results OPC migration along vessels is delayed in tPA knock-out mice during development and during remyelination. tPA enhances OPC migration via an effect dependent on the activation of epidermal growth factor receptor. Conclusion Endogenous tPA facilitates the migration of OPCs during development and during remyelination after white matter lesion by the virtue of its epidermal growth factor-like domain. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0160-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Camille Leonetti
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Richard Macrez
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Mathilde Pruvost
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Yannick Hommet
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Jérémie Bronsard
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Antoine Fournier
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Maxime Perrigault
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Isabel Machin
- Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain.,Grupo de Neuroinmuno-reparación, Hospital Nacional de Parapléjicos, Toledo, Spain
| | - Denis Vivien
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Diego Clemente
- Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain.,Grupo de Neuroinmuno-reparación, Hospital Nacional de Parapléjicos, Toledo, Spain
| | - Fernando De Castro
- Grupo de Neurobiología del Desarrollo-GNDe, Hospital Nacional de Parapléjicos-SESCAM, Toledo, Spain.,Grupo de Neurobiología del Desarrollo (GNDe), Instituto Cajal, CSIC, Madrid, Spain
| | - Eric Maubert
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France
| | - Fabian Docagne
- Normandie Univ, UNICAEN, INSERM U1237, Physiology and imaging of neurological disorders (PhIND), Cyceron, Caen, 14000, France. .,Inserm, Centre Cyceron, Bvd Becquerel, BP5229, Caen Cedex, 14074, France.
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26
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Kazanis I, Evans KA, Andreopoulou E, Dimitriou C, Koutsakis C, Karadottir RT, Franklin RJM. Subependymal Zone-Derived Oligodendroblasts Respond to Focal Demyelination but Fail to Generate Myelin in Young and Aged Mice. Stem Cell Reports 2017; 8:685-700. [PMID: 28196689 PMCID: PMC5355571 DOI: 10.1016/j.stemcr.2017.01.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 01/10/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2023] Open
Abstract
Two populations of oligodendrogenic progenitors co-exist within the corpus callosum (CC) of the adult mouse. Local, parenchymal oligodendrocyte progenitor cells (pOPCs) and progenitors generated in the subependymal zone (SEZ) cytogenic niche. pOPCs are committed perinatally and retain their numbers through self-renewing divisions, while SEZ-derived cells are relatively “young,” being constantly born from neural stem cells. We compared the behavior of these populations, labeling SEZ-derived cells using hGFAP:CreErt2 mice, within the homeostatic and regenerating CC of the young-adult and aging brain. We found that SEZ-derived oligodendroglial progenitors have limited self-renewing potential and are therefore not bona fide OPCs but rather “oligodendroblasts” more similar to the neuroblasts of the neurogenic output of the SEZ. In the aged CC their mitotic activity is much reduced, although they still act as a “fast-response element” to focal demyelination. In contrast to pOPCs, they fail to generate mature myelinating oligodendrocytes at all ages studied.
SEZ-derived cells in the CC are oligodendroblasts and not OPCs Oligodendroblasts have limited self-renewal capacity and do not make myelin Oligodendroblasts respond rapidly after demyelination Aging does not affect the oligodendroblast-pOPC balance
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Affiliation(s)
- Ilias Kazanis
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK; Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece.
| | - Kimberley A Evans
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK
| | - Evangelia Andreopoulou
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | - Christina Dimitriou
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | - Christos Koutsakis
- Lab of Developmental Biology, Department of Biology, University of Patras, Patras 26500, Greece
| | | | - Robin J M Franklin
- Wellcome Trust-MRC Cambridge Stem Cell Biology Institute, University of Cambridge, Cambridge CB2 0AH, UK.
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27
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Dulamea AO. Role of Oligodendrocyte Dysfunction in Demyelination, Remyelination and Neurodegeneration in Multiple Sclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 958:91-127. [PMID: 28093710 DOI: 10.1007/978-3-319-47861-6_7] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS) during development and throughout adulthood. They result from a complex and well controlled process of activation, proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs) from the germinative niches of the CNS. In multiple sclerosis (MS), the complex pathological process produces dysfunction and apoptosis of OLs leading to demyelination and neurodegeneration. This review attempts to describe the patterns of demyelination in MS, the steps involved in oligodendrogenesis and myelination in healthy CNS, the different pathways leading to OLs and myelin loss in MS, as well as principles involved in restoration of myelin sheaths. Environmental factors and their impact on OLs and pathological mechanisms of MS are also discussed. Finally, we will present evidence about the potential therapeutic targets in re-myelination processes that can be accessed in order to develop regenerative therapies for MS.
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Affiliation(s)
- Adriana Octaviana Dulamea
- Neurology Clinic, University of Medicine and Pharmacy "Carol Davila", Fundeni Clinical Institute, Building A, Neurology Clinic, Room 201, 022328, Bucharest, Romania.
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28
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Lu H, Song X, Wang F, Wang G, Wu Y, Wang Q, Wang Y, Yang GY, Zhang Z. Hyperexpressed Netrin-1 Promoted Neural Stem Cells Migration in Mice after Focal Cerebral Ischemia. Front Cell Neurosci 2016; 10:223. [PMID: 27746720 PMCID: PMC5042963 DOI: 10.3389/fncel.2016.00223] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 09/16/2016] [Indexed: 11/13/2022] Open
Abstract
Endogenous Netrin-1 (NT-1) protein was significantly increased after cerebral ischemia, which may participate in the repair after transient cerebral ischemic injury. In this work, we explored whether NT-1 can be steadily overexpressed by adeno-associated virus (AAV) and the exogenous NT-1 can promote neural stem cells migration from the subventricular zone (SVZ) region after cerebral ischemia. Adult CD-1 mice were injected stereotacticly with AAV carrying NT-1 gene (AAV-NT-1). Mice underwent 60 min of middle cerebral artery (MCA) occlusion 1 week after injection. We found that NT-1 mainly expressed in neuron and astrocyte, and the expression level of NT-1 significantly increased 1 week after AAV-NT-1 gene transfer and lasted for 28 days, even after transient middle cerebral artery occlusion (tMCAO) as well (p < 0.05). Immunohistochemistry results showed that the number of neural stem cells was greatly increased in the SVZ region of AAV-NT-1-transduced mice compared with control mice. Our study showed that overexpressed NT-1 promoted neural stem cells migration from SVZ. This result suggested that NT-1 is a promising factor for repairing and remodeling after focal cerebral ischemia.
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Affiliation(s)
- Haiyan Lu
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Xiaoyan Song
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Feng Wang
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Guodong Wang
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Yuncheng Wu
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Qiaoshu Wang
- Department of Neurology, Shanghai General Hospital, Shanghai JiaoTong University Shanghai, China
| | - Yongting Wang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University Shanghai, China
| | - Guo-Yuan Yang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University Shanghai, China
| | - Zhijun Zhang
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University Shanghai, China
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29
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Tognatta R, Miller RH. Contribution of the oligodendrocyte lineage to CNS repair and neurodegenerative pathologies. Neuropharmacology 2016; 110:539-547. [PMID: 27108096 DOI: 10.1016/j.neuropharm.2016.04.026] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/01/2016] [Accepted: 04/19/2016] [Indexed: 12/22/2022]
Abstract
The concept of the oligodendrocyte lineage as simply a source of myelinating cells in the vertebrate CNS is undergoing radical revision. Elucidation of the origins of oligodendrocytes in the CNS has led to identification of important signaling pathways, the timing and mechanism of lineage commitments and overlapping as well as redundant functionality among oligodendrocytes. The realization that a significant proportion of the oligodendrocyte lineage cells remain in a proliferative and immature state suggests they have roles other than as a reservoir of myelinating cells. While early studies were focused on understanding the development of oligodendrocytes, more recent work has begun to define the role of oligodendrocyte lineage cells in CNS functionality and the identification of new avenues for neural repair. A relatively unexplored aspect of the oligodendrocyte lineage is their contribution either directly or indirectly to the pathology of neurodegenerative diseases such as ALS and Alzheimer's disease. Here we briefly consider the potential role of oligodendrocyte lineage cells as mediators of neural repair and neurodegeneration in the vertebrate CNS. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
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Affiliation(s)
- Reshmi Tognatta
- George Washington University, School of Medicine and Health Sciences, 2300 Eye Street NW, Ross Hall 709G, Washington, DC, 20037, USA
| | - Robert H Miller
- George Washington University, School of Medicine and Health Sciences, 2300 Eye Street NW, Ross Hall 709G, Washington, DC, 20037, USA.
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30
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Xie D, Shen F, He S, Chen M, Han Q, Fang M, Zeng H, Chen C, Deng Y. IL-1β induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats. Glia 2016; 64:583-602. [PMID: 26678483 DOI: 10.1002/glia.22950] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 11/08/2015] [Accepted: 11/18/2015] [Indexed: 02/05/2023]
Abstract
Neuroinflammation elicited by microglia plays a key role in periventricular white matter (PWM) damage (PWMD) induced by infectious exposure. This study aimed to determine if microglia-derived interleukin-1β (IL-1β) would induce hypomyelination through suppression of maturation of oligodendrocyte progenitor cells (OPCs) in the developing PWM. Sprague-Dawley rats (1-day old) were injected with lipopolysaccharide (LPS) (1 mg/kg) intraperitoneally, following which upregulated expression of IL-1β and IL-1 receptor 1 (IL-1R1 ) was observed. This was coupled with enhanced apoptosis and suppressed proliferation of OPCs in the PWM. The number of PDGFR-α and NG2-positive OPCs was significantly decreased in the PWM at 24 h and 3 days after injection of LPS, whereas it was increased at 14 days and 28 days. The protein expression of Olig1, Olig2, and Nkx2.2 was significantly reduced, and mRNA expression of Tcf4 and Axin2 was upregulated in the developing PWM after LPS injection. The expression of myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3"-phosphodiesterase (CNPase) was downregulated in the PWM at 14 days and 28 days after LPS injection; this was linked to reduction of the proportion of myelinated axons and thinner myelin sheath as revealed by electron microscopy. Primary cultured OPCs treated with IL-1β showed the failure of maturation and proliferation. Furthermore, FYN/MEK/ERK signaling pathway was involved in suppression of maturation of primary OPCs induced by IL-1β administration. Our results suggest that following LPS injection, microglia are activated and produce IL-1β in the PWM in the neonatal rats. Excess IL-1β inhibits the maturation of OPCs via suppression of FYN/MEK/ERK phosphorylation thereby leading to axonal hypomyelination.
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Affiliation(s)
- Di Xie
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Fengcai Shen
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
- Shantou University Medical College (FCS), Shantou, Guangdong, People's Republic of China. 515063
| | - Shaoru He
- Department of Neonatology, Guangdong General Hospital, Guangzhou, People's Republic of China
| | - Mengmeng Chen
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
- Shantou University Medical College (FCS), Shantou, Guangdong, People's Republic of China. 515063
| | - Qianpeng Han
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Ming Fang
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Hongke Zeng
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Chunbo Chen
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
| | - Yiyu Deng
- Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China
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31
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Ke X, Liu C, Wang Y, Ma J, Mao X, Li Q. Netrin-1 promotes mesenchymal stem cell revascularization of limb ischaemia. Diab Vasc Dis Res 2016; 13:145-156. [PMID: 26818229 DOI: 10.1177/1479164115611594] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
This study examines the effect and mechanism of action of Netrin-1 on bone marrow mesenchymal stem cells in angiogenesis. Tube formation and migration of bone marrow mesenchymal stem cells were observed in cell culture. Bone marrow mesenchymal stem cells or Netrin-1-bone marrow mesenchymal stem cells were injected into the ischaemic area of the rat hind limb on the first day after surgery. Laser Doppler perfusion imaging was performed to analyse the levels of vascular endothelial growth factor in plasma and muscles, and immunohistochemistry and immunofluorescence were used to analyse angiogenesis. Bone marrow mesenchymal stem cells in medium containing Netrin-1 markedly increased the number of tubes formed and the migration of bone marrow mesenchymal stem cells compared with the untreated control group. The function of Netrin-1 in tube formation and migration is similar to vascular endothelial growth factor, and combined with vascular endothelial growth factor, Netrin-1 has more enhanced effect than in the other three groups. The Netrin-1-bone marrow mesenchymal stem cell group had better augmented blood-perfusion scores and vessel densities, as well as improved function of the ischaemic limb than that of the group injected with bone marrow mesenchymal stem cells (treated with bone marrow mesenchymal stem cells individually) or the control group (treated with medium). These results suggest that Netrin-1 has the ability to augment the angiogenesis of bone marrow mesenchymal stem cells and improve the function of the ischaemic hind limb by increasing the level of vascular endothelial growth factor.
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Affiliation(s)
- Xianjin Ke
- Department of Neurology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chenxiao Liu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ying Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaoming Mao
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Qian Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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32
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Koutsakis C, Kazanis I. How Necessary is the Vasculature in the Life of Neural Stem and Progenitor Cells? Evidence from Evolution, Development and the Adult Nervous System. Front Cell Neurosci 2016; 10:35. [PMID: 26909025 PMCID: PMC4754404 DOI: 10.3389/fncel.2016.00035] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/01/2016] [Indexed: 12/24/2022] Open
Abstract
Augmenting evidence suggests that such is the functional dependance of neural stem cells (NSCs) on the vasculature that they normally reside in “perivascular niches”. Two examples are the “neurovascular” and the “oligovascular” niches of the adult brain, which comprise specialized microenvironments where NSCs or oligodendrocyte progenitor cells survive and remain mitotically active in close proximity to blood vessels (BVs). The often observed co-ordination of angiogenesis and neurogenesis led to these processes being described as “coupled”. Here, we adopt an evo-devo approach to argue that some stages in the life of a NSC, such as specification and commitment, are independent of the vasculature, while stages such as proliferation and migration are largely dependent on BVs. We also explore available evidence on the possible involvement of the vasculature in other phenomena such as the diversification of NSCs during evolution and we provide original data on the senescence of NSCs in the subependymal zone stem cell niche. Finally, we will comment on the other side of the story; that is, on how much the vasculature is dependent on NSCs and their progeny.
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Affiliation(s)
- Christos Koutsakis
- Laboratory of Developmental Biology, Department of Biology, University of Patras Patras, Greece
| | - Ilias Kazanis
- Laboratory of Developmental Biology, Department of Biology, University of PatrasPatras, Greece; Wellcome Trust-MRC Cambridge Stem Cell Institute, University of CambridgeCambridge, UK
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33
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Dong X, Chen K, Cuevas-Diaz Duran R, You Y, Sloan SA, Zhang Y, Zong S, Cao Q, Barres BA, Wu JQ. Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination. PLoS Genet 2015; 11:e1005669. [PMID: 26683846 PMCID: PMC4980008 DOI: 10.1371/journal.pgen.1005669] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 10/23/2015] [Indexed: 02/01/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) (> 200 bp) play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS) development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF) occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC) differentiation from Neural Stem Cells (NSCs) and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE) mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation)-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and analysis results via the interactive genome browser at our laboratory website that is freely accessible to the research community. This is the first lncRNA expression database of collective populations of glia, vascular cells, and neurons. We anticipate that these studies will advance the knowledge of this major class of non-coding genes and their potential roles in neurological development and diseases. Between 70 and 90% of the mammalian genome is transcribed at some point during development; however, only < 2% of the genome is associated with protein-coding genes. Emerging evidence suggests that long non-coding RNAs (lncRNAs; > 200 bp) play important roles in cell fate determination. In the present study, we broadened the lncRNA catalog by ab initio reconstruction of the transcriptomes of purified mouse cortex cell populations. More than 5000 lncRNAs were detected in the brain cell types studied. Predicting lncRNA functions using a ‘guilt-by-association’ approach revealed potential functions of lncRNAs in Central Nervous System development. Additionally, we analyzed transcription factor occupancy in the upstream regulatory regions of the lncRNAs. By integrating differential gene expression and transcription factor occupancy information, lncRNAs that are likely involved in oligodendrocyte precursor cell formation were identified. Loss-of-function experiments confirmed that the top candidate, lnc-OPC (long non-coding RNA in OPC), significantly reduces OPC differentiation from NSCs. Interestingly, lnc-OPC is up-regulated in glial progenitors of mouse models for multiple sclerosis. Our results demonstrated the role of lncRNA in the context of oligodendrocyte cell fate determination, and provided an extensive resource and a powerful analysis framework for future functional investigations of lncRNAs in CNS cell types.
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Affiliation(s)
- Xiaomin Dong
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Kenian Chen
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Raquel Cuevas-Diaz Duran
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Yanan You
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Steven A. Sloan
- Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Ye Zhang
- Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Shan Zong
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Qilin Cao
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
| | - Ben A. Barres
- Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Jia Qian Wu
- The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston Medical School, Houston, Texas, United States of America
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas, United States of America
- * E-mail:
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34
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Marlier Q, Verteneuil S, Vandenbosch R, Malgrange B. Mechanisms and Functional Significance of Stroke-Induced Neurogenesis. Front Neurosci 2015; 9:458. [PMID: 26696816 PMCID: PMC4672088 DOI: 10.3389/fnins.2015.00458] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 11/16/2015] [Indexed: 01/01/2023] Open
Abstract
Stroke affects one in every six people worldwide, and is the leading cause of adult disability. After stroke, some limited spontaneous recovery occurs, the mechanisms of which remain largely unknown. Multiple, parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. For years, clinical studies have tried to use exogenous cell therapy as a means of brain repair, with varying success. Since the rediscovery of adult neurogenesis and the identification of adult neural stem cells in the late nineties, one promising field of investigation is focused upon triggering and stimulating this self-repair system to replace the neurons lost following brain injury. For instance, it is has been demonstrated that the adult brain has the capacity to produce large numbers of new neurons in response to stroke. The purpose of this review is to provide an updated overview of stroke-induced adult neurogenesis, from a cellular and molecular perspective, to its impact on brain repair and functional recovery.
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Affiliation(s)
- Quentin Marlier
- GIGA-Neurosciences, University of Liege, C.H.U. Sart Tilman Liege, Belgium
| | | | - Renaud Vandenbosch
- GIGA-Neurosciences, University of Liege, C.H.U. Sart Tilman Liege, Belgium
| | - Brigitte Malgrange
- GIGA-Neurosciences, University of Liege, C.H.U. Sart Tilman Liege, Belgium
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35
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Porter LF, Galli GG, Williamson S, Selley J, Knight D, Elcioglu N, Aydin A, Elcioglu M, Venselaar H, Lund AH, Bonshek R, Black GC, Manson FD. A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome. Hum Mol Genet 2015; 24:6565-79. [PMID: 26395458 PMCID: PMC4634368 DOI: 10.1093/hmg/ddv345] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Revised: 07/29/2015] [Accepted: 08/18/2015] [Indexed: 12/11/2022] Open
Abstract
Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 (PRDM5) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5 Δ exons 9-14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and Δ exons 9-14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures (COL13A1, COL15A1, NTN1, CDH5) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9-14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Δ exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.
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Affiliation(s)
- Louise F Porter
- Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK, Manchester Royal Eye Hospital, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK, Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | - Giorgio G Galli
- Stem Cell Program, Boston Children's Hospital, Harvard Stem Cell and Regenerative Biology Department and Harvard Stem Cell Institute, Harvard University, Boston, MA, USA, Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
| | - Sally Williamson
- Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK
| | - Julian Selley
- Faculty of Life Sciences, Michael Smith Building, Manchester, UK
| | - David Knight
- Faculty of Life Sciences, Michael Smith Building, Manchester, UK
| | - Nursel Elcioglu
- Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey
| | - Ali Aydin
- Department of Ophthalmology, University of Medipol Medical Faculty, Istanbul, Turkey
| | - Mustafa Elcioglu
- Department of Ophthalmology, Okmeydani Research and Training Hospital, Istanbul, Turkey
| | - Hanka Venselaar
- Centre of Molecular and Biomolecular Informatics, Radboudumc Institute for Molecular Life Sciences, Nijmegen, The Netherlands and
| | - Anders H Lund
- Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
| | - Richard Bonshek
- Manchester Royal Eye Hospital, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK, National Ophthalmic Pathology Service Laboratory, Department of Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Graeme C Black
- Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK, Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK
| | - Forbes D Manson
- Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK
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Montalbán-Loro R, Domingo-Muelas A, Bizy A, Ferrón SR. Epigenetic regulation of stemness maintenance in the neurogenic niches. World J Stem Cells 2015; 7:700-710. [PMID: 26029342 PMCID: PMC4444611 DOI: 10.4252/wjsc.v7.i4.700] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/12/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
In the adult mouse brain, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are two zones that contain neural stem cells (NSCs) with the capacity to give rise to neurons and glia during the entire life of the animal. Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. At the molecular level, those epigenetic mechanisms comprise chemical modifications of DNA such as methylation, hydroxymethylation and histone modifications needed for the maintenance of NSC identity. Genomic imprinting is another normal epigenetic process leading to parental-specific expression of a gene, known to be implicated in the control of gene dosage in the neurogenic niches. The generation of induced pluripotent stem cells from NSCs by expression of defined transcription factors, provide key insights into fundamental principles of stem cell biology. Epigenetic modifications can also occur during reprogramming of NSCs to pluripotency and a better understanding of this process will help to elucidate the mechanisms required for stem cell maintenance. This review takes advantage of recent studies from the epigenetic field to report knowledge regarding the mechanisms of stemness maintenance of neural stem cells in the neurogenic niches.
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Cheyuo C, Aziz M, Yang WL, Jacob A, Zhou M, Wang P. Milk fat globule-EGF factor VIII attenuates CNS injury by promoting neural stem cell proliferation and migration after cerebral ischemia. PLoS One 2015; 10:e0122833. [PMID: 25867181 PMCID: PMC4394995 DOI: 10.1371/journal.pone.0122833] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 02/11/2015] [Indexed: 11/18/2022] Open
Abstract
The mediators in activating neural stem cells during the regenerative process of neurogenesis following stroke have not been fully identified. Milk fat globule-EGF Factor VIII (MFG-E8), a secreted glycoprotein serves several cellular functions by binding to its receptor, αv β3-integrin. However, its role in regulating neural stem cells after stroke has not been determined yet. We therefore, aim to reveal whether MFG-E8 promotes neural stem cell proliferation and migration during stroke. Stroke was induced in wild-type (Wt) and MFG-E8-deficinet (Mfge8-/-) mice by transient middle cerebral artery occlusion (tMCAO). Commercially available recombinant mouse MFG-E8 (rmMFG-E8) was used for mechanistic assays in neural stem cell line, while the in house prepared recombinant human MFG-E8 (rhMFG-E8) was used for in vivo administration into rats with tMCAO. The in vitro effects of recombinant rmMFG-E8 for the neural stem cell proliferation and migration were determined by BrdU and transwell migration assay, respectively. The expression of cyclin D2, p53 and netrin-1, was analyzed by qPCR. We report that the treatment of rhMFG-E8 significantly improved the neurological deficit score, body weight lost and neural stem cell proliferation in a rat model of tMCAO. Conversely, decreased neural stem cell proliferation was observed in Mfge8-/- mice in comparison with the Wt counterparts underwent tMCAO. rmMFG-E8 stimulated the proliferation of mouse embryonic neural stem cells via upregulation of cyclin D2 and downregulation of p53, which is mediated by αv β3-integrin. rmMFG-E8 also promoted mouse embryonic neural stem cell migration via αv β3-integrin dependent manner in upregulating netrin-1. Our findings suggest MFG-E8 to promote neural stem cell proliferation and migration, which therefore establishes a promising therapeutic strategy for cerebral ischemia.
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Affiliation(s)
- Cletus Cheyuo
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Monowar Aziz
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America
| | - Weng-Lang Yang
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America
| | - Asha Jacob
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America
| | - Mian Zhou
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America
| | - Ping Wang
- Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
- Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America
- * E-mail:
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Shaker MR, Kim JY, Kim H, Sun W. Identification and characterization of secondary neural tube-derived embryonic neural stem cells in vitro. Stem Cells Dev 2015; 24:1171-81. [PMID: 25706228 DOI: 10.1089/scd.2014.0506] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Secondary neurulation is an embryonic progress that gives rise to the secondary neural tube, the precursor of the lower spinal cord region. The secondary neural tube is derived from aggregated Sox2-expressing neural cells at the dorsal region of the tail bud, which eventually forms rosette or tube-like structures to give rise to neural tissues in the tail bud. We addressed whether the embryonic tail contains neural stem cells (NSCs), namely secondary NSCs (sNSCs), with the potential for self-renewal in vitro. Using in vitro neurosphere assays, neurospheres readily formed at the rosette and neural-tube levels, but less frequently at the tail bud tip level. Furthermore, we identified that sNSC-generated neurospheres were significantly smaller in size compared with cortical neurospheres. Interestingly, various cell cycle analyses revealed that this difference was not due to a reduction in the proliferation rate of NSCs, but rather the neuronal commitment of sNSCs, as sNSC-derived neurospheres contain more committed neuronal progenitor cells, even in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). These results suggest that the higher tendency for sNSCs to spontaneously differentiate into progenitor cells may explain the limited expansion of the secondary neural tube during embryonic development.
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Affiliation(s)
- Mohammed R Shaker
- Department of Anatomy, Brain Korea 21 Program, Korea University College of Medicine , Seoul, Korea
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Shi H, Hu X, Leak RK, Shi Y, An C, Suenaga J, Chen J, Gao Y. Demyelination as a rational therapeutic target for ischemic or traumatic brain injury. Exp Neurol 2015; 272:17-25. [PMID: 25819104 DOI: 10.1016/j.expneurol.2015.03.017] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 03/15/2015] [Accepted: 03/18/2015] [Indexed: 12/11/2022]
Abstract
Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients.
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Affiliation(s)
- Hong Shi
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China
| | - Xiaoming Hu
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA
| | - Rehana K Leak
- Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
| | - Yejie Shi
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA
| | - Chengrui An
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Jun Suenaga
- Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Jun Chen
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
| | - Yanqin Gao
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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40
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O'Leary CJ, Bradford D, Chen M, White A, Blackmore DG, Cooper HM. The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit. Stem Cells 2015; 33:503-14. [DOI: 10.1002/stem.1861] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 07/31/2014] [Accepted: 09/06/2014] [Indexed: 01/16/2023]
Affiliation(s)
- Conor J. O'Leary
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - DanaKai Bradford
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Min Chen
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Amanda White
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Daniel G. Blackmore
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Helen M. Cooper
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
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41
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Michailidou I, de Vries HE, Hol EM, van Strien ME. Activation of endogenous neural stem cells for multiple sclerosis therapy. Front Neurosci 2015; 8:454. [PMID: 25653584 PMCID: PMC4299409 DOI: 10.3389/fnins.2014.00454] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 12/22/2014] [Indexed: 12/29/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions.
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Affiliation(s)
- Iliana Michailidou
- Department of Astrocyte Biology and Neurodegeneration, The Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Sciences Amsterdam, Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Netherlands
| | - Elly M Hol
- Department of Astrocyte Biology and Neurodegeneration, The Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Sciences Amsterdam, Netherlands ; Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam Amsterdam, Netherlands ; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, Netherlands
| | - Miriam E van Strien
- Department of Astrocyte Biology and Neurodegeneration, The Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Sciences Amsterdam, Netherlands ; Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, Netherlands
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42
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Ramasamy SK, Kusumbe AP, Adams RH. Regulation of tissue morphogenesis by endothelial cell-derived signals. Trends Cell Biol 2014; 25:148-57. [PMID: 25529933 DOI: 10.1016/j.tcb.2014.11.007] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 11/21/2014] [Accepted: 11/24/2014] [Indexed: 02/08/2023]
Abstract
Endothelial cells (ECs) form an extensive network of blood vessels that has numerous essential functions in the vertebrate body. In addition to their well-established role as a versatile transport network, blood vessels can induce organ formation or direct growth and differentiation processes by providing signals in a paracrine (angiocrine) fashion. Tissue repair also requires the local restoration of vasculature. ECs are emerging as important signaling centers that coordinate regeneration and help to prevent deregulated, disease-promoting processes. Vascular cells are also part of stem cell niches and have key roles in hematopoiesis, bone formation, and neurogenesis. Here, we review these newly identified roles of ECs in the regulation of organ morphogenesis, maintenance, and regeneration.
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Affiliation(s)
- Saravana K Ramasamy
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, D-48149 Münster, Germany
| | - Anjali P Kusumbe
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, D-48149 Münster, Germany
| | - Ralf H Adams
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, D-48149 Münster, Germany.
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43
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Gallo V, Deneen B. Glial development: the crossroads of regeneration and repair in the CNS. Neuron 2014; 83:283-308. [PMID: 25033178 DOI: 10.1016/j.neuron.2014.06.010] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2014] [Indexed: 02/07/2023]
Abstract
Given the complexities of the mammalian CNS, its regeneration is viewed as the holy grail of regenerative medicine. Extraordinary efforts have been made to understand developmental neurogenesis, with the hopes of clinically applying this knowledge. CNS regeneration also involves glia, which comprises at least 50% of the cellular constituency of the brain and is involved in all forms of injury and disease response, recovery, and regeneration. Recent developmental studies have given us unprecedented insight into the processes that regulate the generation of CNS glia. Because restorative processes often parallel those found in development, we will peer through the lens of developmental gliogenesis to gain a clearer understanding of the processes that underlie glial regeneration under pathological conditions. Specifically, this review will focus on key signaling pathways that regulate astrocyte and oligodendrocyte development and describe how these mechanisms are reutilized in these populations during regeneration and repair after CNS injury.
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Affiliation(s)
- Vittorio Gallo
- Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
| | - Benjamin Deneen
- Department of Neuroscience and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
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44
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Tepavčević V, Kerninon C, Aigrot MS, Meppiel E, Mozafari S, Arnould-Laurent R, Ravassard P, Kennedy TE, Nait-Oumesmar B, Lubetzki C. Early netrin-1 expression impairs central nervous system remyelination. Ann Neurol 2014; 76:252-68. [DOI: 10.1002/ana.24201] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/16/2014] [Accepted: 06/16/2014] [Indexed: 12/22/2022]
Affiliation(s)
- Vanja Tepavčević
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Christophe Kerninon
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Marie Stéphane Aigrot
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Elodie Meppiel
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Sabah Mozafari
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Raphaelle Arnould-Laurent
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Philippe Ravassard
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Timothy E. Kennedy
- Department of Neurology and Neurosurgery; Montreal Neurological Institute, McGill University; Montreal Quebec Canada
| | - Brahim Nait-Oumesmar
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
| | - Catherine Lubetzki
- Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière; Paris France
- National Institute of Health and Medical Research (INSERM); U1127 Paris France
- National Center for Scientific Research (CNRS), Mixed Unit of Research 7225; Paris France
- Pitié-Salpêtrière Hospital; Public Hospital Network of Paris (AP-HP); Paris France
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Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SPJ, Zahed H, Maltepe E, Rowitch DH. Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell 2014; 158:383-396. [PMID: 25018103 DOI: 10.1016/j.cell.2014.04.052] [Citation(s) in RCA: 309] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 03/13/2014] [Accepted: 04/22/2014] [Indexed: 12/30/2022]
Abstract
Myelin sheaths provide critical functional and trophic support for axons in white matter tracts of the brain. Oligodendrocyte precursor cells (OPCs) have extraordinary metabolic requirements during development as they differentiate to produce multiple myelin segments, implying that they must first secure adequate access to blood supply. However, mechanisms that coordinate myelination and angiogenesis are unclear. Here, we show that oxygen tension, mediated by OPC-encoded hypoxia-inducible factor (HIF) function, is an essential regulator of postnatal myelination. Constitutive HIF1/2α stabilization resulted in OPC maturation arrest through autocrine activation of canonical Wnt7a/7b. Surprisingly, such OPCs also show paracrine activity that induces excessive postnatal white matter angiogenesis in vivo and directly stimulates endothelial cell proliferation in vitro. Conversely, OPC-specific HIF1/2α loss of function leads to insufficient angiogenesis in corpus callosum and catastrophic axon loss. These findings indicate that OPC-intrinsic HIF signaling couples postnatal white matter angiogenesis, axon integrity, and the onset of myelination in mammalian forebrain.
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Affiliation(s)
- Tracy J Yuen
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - John C Silbereis
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Amelie Griveau
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Sandra M Chang
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Richard Daneman
- Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Stephen P J Fancy
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Hengameh Zahed
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Medical Science Training Program, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Emin Maltepe
- Division of Neonatology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - David H Rowitch
- Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Division of Neonatology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
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Chen T, Chen D, Li F, Tan Z. Netrin-1 with stem cells promote angiogenesis in limb ischemic rats. J Surg Res 2014; 192:664-9. [PMID: 25240286 DOI: 10.1016/j.jss.2014.07.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/08/2014] [Accepted: 07/01/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND Recent findings have elucidated that netrin-1 has ability of promoting angiogenesis besides the functions in nervous system. Autologous mesenchymal stem cells (MSCs) transplantation is now proved to be an effective method to treat peripheral arterial disease. However there are still many patients who cannot complete full treatments. Therefore it is necessary to improve the effectiveness. This study estimated the curative effects in chronic limb ischemia when MSCs allied with netrin-1. MATERIALS AND METHODS Thirty-six rats were made into chronic limb ischemia models. They were randomly assigned to four groups, netrin-1 + MSCs group (treated with netrin-1 and MSCs derived from peripheral blood), MSCs group (treated with MSCs individually), netrin-1 group (treated with netrin-1 individually), and control group (treated with saline). Measurements of murine behaviors, vascular endothelial growth factor expression, and capillary density in ischemia limb were performed on days 7, 14, and 28 after treatments; measurements of contraction force in ischemia limb was performed on day 28 after treatments to compare differences among the groups. RESULTS Netrin-1 allied with MSCs significantly increased Tarlov score, vascular endothelial growth factor expression, capillary density, and muscular strength in ischemia limb. CONCLUSIONS Netrin-1 allied with MSCs derived from peripheral blood significantly promoted angiogenesis in aged rats with chronic limb ischemia. It may be a promising method of treating peripheral arterial disease in the future.
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Affiliation(s)
- Tao Chen
- Department of Vascular Surgery, Zhongnan Hospital of Wuhan University, Zhongnan Hospital, Wuhan city, Hubei province, China; Department of Vascular Surgery, Affiliated Xiangyang Central Hospital of Hubei University of Arts and Science, Xiangyang Center Hospital, Xiangyang city, Hubei province, China
| | - Dejie Chen
- Department of Vascular Surgery, Affiliated Xiangyang Central Hospital of Hubei University of Arts and Science, Xiangyang Center Hospital, Xiangyang city, Hubei province, China
| | - Fangfang Li
- Department of Pharmacy, Affiliated Xiangyang Central Hospital of Hubei University of Arts and Science, Xiangyang Center Hospital, Xiangyang city, Hubei province, China
| | - Zui Tan
- Department of Vascular Surgery, Zhongnan Hospital of Wuhan University, Zhongnan Hospital, Wuhan city, Hubei province, China.
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Repunte-Canonigo V, Lefebvre C, George O, Kawamura T, Morales M, Koob GF, Califano A, Masliah E, Sanna PP. Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats. Mol Neurodegener 2014; 9:26. [PMID: 24980976 PMCID: PMC4107468 DOI: 10.1186/1750-1326-9-26] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 06/19/2014] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS. RESULTS We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington's disease, Parkinson's disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function. CONCLUSIONS Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Pietro Paolo Sanna
- Molecular and Cellular Neuroscience Department, La Jolla, CA 92037, USA.
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48
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El Waly B, Macchi M, Cayre M, Durbec P. Oligodendrogenesis in the normal and pathological central nervous system. Front Neurosci 2014; 8:145. [PMID: 24971048 PMCID: PMC4054666 DOI: 10.3389/fnins.2014.00145] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/23/2014] [Indexed: 12/26/2022] Open
Abstract
Oligodendrocytes (OLGs) are generated late in development and myelination is thus a tardive event in the brain developmental process. It is however maintained whole life long at lower rate, and myelin sheath is crucial for proper signal transmission and neuronal survival. Unfortunately, OLGs present a high susceptibility to oxidative stress, thus demyelination often takes place secondary to diverse brain lesions or pathologies. OLGs can also be the target of immune attacks, leading to primary demyelination lesions. Following oligodendrocytic death, spontaneous remyelination may occur to a certain extent. In this review, we will mainly focus on the adult brain and on the two main sources of progenitor cells that contribute to oligodendrogenesis: parenchymal oligodendrocyte precursor cells (OPCs) and subventricular zone (SVZ)-derived progenitors. We will shortly come back on the main steps of oligodendrogenesis in the postnatal and adult brain, and summarize the key factors involved in the determination of oligodendrocytic fate. We will then shed light on the main causes of demyelination in the adult brain and present the animal models that have been developed to get insight on the demyelination/remyelination process. Finally, we will synthetize the results of studies searching for factors able to modulate spontaneous myelin repair.
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Affiliation(s)
- Bilal El Waly
- CNRS, Institut de Biologie du Développement de Marseille UMR 7288, Aix Marseille Université Marseille, France
| | - Magali Macchi
- CNRS, Institut de Biologie du Développement de Marseille UMR 7288, Aix Marseille Université Marseille, France
| | - Myriam Cayre
- CNRS, Institut de Biologie du Développement de Marseille UMR 7288, Aix Marseille Université Marseille, France
| | - Pascale Durbec
- CNRS, Institut de Biologie du Développement de Marseille UMR 7288, Aix Marseille Université Marseille, France
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Sawada M, Matsumoto M, Sawamoto K. Vascular regulation of adult neurogenesis under physiological and pathological conditions. Front Neurosci 2014; 8:53. [PMID: 24672424 PMCID: PMC3955849 DOI: 10.3389/fnins.2014.00053] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 02/26/2014] [Indexed: 01/16/2023] Open
Abstract
Neural stem cells in the mammalian adult brain continuously produce new neurons throughout life. Accumulating evidence in rodents suggests that various aspects of adult neurogenesis, including the genesis, migration, and maturation of new neurons, are regulated by factors derived from blood vessels and their microenvironment. Brain injury enhances both neurogenesis and angiogenesis, thereby promoting the cooperative regeneration of neurons and blood vessels. In this paper, we briefly review the mechanisms for the vascular regulation of adult neurogenesis in the ventricular-subventricular zone under physiological and pathological conditions, and discuss their clinical potential for brain regeneration strategies.
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Affiliation(s)
- Masato Sawada
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
| | - Mami Matsumoto
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
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50
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Kaneko N, Kako E, Sawamoto K. Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives. Front Cell Neurosci 2013; 7:235. [PMID: 24348331 PMCID: PMC3842008 DOI: 10.3389/fncel.2013.00235] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 11/08/2013] [Indexed: 12/17/2022] Open
Abstract
In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine.
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Affiliation(s)
- Naoko Kaneko
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
| | - Eisuke Kako
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan ; Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences Nagoya, Japan
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