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Blaszczyk GJ, Mohammadnia A, Piscopo VEC, Sirois J, Cui QL, Yaqubi M, Durcan TM, Schneider R, Antel JP. Pro-Inflammatory Molecules Implicated in Multiple Sclerosis Divert the Development of Human Oligodendrocyte Lineage Cells. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2025; 12:e200407. [PMID: 40393021 PMCID: PMC12094787 DOI: 10.1212/nxi.0000000000200407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/21/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND AND OBJECTIVES Oligodendrocytes (OLs) and their myelin-forming processes are lost during the disease course of multiple sclerosis (MS), targeted by infiltrating leukocytes and their effector cytokines. Myelin repair is considered to be dependent on recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). The basis of remyelination failure during the disease course of MS remains to be defined. The aim of this study was to determine the impact of the proinflammatory molecules tumor necrosis factor-⍺ (TNF⍺) and interferon-γ (IFNγ) on the differentiation of human OPCs. METHODS We generated human OPCs from induced pluripotent stem cells with a reporter gene under the OL-specific transcription factor SOX10. We treated the cells in vitro with TNF⍺ or IFNγ and evaluated effects regarding cell viability, expression of OL lineage markers, and coexpression of astrocyte markers. To relate our findings to the molecular properties of OPCs as found in the MS brain, we reanalyzed publicly available single-nuclear RNA sequencing (RNAseq) datasets. RESULTS Our analysis indicated that both TNF⍺ and IFNγ decreased the proportion of cells differentiating into the OL lineage, consistent with previous reports. Uniquely, we now observe that the TNF⍺ effect is linked to aberrant OPC differentiation in that a subset of O4+, reporter-positive cells coexpressing the astrocytic marker aquaporin-4. At the transcriptomic level, the cells acquire an astrocyte-like signature alongside a conserved reactive phenotype while downregulating OL lineage genes. Analysis of single-nuclear RNAseq datasets from the human MS brain revealed a subset of OPCs expressing an astrocytic signature. DISCUSSION In the context of MS, these results imply that OPCs are present but inhibited from differentiating along the OL lineage, with a subset acquiring a reactive and stem cell-like phenotype, reducing their capacity to contribute toward repair. These findings help define a potential basis for the impaired myelin repair in MS and provide a prospective route for regenerative treatment.
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Affiliation(s)
- Gabriela J Blaszczyk
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, Montreal, Canada
- The Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Abdulshakour Mohammadnia
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, Montreal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Valerio E C Piscopo
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, Montreal, Canada; and
| | - Julien Sirois
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, Montreal, Canada; and
| | - Qiao-Ling Cui
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, Montreal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Moein Yaqubi
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, Montreal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Thomas M Durcan
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, Montreal, Canada; and
| | - Raphael Schneider
- The Keenan Research Center for Biomedical Science, Unity Health Toronto, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- BARLO MS Center, Unity Health Toronto, Toronto, Canada
| | - Jack P Antel
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, Montreal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
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Liu H, Yuan Y, Li J, Lan Z, Dai Z, Li G, Xiao K, Pu Y, He C, Qin S, Su Z. Establishment of an efficient and economical method for primary oligodendrocyte progenitor cell culture from neonatal mouse brain. Brain Res 2025; 1853:149519. [PMID: 40023233 DOI: 10.1016/j.brainres.2025.149519] [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: 10/11/2024] [Revised: 02/05/2025] [Accepted: 02/17/2025] [Indexed: 03/04/2025]
Abstract
The primary culture of oligodendrocyte progenitor cells (OPCs) provides an indispensable tool for characterizing their biological properties and myelin repair potential. However, the current OPC preparation methods are mainly limited to rat tissues, and it remains a substantial challenge for replicating the primary culture from mouse tissues to generate large quantities of high-quality OPCs. Here, we describe a protocol to successfully establish highly enriched OPC cultures from the cerebral cortex of mice at the age of neonatal 3 days. OPCs were isolated and purified from the bed layer of astrocytes by shaking for 6 h at 250 rpm. Using this protocol, mouse OPCs can be easily produced in bulk and economically without the need for specific cell-surface antibodies and equipment. These mouse OPC cultures were identified by immunocytochemical, immunobloting and RNA-seq analysis. Furthermore, they could be expanded in vitro and differentiate into mature oligodendrocytes. We propose this method as a viable and affordable protocol to obtain mouse OPC culture, which should significantly facilitate studies on OPC lineage progression and their application in myelin-related disease modeling and regenerative medicine.
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Affiliation(s)
- Hong Liu
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Yimin Yuan
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China; Department of Pain Medicine, School of Anesthesiology, Naval Medical University, Shanghai 200433, China
| | - Jiali Li
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Zhida Lan
- Department of Anatomy, College of Basic Medicine, Naval Medical University, Shanghai 200433, China
| | - Ziwei Dai
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Guanyu Li
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Kouwei Xiao
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Yingyan Pu
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Cheng He
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China
| | - Shangyao Qin
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China.
| | - Zhida Su
- Institute of Neuroscience, Key Laboratory of Molecular Neurobiology of Ministry of Education and the Collaborative Innovation Center for Brain Science, Naval Medical University, Shanghai 200433, China.
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Yang Z. The Principle of Cortical Development and Evolution. Neurosci Bull 2025; 41:461-485. [PMID: 39023844 PMCID: PMC11876516 DOI: 10.1007/s12264-024-01259-2] [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: 05/29/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024] Open
Abstract
Human's robust cognitive abilities, including creativity and language, are made possible, at least in large part, by evolutionary changes made to the cerebral cortex. This paper reviews the biology and evolution of mammalian cortical radial glial cells (primary neural stem cells) and introduces the concept that a genetically step wise process, based on a core molecular pathway already in use, is the evolutionary process that has molded cortical neurogenesis. The core mechanism, which has been identified in our recent studies, is the extracellular signal-regulated kinase (ERK)-bone morphogenic protein 7 (BMP7)-GLI3 repressor form (GLI3R)-sonic hedgehog (SHH) positive feedback loop. Additionally, I propose that the molecular basis for cortical evolutionary dwarfism, exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor, is an increase in SHH signaling in radial glia, that antagonizes ERK-BMP7 signaling. Finally, I propose that: (1) SHH signaling is not a key regulator of primate cortical expansion and folding; (2) human cortical radial glial cells do not generate neocortical interneurons; (3) human-specific genes may not be essential for most cortical expansion. I hope this review assists colleagues in the field, guiding research to address gaps in our understanding of cortical development and evolution.
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Affiliation(s)
- Zhengang Yang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Neurology, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Kim H, Kim BJ, Koh S, Cho HJ, Kim BG, Choi JY. Cryopreservation of primary neonatal rat oligodendrocytes and recapitulation of in vitro oligodendrocyte characteristics. Front Cell Neurosci 2025; 18:1520992. [PMID: 39872018 PMCID: PMC11769993 DOI: 10.3389/fncel.2024.1520992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/30/2024] [Indexed: 01/29/2025] Open
Abstract
Introduction In vitro, primary rat oligodendrocytes (OLs) are widely used for research on OL development, physiology, and pathophysiology in demyelinating diseases such as multiple sclerosis. Primary culture methods for OLs from rats have been developed and improved over time, but there are still multiple aspects in which efficiency can be boosted. Methods To make use of excess oligodendrocyte progenitor cells (OPCs) from primary cultures, a cryopreservation process utilizing a commercially available serum-free cryopreservation medium was established to passage and freeze OPCs at -80°C for later use. Results Cryopreserved OPCs stored for up to 6 months were viable, and retained their OL lineage purity of ~98%. While OPCs cryopreserved for 3-6 months showed a decrease in cell density after two days of proliferation, ~17% of cryopreserved OPCs maintained the potential for proliferation comparable to control OPCs that had not frozen. After induction of differentiation for four days, ~43% of both control and cryopreserved OPCs differentiated into mature OLs, and when differentiation was induced on aligned nanofibers mimicking axonal structure, myelin sheath-like structures indicative of in vitro myelination was observed in all experimental groups. Conclusion The validation of cryopreserved primary OLs as a functionally robust in vitro model can help improve the efficiency of primary OL culture, expand its applications, and reduce the inevitable sacrifice of animals.
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Affiliation(s)
- Hanki Kim
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Bum Jun Kim
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
| | - Seungyon Koh
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
- Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyo Jin Cho
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Byung Gon Kim
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jun Young Choi
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea
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Yokoyama K, Hiraoka Y, Abe Y, Tanaka KF. Visualization of myelin-forming oligodendrocytes in the adult mouse brain. J Neurochem 2025; 169:e16218. [PMID: 39233334 PMCID: PMC11657928 DOI: 10.1111/jnc.16218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/10/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024]
Abstract
Oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs) is considered to result in two populations: premyelinating and myelinating OLs. Recent single-cell RNA sequence data subdivided these populations into newly formed (NFOLs), myelin-forming (MFOLs), and mature (MOLs) oligodendrocytes. However, which newly proposed population corresponds to premyelinating or myelinating OLs is unknown. We focused on the NFOL-specific long non-coding oligodendrocyte 1 gene (LncOL1) and sought to label NFOLs under the control of the LncOL1 promoter using a tetracycline-controllable gene induction system. We demonstrated that LncOL1 was expressed by premyelinating OLs and that the MFOL-specific gene, Ctps, was not, indicating that NFOLs correspond to premyelinating OLs and that MFOLs and MOLs correspond to myelinating OLs. We then generated a LncOL1-tTA mouse in which a tetracycline transactivator (tTA) cassette was inserted downstream from the LncOL1 transcription initiation site. By crossing the LncOL1-tTA mice with tetO reporter mice, we generated LncOL1-tTA::tetO-yellow fluorescent protein (YFP) double-transgenic (LncOL1-YFP) mice. Although LncOL1 is non-coding, YFP was detected in LncOL1-YFP mice, indicating successful tTA translation. Unexpectedly, we found that the morphology of LncOL1-tTA-driven YFP+ cells was distinct from that of LncOL1+ premyelinating OLs and that the labeled cells instead appeared as myelinating OLs. We demonstrated from their RNA expression that YFP-labeled OLs were MFOLs, but not MOLs. Using the unique property of delayed YFP induction, we sought to determine whether MFOLs are constantly supplied from OPCs and differentiate into MOLs, or whether MFOLs pause their differentiation and sustain this stage in the adult brain. To achieve this objective, we irradiated adult LncOL1-YFP brains with X-rays to deplete dividing OPCs and their progeny. The irradiation extinguished YFP-labeled OLs, indicating that adult OPCs differentiated into MOLs during a single period. We established a new transgenic mouse line that genetically labels MFOLs, providing a reliable tool for investigating the dynamics of adult oligodendrogenesis.
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Affiliation(s)
- Kiichi Yokoyama
- Division of Brain SciencesInstitute for Advanced Medical Research, Keio University School of MedicineTokyoJapan
| | - Yuichi Hiraoka
- Laboratory of Molecular NeuroscienceMedical Research Institute, Tokyo Medical and Dental UniversityTokyoJapan
- Laboratory of Genome Editing for Biomedical ResearchMedical Research Institute, Tokyo Medical and Dental UniversityTokyoJapan
| | - Yoshifumi Abe
- Division of Brain SciencesInstitute for Advanced Medical Research, Keio University School of MedicineTokyoJapan
| | - Kenji F. Tanaka
- Division of Brain SciencesInstitute for Advanced Medical Research, Keio University School of MedicineTokyoJapan
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He Y, Xu Z, He Y, Liu J, Li J, Wang S, Xiao L. Preventing production of new oligodendrocytes impairs remyelination and sustains behavioural deficits after demyelination. Biochem Biophys Res Commun 2024; 733:150592. [PMID: 39213705 DOI: 10.1016/j.bbrc.2024.150592] [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: 05/23/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
Damage to oligodendrocytes (OLs) and myelin sheaths (demyelination) has been shown to be associated with numerous neurological and psychiatric disorders. Remyelination is a rare and reliable regenerative response that occurs in the central nervous system (CNS). It is generally believed that OL progenitor cells (OPCs) are the cell source to generate new OLs to remyelinate the demyelinated axons. However, several recent studies have argued that pre-existing mature OLs that survive within the demyelinated area are responsible for remyelination. Here, by conditional knock-out (KO) of a transcription factor gene that is essential for OPC differentiation, namely myelin regulatory factor (Myrf), to block the production of adult new OLs and examined its effect on remyelination after cuprizone (CPZ)-induced demyelination. We found that OPCs specific Myrf cKO mice show dramatic impairment in remyelination after 4 weeks of recovery from 5 weeks of CPZ diet and they leave over significant behavioral deficits such as anxiety-like behavior, decreased motor skills, and impaired memory compared to control mice that have recovered for the same time. Our data support the idea that OPCs are the major cell sources for myelin regeneration, suggesting that targeting the activation of OPCs and promoting their differentiation to boost new OLs production is critical for therapeutic intervention for demyelinating diseases such as multiple sclerosis (MS).
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Affiliation(s)
- Yuehua He
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Zhengtao Xu
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Yongxiang He
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Junhong Liu
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Jiong Li
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Shuming Wang
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China
| | - Lin Xiao
- Key Laboratory of Brain, Cognition and Education Sciences of Ministry of Education, Institute for Brain Research and Rehabilitation, Guangdong Key Laboratory of Mental Health and Cognitive Science, and Center for Studies of Psychological Application, South China Normal University, Guangzhou, 510631, China.
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Tang W, Wang Q, Sun M, Liu C, Huang Y, Zhou M, Zhang X, Meng Z, Zhang J. The gut microbiota-oligodendrocyte axis: A promising pathway for modulating oligodendrocyte homeostasis and demyelination-associated disorders. Life Sci 2024; 354:122952. [PMID: 39127317 DOI: 10.1016/j.lfs.2024.122952] [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: 04/23/2024] [Revised: 07/22/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
The bidirectional regulation between the gut microbiota and brain, known as gut-brain axis, has received significant attention. The myelin sheath, produced by oligodendrocytes or Schwann cells, is essential for efficient nervous signal transmission and the maintenance of brain function. Growing evidence shows that both oligodendrogenesis and myelination are modulated by gut microbiota and its metabolites, and when dysbiosis occurs, changes in the microbiota composition and/or associated metabolites may impact developmental myelination and the occurrence of neurodevelopmental disabilities. Although the link between the microbiota and demyelinating disease such as multiple sclerosis has been extensively studied, our knowledge about the role of the microbiota in other myelin-related disorders, such as neurodegenerative diseases, is limited. Mechanistically, the microbiota-oligodendrocyte axis is primarily mediated by factors such as inflammation, the vagus nerve, endocrine hormones, and microbiota metabolites as evidenced by metagenomics, metabolomics, vagotomy, and morphological and molecular approaches. Treatments targeting this axis include probiotics, prebiotics, microbial metabolites, herbal bioactive compounds, and specific dietary management. In addition to the commonly used approaches, viral vector-mediated tracing and gene manipulation, integrated multiomics and multicenter clinical trials will greatly promote the mechanistic and interventional studies and ultimately, the development of new preventive and therapeutic strategies against gut-oligodendrocyte axis-mediated brain impairments. Interestingly, recent findings showed that microbiota dysbiosis can be induced by hippocampal myelin damage and is reversible by myelin-targeted drugs, which provides new insights into understanding how hippocampus-based functional impairment (such as in neurodegenerative Alzheimer's disease) regulates the peripheral homeostasis of microbiota and associated systemic disorders.
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Affiliation(s)
- Wen Tang
- Department of Gastroenterology, Chongqing Western Hospital, Chongqing 400052, China
| | - Qi Wang
- Department of Neurobiology, Army Medical University, Chongqing 400038, China
| | - Mingguang Sun
- Department of Neurology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China; Department of Neurology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing University of Chinese Medicine, Beijing 100853, China
| | - Chang''e Liu
- Department of Nutrition, The Seventh Medical Center of Chinese PLA General Hospital, Beijing 100700, China
| | - Yonghua Huang
- Department of Neurology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing 100700, China
| | - Maohu Zhou
- Department of Neurobiology, Army Medical University, Chongqing 400038, China
| | - Xuan Zhang
- Department of Neurobiology, Army Medical University, Chongqing 400038, China
| | - Zhaoyou Meng
- Department of Neurology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
| | - Jiqiang Zhang
- Department of Neurobiology, Army Medical University, Chongqing 400038, China.
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Ma Z, Zhang W, Wang C, Su Y, Yi C, Niu J. A New Acquaintance of Oligodendrocyte Precursor Cells in the Central Nervous System. Neurosci Bull 2024; 40:1573-1589. [PMID: 39042298 PMCID: PMC11422404 DOI: 10.1007/s12264-024-01261-8] [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: 11/06/2023] [Accepted: 03/21/2024] [Indexed: 07/24/2024] Open
Abstract
Oligodendrocyte precursor cells (OPCs) are a heterogeneous multipotent population in the central nervous system (CNS) that appear during embryogenesis and persist as resident cells in the adult brain parenchyma. OPCs could generate oligodendrocytes to participate in myelination. Recent advances have renewed our knowledge of OPC biology by discovering novel markers of oligodendroglial cells, the myelin-independent roles of OPCs, and the regulatory mechanism of OPC development. In this review, we will explore the updated knowledge on OPC identity, their multifaceted roles in the CNS in health and diseases, as well as the regulatory mechanisms that are involved in their developmental stages, which hopefully would contribute to a further understanding of OPCs and attract attention in the field of OPC biology.
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Affiliation(s)
- Zexuan Ma
- Department of Histology and Embryology, College of basic medicine, Third Military Medical University, Chongqing, 400038, China
| | - Wei Zhang
- Department of Histology and Embryology, College of basic medicine, Third Military Medical University, Chongqing, 400038, China
| | - Chenmeng Wang
- Department of Histology and Embryology, College of basic medicine, Third Military Medical University, Chongqing, 400038, China
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China
| | - Yixun Su
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China
| | - Chenju Yi
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China.
- Shenzhen Key Laboratory of Chinese Medicine Active substance screening and Translational Research, Shenzhen, 518107, China.
| | - Jianqin Niu
- Department of Histology and Embryology, College of basic medicine, Third Military Medical University, Chongqing, 400038, China.
- Chongqing Key Laboratory of Neurobiology, Chongqing, 400038, China.
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9
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Bottero M, Pessina G, Bason C, Vigo T, Uccelli A, Ferrara G. Nerve-Glial antigen 2: unmasking the enigmatic cellular identity in the central nervous system. Front Immunol 2024; 15:1393842. [PMID: 39136008 PMCID: PMC11317297 DOI: 10.3389/fimmu.2024.1393842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/05/2024] [Indexed: 08/15/2024] Open
Abstract
Chondroitin sulfate proteoglycans (CSPGs) are fundamental components of the extracellular matrix in the central nervous system (CNS). Among these, the Nerve-Glial antigen 2 (NG2) stands out as a transmembrane CSPG exclusively expressed in a different population of cells collectively termed NG2-expressing cells. These enigmatic cells, found throughout the developing and adult CNS, have been indicated with various names, including NG2 progenitor cells, polydendrocytes, synantocytes, NG2 cells, and NG2-Glia, but are more commonly referred to as oligodendrocyte progenitor cells. Characterized by high proliferation rates and unique morphology, NG2-expressing cells stand apart from neurons, astrocytes, and oligodendrocytes. Intriguingly, some NG2-expressing cells form functional glutamatergic synapses with neurons, challenging the long-held belief that only neurons possess the intricate machinery required for neurotransmission. In the CNS, the complexity surrounding NG2-expressing cells extends to their classification. Additionally, NG2 expression has been documented in pericytes and immune cells, suggesting a role in regulating brain innate immunity and neuro-immune crosstalk in homeostasis. Ongoing debates revolve around their heterogeneity, potential as progenitors for various cell types, responses to neuroinflammation, and the role of NG2. Therefore, this review aims to shed light on the enigma of NG2-expressing cells by delving into their structure, functions, and signaling pathways. We will critically evaluate the literature on NG2 expression across the CNS, and address the contentious issues surrounding their classification and roles in neuroinflammation and neurodegeneration. By unraveling the intricacies of NG2-expressing cells, we hope to pave the way for a more comprehensive understanding of their contributions to CNS health and during neurological disorders.
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Affiliation(s)
- Marta Bottero
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giada Pessina
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | | | - Tiziana Vigo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Antonio Uccelli
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
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Zveik O, Rechtman A, Ganz T, Vaknin-Dembinsky A. The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells. Mol Neurodegener 2024; 19:53. [PMID: 38997755 PMCID: PMC11245841 DOI: 10.1186/s13024-024-00742-8] [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: 05/29/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.
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Affiliation(s)
- Omri Zveik
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Ariel Rechtman
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Tal Ganz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel
| | - Adi Vaknin-Dembinsky
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Kerem P.O.B. 12000, Jerusalem, 91120, Israel.
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11
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Piscopo VEC, Chapleau A, Blaszczyk GJ, Sirois J, You Z, Soubannier V, Chen CXQ, Bernard G, Antel JP, Durcan TM. The use of a SOX10 reporter toward ameliorating oligodendrocyte lineage differentiation from human induced pluripotent stem cells. Glia 2024; 72:1165-1182. [PMID: 38497409 DOI: 10.1002/glia.24524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/01/2024] [Accepted: 03/04/2024] [Indexed: 03/19/2024]
Abstract
Oligodendrocytes (OLs) are key players in the central nervous system, critical for the formation and maintenance of the myelin sheaths insulating axons, ensuring efficient neuronal communication. In the last decade, the use of human induced pluripotent stem cells (iPSCs) has become essential for recapitulating and understanding the differentiation and role of OLs in vitro. Current methods include overexpression of transcription factors for rapid OL generation, neglecting the complexity of OL lineage development. Alternatively, growth factor-based protocols offer physiological relevance but struggle with efficiency and cell heterogeneity. To address these issues, we created a novel SOX10-P2A-mOrange iPSC reporter line to track and purify oligodendrocyte precursor cells. Using this reporter cell line, we analyzed an existing differentiation protocol and shed light on the origin of glial cell heterogeneity. Additionally, we have modified the differentiation protocol, toward enhancing reproducibility, efficiency, and terminal maturity. Our approach not only advances OL biology but also holds promise to accelerate research and translational work with iPSC-derived OLs.
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Affiliation(s)
- Valerio E C Piscopo
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Alexandra Chapleau
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Gabriela J Blaszczyk
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Julien Sirois
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Zhipeng You
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Vincent Soubannier
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Carol X-Q Chen
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Geneviève Bernard
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
- Department of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada
- Division of Medical Genetics, Department of Internal Medicine, McGill University Health Center, Montreal, Quebec, Canada
| | - Jack P Antel
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
- Neuroimmunology Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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12
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Mariani JN, Mansky B, Madsen PM, Salinas D, Kesmen D, Huynh NPT, Kuypers NJ, Kesel ER, Bates J, Payne C, Chandler-Militello D, Benraiss A, Goldman SA. Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells. Nat Commun 2024; 15:3873. [PMID: 38719882 PMCID: PMC11079006 DOI: 10.1038/s41467-024-48118-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.
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Affiliation(s)
- John N Mariani
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
| | - Benjamin Mansky
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Pernille M Madsen
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen, 2200, Denmark
| | - Dennis Salinas
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Deniz Kesmen
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Nguyen P T Huynh
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen, 2200, Denmark
| | - Nicholas J Kuypers
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Erin R Kesel
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Janna Bates
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Casey Payne
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Devin Chandler-Militello
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Abdellatif Benraiss
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
- Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen, 2200, Denmark.
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13
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Rogujski P, Lukomska B, Janowski M, Stanaszek L. Glial-restricted progenitor cells: a cure for diseased brain? Biol Res 2024; 57:8. [PMID: 38475854 DOI: 10.1186/s40659-024-00486-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
The central nervous system (CNS) is home to neuronal and glial cells. Traditionally, glia was disregarded as just the structural support across the brain and spinal cord, in striking contrast to neurons, always considered critical players in CNS functioning. In modern times this outdated dogma is continuously repelled by new evidence unravelling the importance of glia in neuronal maintenance and function. Therefore, glia replacement has been considered a potentially powerful therapeutic strategy. Glial progenitors are at the center of this hope, as they are the source of new glial cells. Indeed, sophisticated experimental therapies and exciting clinical trials shed light on the utility of exogenous glia in disease treatment. Therefore, this review article will elaborate on glial-restricted progenitor cells (GRPs), their origin and characteristics, available sources, and adaptation to current therapeutic approaches aimed at various CNS diseases, with particular attention paid to myelin-related disorders with a focus on recent progress and emerging concepts. The landscape of GRP clinical applications is also comprehensively presented, and future perspectives on promising, GRP-based therapeutic strategies for brain and spinal cord diseases are described in detail.
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Affiliation(s)
- Piotr Rogujski
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland
| | - Miroslaw Janowski
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
| | - Luiza Stanaszek
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106, Warsaw, Poland.
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14
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Hill RA, Nishiyama A, Hughes EG. Features, Fates, and Functions of Oligodendrocyte Precursor Cells. Cold Spring Harb Perspect Biol 2024; 16:a041425. [PMID: 38052500 PMCID: PMC10910408 DOI: 10.1101/cshperspect.a041425] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) are a central nervous system resident population of glia with a distinct molecular identity and an ever-increasing list of functions. OPCs generate oligodendrocytes throughout development and across the life span in most regions of the brain and spinal cord. This process involves a complex coordination of molecular checkpoints and biophysical cues from the environment that initiate the differentiation and integration of new oligodendrocytes that synthesize myelin sheaths on axons. Outside of their progenitor role, OPCs have been proposed to play other functions including the modulation of axonal and synaptic development and the participation in bidirectional signaling with neurons and other glia. Here, we review OPC identity and known functions and discuss recent findings implying other roles for these glial cells in brain physiology and pathology.
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Affiliation(s)
- Robert A Hill
- Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, USA
| | - Ethan G Hughes
- Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
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15
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Li Q, Liu S, Zheng T, Li M, Qi B, Zhou L, Liu B, Ma D, Zhao C, Chen Z. Grafted human-induced pluripotent stem cells-derived oligodendrocyte progenitor cells combined with human umbilical vein endothelial cells contribute to functional recovery following spinal cord injury. Stem Cell Res Ther 2024; 15:35. [PMID: 38321505 PMCID: PMC10848469 DOI: 10.1186/s13287-024-03651-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 01/29/2024] [Indexed: 02/08/2024] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a devastating disease that causes extensive damage to oligodendrocytes and neurons leading to demyelination and axonal degeneration. In this study, we co-transplanted cell grafts containing oligodendrocyte progenitor cells (OPCs) derived from human-induced pluripotent stem cells (iPSCs) combined with human umbilical vein endothelial cells (HUVECs), which were reported to promote OPCs survival and migration, into rat contusion models to promote functional recovery after SCI. METHODS OPCs were derived from iPSCs and identified by immunofluorescence at different time points. Functional assays in vitro were performed to evaluate the effect of HUVECs on the proliferation, migration, and survival of OPCs by co-culture and migration assay, as well as on the neuronal axonal growth. A combination of OPCs and HUVECs was transplanted into the rat contusive model. Upon 8 weeks, immunofluorescence staining was performed to test the safety of transplanted cells and to observe the neuronal repairment, myelination, and neural circuit reconstruction at the injured area; also, the functional recovery was assessed by Basso, Beattie, and Bresnahan open-field scale, Ladder climb, SEP, and MEP. Furthermore, the effect of HUVECs on grafts was also determined in vivo. RESULTS Data showed that HUVECs promote the proliferation, migration, and survival of OPCs both in vitro and in vivo. Furthermore, 8 weeks upon engraftment, the rats with OPCs and HUVECs co-transplantation noticeably facilitated remyelination, enhanced functional connection between the grafts and the host and promoted functional recovery. In addition, compared with the OPCs-alone transplantation, the co-transplantation generated more sensory neurons at the lesion border and significantly improved the sensory functional recovery. CONCLUSIONS Our study demonstrates that transplantation of OPCs combined with HUVECs significantly enhances both motor and sensory functional recovery after SCI. No significance was observed between OPCs combined with HUVECs group and OPCs-alone group in motor function recovery, while the sensory function recovery was significantly promoted in OPCs combined with HUVECs groups compared with the other two groups. These findings provide novel insights into the field of SCI research.
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Affiliation(s)
- Qian Li
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Sumei Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Tianqi Zheng
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Mo Li
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Boling Qi
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Liping Zhou
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Bochao Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China
| | - Dan Ma
- Translational Medicine Research Group (TMRG), Aston Medical School, Aston University, Birmingham, B4 7ET, UK
| | - Chao Zhao
- Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China.
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China.
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, 100069, China.
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16
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Janeckova L, Knotek T, Kriska J, Hermanova Z, Kirdajova D, Kubovciak J, Berkova L, Tureckova J, Camacho Garcia S, Galuskova K, Kolar M, Anderova M, Korinek V. Astrocyte-like subpopulation of NG2 glia in the adult mouse cortex exhibits characteristics of neural progenitor cells. Glia 2024; 72:245-273. [PMID: 37772368 DOI: 10.1002/glia.24471] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/30/2023]
Abstract
Glial cells expressing neuron-glial antigen 2 (NG2), also known as oligodendrocyte progenitor cells (OPCs), play a critical role in maintaining brain health. However, their ability to differentiate after ischemic injury is poorly understood. The aim of this study was to investigate the properties and functions of NG2 glia in the ischemic brain. Using transgenic mice, we selectively labeled NG2-expressing cells and their progeny in both healthy brain and after focal cerebral ischemia (FCI). Using single-cell RNA sequencing, we classified the labeled glial cells into five distinct subpopulations based on their gene expression patterns. Additionally, we examined the membrane properties of these cells using the patch-clamp technique. Of the identified subpopulations, three were identified as OPCs, whereas the fourth subpopulation had characteristics indicative of cells likely to develop into oligodendrocytes. The fifth subpopulation of NG2 glia showed astrocytic markers and had similarities to neural progenitor cells. Interestingly, this subpopulation was present in both healthy and post-ischemic tissue; however, its gene expression profile changed after ischemia, with increased numbers of genes related to neurogenesis. Immunohistochemical analysis confirmed the temporal expression of neurogenic genes and showed an increased presence of NG2 cells positive for Purkinje cell protein-4 at the periphery of the ischemic lesion 12 days after FCI, as well as NeuN-positive NG2 cells 28 and 60 days after injury. These results suggest the potential development of neuron-like cells arising from NG2 glia in the ischemic tissue. Our study provides insights into the plasticity of NG2 glia and their capacity for neurogenesis after stroke.
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Affiliation(s)
- Lucie Janeckova
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Tomas Knotek
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jan Kriska
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Hermanova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Denisa Kirdajova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Kubovciak
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Linda Berkova
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jana Tureckova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Sara Camacho Garcia
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Katerina Galuskova
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Michal Kolar
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Miroslava Anderova
- Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
| | - Vladimir Korinek
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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17
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Yugami M, Hayakawa-Yano Y, Ogasawara T, Yokoyama K, Furukawa T, Hara H, Hashikami K, Tsuji I, Takebayashi H, Araki S, Okano H, Yano M. Sbp2l contributes to oligodendrocyte maturation through translational control in Tcf7l2 signaling. iScience 2023; 26:108451. [PMID: 38213786 PMCID: PMC10783607 DOI: 10.1016/j.isci.2023.108451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/09/2023] [Accepted: 11/10/2023] [Indexed: 01/13/2024] Open
Abstract
Oligodendrocytes (OLs) are the myelin-forming cells in the CNS that support neurons through the insulating sheath of axons. This unique feature and developmental processes are achieved by extrinsic and intrinsic gene expression programs, where RNA-binding proteins can contribute to dynamic and fine-tuned post-transcriptional regulation. Here, we identified SECIS-binding protein 2-like (Sbp2l), which is specifically expressed in OLs by integrated transcriptomics. Histological analysis revealed that Sbp2l is a molecular marker of OL maturation. Sbp2l knockdown (KD) led to suppression of matured OL markers, but not a typical selenoprotein, Gpx4. Transcriptome analysis demonstrated that Sbp2l KD decreased cholesterol-biosynthesis-related genes regulated by Tcf7l2 transcription factor. Indeed, we confirmed the downregulation of Tcf7l2 protein without changing its mRNA in Sbp2l KD OPCs. Furthermore, Sbp2l KO mice showed the decrease of Tcf7l2 protein and deficiency of OL maturation. These results suggest that Sbp2l contributes to OL maturation by translational control of Tcf7l2.
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Affiliation(s)
- Masato Yugami
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Yoshika Hayakawa-Yano
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata, Niigata 951-8510, Japan
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takahisa Ogasawara
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Kazumasa Yokoyama
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Takako Furukawa
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata, Niigata 951-8510, Japan
| | - Hiroe Hara
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Kentaro Hashikami
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Isamu Tsuji
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Hirohide Takebayashi
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata, Niigata 951-8510, Japan
| | - Shinsuke Araki
- Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masato Yano
- Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachidori, Chuo-ku, Niigata, Niigata 951-8510, Japan
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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18
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Ganz T, Zveik O, Fainstein N, Lachish M, Rechtman A, Sofer L, Brill L, Ben-Hur T, Vaknin-Dembinsky A. Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS. Glia 2023; 71:2815-2831. [PMID: 37610097 DOI: 10.1002/glia.24453] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/23/2023] [Accepted: 07/24/2023] [Indexed: 08/24/2023]
Abstract
Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.
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Affiliation(s)
- Tal Ganz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Omri Zveik
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Nina Fainstein
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Marva Lachish
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel Rechtman
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Lihi Sofer
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Livnat Brill
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tamir Ben-Hur
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Adi Vaknin-Dembinsky
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
- The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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19
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Pfeiffer F. Commentary on: Bai, X., Zhao, N., Koupourtidou, C., Fang, L.-P., Schwarz, V., Caudal, L.C., Zhao, R., Hirrlinger, J., Walz, W., Bian, S., Huang, W., Ninkovic, J., Kirchhoff, F., Scheller, A. "In the mouse cortex, oligodendrocytes regain a plastic capacity, transforming into astrocytes after acute injury". Pflugers Arch 2023; 475:1129-1131. [PMID: 37522928 PMCID: PMC10499714 DOI: 10.1007/s00424-023-02846-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/01/2023]
Affiliation(s)
- Friederike Pfeiffer
- Department of Neurophysiology, Institute of Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany.
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20
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Xiao Y, Czopka T. Myelination-independent functions of oligodendrocyte precursor cells in health and disease. Nat Neurosci 2023; 26:1663-1669. [PMID: 37653126 DOI: 10.1038/s41593-023-01423-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/27/2023] [Indexed: 09/02/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) are a population of tissue-resident glial cells found throughout the CNS, constituting approximately 5% of all CNS cells and persisting from development to adulthood and aging. The canonical role of OPCs is to give rise to myelinating oligodendrocytes. However, additional functions of OPCs beyond this traditional role as precursors have been suggested for a long time. In this Perspective, we provide an overview of the multiple myelination-independent functions that have been described for OPCs in the context of neuron development, angiogenesis, inflammatory response, axon regeneration and their recently discovered roles in neural circuit remodeling.
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Affiliation(s)
- Yan Xiao
- Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany
| | - Tim Czopka
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
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21
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Zhu Y, Luan C, Gong L, Gu Y, Wang X, Sun H, Chen Z, Zhou Q, Liu C, Shan Q, Gu X, Zhou S. SnRNA-seq reveals the heterogeneity of spinal ventral horn and mechanism of motor neuron axon regeneration. iScience 2023; 26:107264. [PMID: 37502257 PMCID: PMC10368823 DOI: 10.1016/j.isci.2023.107264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 05/02/2023] [Accepted: 06/27/2023] [Indexed: 07/29/2023] Open
Abstract
Spinal motor neurons, the distinctive neurons of the central nervous system, extend into the peripheral nervous system and have outstanding ability of axon regeneration after injury. Here, we explored the heterogeneity of spinal ventral horn cells after rat sciatic nerve crush via single-nuclei RNA sequencing. Interestingly, regeneration mainly occurred in a Sncg+ and Anxa2+ motor neuron subtype (MN2) surrounded by a newly emerged microglia subtype (Mg6) after injury. Subsequently, microglia depletion slowed down the regeneration of sciatic nerve. OPCs were also involved into the regeneration process. Knockdown of Cacna2d2 in vitro and systemic blocking of Cacna2d2 in vivo improved the axon growth ability, hinting us the importance of Ca2+. Ultimately, we proposed three possible phases of motor neuron axon regeneration: preparation stage, early regeneration stage, and regeneration stage. Taken together, our study provided a resource for deciphering the underlying mechanism of motor neuron axon regeneration in a single cell dimension.
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Affiliation(s)
- Ye Zhu
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300000, China
| | - Chengcheng Luan
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300000, China
| | - Leilei Gong
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Yun Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Xinghui Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Zhifeng Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Qiang Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Chang Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Qi Shan
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300000, China
| | - Xiaosong Gu
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300000, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Songlin Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
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22
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López-Muguruza E, Matute C. Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis. Int J Mol Sci 2023; 24:12912. [PMID: 37629092 PMCID: PMC10454078 DOI: 10.3390/ijms241612912] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients.
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Affiliation(s)
- Eneritz López-Muguruza
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain;
- Department of Neurosciences, University of the Basque Country UPV/EHU, 48940 Leioa, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Carlos Matute
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain;
- Department of Neurosciences, University of the Basque Country UPV/EHU, 48940 Leioa, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
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23
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Werner L, Gliem M, Rychlik N, Pavic G, Reiche L, Kirchhoff F, Silva Oliveira Junior M, Gruchot J, Meuth SG, Küry P, Göttle P. A Novel Ex Vivo Model to Study Therapeutic Treatments for Myelin Repair following Ischemic Damage. Int J Mol Sci 2023; 24:10972. [PMID: 37446147 DOI: 10.3390/ijms241310972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Stroke is a major reason for persistent disability due to insufficient treatment strategies beyond reperfusion, leading to oligodendrocyte death and axon demyelination, persistent inflammation and astrogliosis in peri-infarct areas. After injury, oligodendroglial precursor cells (OPCs) have been shown to compensate for myelin loss and prevent axonal loss through the replacement of lost oligodendrocytes, an inefficient process leaving axons chronically demyelinated. Phenotypic screening approaches in demyelinating paradigms revealed substances that promote myelin repair. We established an ex vivo adult organotypic coronal slice culture (OCSC) system to study repair after stroke in a resource-efficient way. Post-photothrombotic OCSCs can be manipulated for 8 d by exposure to pharmacologically active substances testing remyelination activity. OCSCs were isolated from a NG2-CreERT2-td-Tomato knock-in transgenic mouse line to analyze oligodendroglial fate/differentiation and kinetics. Parbendazole boosted differentiation of NG2+ cells and stabilized oligodendroglial fate reflected by altered expression of associated markers PDGFR-α, CC1, BCAS1 and Sox10 and GFAP. In vitro scratch assay and chemical ischemia confirmed the observed effects upon parbendazole treatment. Adult OCSCs represent a fast, reproducible, and quantifiable model to study OPC differentiation competence after stroke. Pharmacological stimulation by means of parbendazole promoted OPC differentiation.
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Affiliation(s)
- Luisa Werner
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Michael Gliem
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Nicole Rychlik
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Goran Pavic
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Laura Reiche
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Frank Kirchhoff
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66424 Homburg, Germany
| | | | - Joel Gruchot
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Sven G Meuth
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Patrick Küry
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Peter Göttle
- Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
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24
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Bai X, Zhao N, Koupourtidou C, Fang LP, Schwarz V, Caudal LC, Zhao R, Hirrlinger J, Walz W, Bian S, Huang W, Ninkovic J, Kirchhoff F, Scheller A. In the mouse cortex, oligodendrocytes regain a plastic capacity, transforming into astrocytes after acute injury. Dev Cell 2023:S1534-5807(23)00192-2. [PMID: 37220747 DOI: 10.1016/j.devcel.2023.04.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 02/16/2023] [Accepted: 04/25/2023] [Indexed: 05/25/2023]
Abstract
Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6.
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Affiliation(s)
- Xianshu Bai
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany.
| | - Na Zhao
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Christina Koupourtidou
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Li-Pao Fang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Veronika Schwarz
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Laura C Caudal
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Renping Zhao
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Johannes Hirrlinger
- Carl-Ludwig-Institute for Physiology, Leipzig University, 04103 Leipzig, Germany; Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
| | - Wolfgang Walz
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany; Department of Psychiatry, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada
| | - Shan Bian
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 200092 Shanghai, China; Frontier Science Center for Stem Cell Research, Tongji University, 200092 Shanghai, China
| | - Wenhui Huang
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany
| | - Jovica Ninkovic
- Department of Cell Biology and Anatomy, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Institute of Stem Cell Research, Helmholtz Zentrum Munich, 85764 Neuherberg-Munich, Germany
| | - Frank Kirchhoff
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany; Experimental Research Center for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anja Scheller
- Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, 66421 Homburg, Germany.
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25
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Liu DD, He JQ, Sinha R, Eastman AE, Toland AM, Morri M, Neff NF, Vogel H, Uchida N, Weissman IL. Purification and characterization of human neural stem and progenitor cells. Cell 2023; 186:1179-1194.e15. [PMID: 36931245 PMCID: PMC10409303 DOI: 10.1016/j.cell.2023.02.017] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 11/06/2022] [Accepted: 02/10/2023] [Indexed: 03/18/2023]
Abstract
The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.
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Affiliation(s)
- Daniel Dan Liu
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA
| | - Joy Q He
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA
| | - Rahul Sinha
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA.
| | - Anna E Eastman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA
| | - Angus M Toland
- Department of Pathology, Stanford Medicine, Stanford, CA 94305, USA
| | | | | | - Hannes Vogel
- Department of Pathology, Stanford Medicine, Stanford, CA 94305, USA
| | - Nobuko Uchida
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford Medicine, Stanford, CA 94305, USA.
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26
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Trangle SS, Rosenberg T, Parnas H, Levy G, Bar E, Marco A, Barak B. In individuals with Williams syndrome, dysregulation of methylation in non-coding regions of neuronal and oligodendrocyte DNA is associated with pathology and cortical development. Mol Psychiatry 2023; 28:1112-1127. [PMID: 36577841 DOI: 10.1038/s41380-022-01921-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 12/03/2022] [Accepted: 12/12/2022] [Indexed: 12/29/2022]
Abstract
Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer-promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type-specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.
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Affiliation(s)
- Sari Schokoroy Trangle
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Tali Rosenberg
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel
| | - Hadar Parnas
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel
| | - Gilad Levy
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Ela Bar
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.,The School of Neurobiology, Biochemistry & Biophysics, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Asaf Marco
- Neuro-Epigenetics Laboratory, Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 7610001, Israel.
| | - Boaz Barak
- The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel. .,Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
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27
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Osorio MJ, Mariani JN, Zou L, Schanz SJ, Heffernan K, Cornwell A, Goldman SA. Glial progenitor cells of the adult human white and grey matter are contextually distinct. Glia 2023; 71:524-540. [PMID: 36334067 PMCID: PMC10100527 DOI: 10.1002/glia.24291] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 09/19/2022] [Accepted: 10/18/2022] [Indexed: 11/07/2022]
Abstract
Genomic analyses have revealed heterogeneity among glial progenitor cells (GPCs), but the compartment selectivity of human GPCs (hGPCs) is unclear. Here, we asked if GPCs of human grey and white brain matter are distinct in their architecture and associated gene expression. RNA profiling of NG2-defined hGPCs derived from adult human neocortex and white matter differed in their expression of genes involved in Wnt, NOTCH, BMP and TGFβ signaling, suggesting compartment-selective biases in fate and self-renewal. White matter hGPCs over-expressed the BMP antagonists BAMBI and CHRDL1, suggesting their tonic suppression of astrocytic fate relative to cortical hGPCs, whose relative enrichment of cytoskeletal genes presaged their greater morphological complexity. In human glial chimeric mice, cortical hGPCs assumed larger and more complex morphologies than white matter hGPCs, and both were more complex than their mouse counterparts. These findings suggest that human grey and white matter GPCs comprise context-specific pools with distinct functional biases.
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Affiliation(s)
- Maria Joana Osorio
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.,Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
| | - John N Mariani
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Lisa Zou
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Steven J Schanz
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Kate Heffernan
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Adam Cornwell
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.,Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
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28
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McCaughey-Chapman A, Connor B. Cell reprogramming for oligodendrocytes: A review of protocols and their applications to disease modeling and cell-based remyelination therapies. J Neurosci Res 2023; 101:1000-1028. [PMID: 36749877 DOI: 10.1002/jnr.25173] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/09/2023]
Abstract
Oligodendrocytes are a type of glial cells that produce a lipid-rich membrane called myelin. Myelin assembles into a sheath and lines neuronal axons in the brain and spinal cord to insulate them. This not only increases the speed and efficiency of nerve signal transduction but also protects the axons from damage and degradation, which could trigger neuronal cell death. Demyelination, which is caused by a loss of myelin and oligodendrocytes, is a prominent feature of many neurological conditions, including Multiple sclerosis (MS), spinal cord injuries (SCI), and leukodystrophies. Demyelination is followed by a time of remyelination mediated by the recruitment of endogenous oligodendrocyte precursor cells, their migration to the injury site, and differentiation into myelin-producing oligodendrocytes. Unfortunately, endogenous remyelination is not sufficient to overcome demyelination, which explains why there are to date no regenerative-based treatments for MS, SCI, or leukodystrophies. To better understand the role of oligodendrocytes and develop cell-based remyelination therapies, human oligodendrocytes have been derived from somatic cells using cell reprogramming. This review will detail the different cell reprogramming methods that have been developed to generate human oligodendrocytes and their applications to disease modeling and cell-based remyelination therapies. Recent developments in the field have seen the derivation of brain organoids from pluripotent stem cells, and protocols have been devised to incorporate oligodendrocytes within the organoids, which will also be reviewed.
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Affiliation(s)
- Amy McCaughey-Chapman
- Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Bronwen Connor
- Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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29
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Duncan GJ, Emery B. End of the road: Astrocyte endfeet regulate OPC migration and myelination. Neuron 2023; 111:139-141. [PMID: 36657394 DOI: 10.1016/j.neuron.2022.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) use the vasculature as a scaffold for their migration. In this issue of Neuron, Su et al. determine that astrocytic ensheathment of the vasculature mediates OPC detachment from blood vessels via the secretion of semaphorins, regulating the timing of oligodendrocyte differentiation.
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Affiliation(s)
- Greg J Duncan
- Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
| | - Ben Emery
- Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
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30
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Cvetanovic M, Gray M. Contribution of Glial Cells to Polyglutamine Diseases: Observations from Patients and Mouse Models. Neurotherapeutics 2023; 20:48-66. [PMID: 37020152 PMCID: PMC10119372 DOI: 10.1007/s13311-023-01357-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 04/07/2023] Open
Abstract
Neurodegenerative diseases are broadly characterized neuropathologically by the degeneration of vulnerable neuronal cell types in a specific brain region. The degeneration of specific cell types has informed on the various phenotypes/clinical presentations in someone suffering from these diseases. Prominent neurodegeneration of specific neurons is seen in polyglutamine expansion diseases including Huntington's disease (HD) and spinocerebellar ataxias (SCA). The clinical manifestations observed in these diseases could be as varied as the abnormalities in motor function observed in those who have Huntington's disease (HD) as demonstrated by a chorea with substantial degeneration of striatal medium spiny neurons (MSNs) or those with various forms of spinocerebellar ataxia (SCA) with an ataxic motor presentation primarily due to degeneration of cerebellar Purkinje cells. Due to the very significant nature of the degeneration of MSNs in HD and Purkinje cells in SCAs, much of the research has centered around understanding the cell autonomous mechanisms dysregulated in these neuronal cell types. However, an increasing number of studies have revealed that dysfunction in non-neuronal glial cell types contributes to the pathogenesis of these diseases. Here we explore these non-neuronal glial cell types with a focus on how each may contribute to the pathogenesis of HD and SCA and the tools used to evaluate glial cells in the context of these diseases. Understanding the regulation of supportive and harmful phenotypes of glia in disease could lead to development of novel glia-focused neurotherapeutics.
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Affiliation(s)
- Marija Cvetanovic
- Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, Minneapolis, USA
| | - Michelle Gray
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
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31
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Spatiotemporal dynamics of the cellular components involved in glial scar formation following spinal cord injury. Biomed Pharmacother 2022; 153:113500. [DOI: 10.1016/j.biopha.2022.113500] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/19/2022] [Accepted: 07/30/2022] [Indexed: 11/30/2022] Open
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32
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Beiter RM, Rivet-Noor C, Merchak AR, Bai R, Johanson DM, Slogar E, Sol-Church K, Overall CC, Gaultier A. Evidence for oligodendrocyte progenitor cell heterogeneity in the adult mouse brain. Sci Rep 2022; 12:12921. [PMID: 35902669 PMCID: PMC9334628 DOI: 10.1038/s41598-022-17081-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/20/2022] [Indexed: 12/25/2022] Open
Abstract
Oligodendrocyte progenitor cells (OPCs) account for approximately 5% of the adult brain and have been historically studied for their role in myelination. In the adult brain, OPCs maintain their proliferative capacity and ability to differentiate into oligodendrocytes throughout adulthood, even though relatively few mature oligodendrocytes are produced post-developmental myelination. Recent work has begun to demonstrate that OPCs likely perform multiple functions in both homeostasis and disease and can significantly impact behavioral phenotypes such as food intake and depressive symptoms. However, the exact mechanisms through which OPCs might influence brain function remain unclear. The first step in further exploration of OPC function is to profile the transcriptional repertoire and assess the heterogeneity of adult OPCs. In this work, we demonstrate that adult OPCs are transcriptionally diverse and separate into two distinct populations in the homeostatic brain. These two groups show distinct transcriptional signatures and enrichment of biological processes unique to individual OPC populations. We have validated these OPC populations using multiple methods, including multiplex RNA in situ hybridization and RNA flow cytometry. This study provides an important resource that profiles the transcriptome of adult OPCs and will provide a toolbox for further investigation into novel OPC functions.
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Affiliation(s)
- Rebecca M Beiter
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.,Graduate Program in Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Courtney Rivet-Noor
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.,Graduate Program in Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Andrea R Merchak
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.,Graduate Program in Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Robin Bai
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - David M Johanson
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Erica Slogar
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Katia Sol-Church
- Genome Analysis and Technology Core, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Christopher C Overall
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Alban Gaultier
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. .,Graduate Program in Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
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33
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Immediate Early Gene c-fos in the Brain: Focus on Glial Cells. Brain Sci 2022; 12:brainsci12060687. [PMID: 35741573 PMCID: PMC9221432 DOI: 10.3390/brainsci12060687] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/13/2022] Open
Abstract
The c-fos gene was first described as a proto-oncogene responsible for the induction of bone tumors. A few decades ago, activation of the protein product c-fos was reported in the brain after seizures and other noxious stimuli. Since then, multiple studies have used c-fos as a brain activity marker. Although it has been attributed to neurons, growing evidence demonstrates that c-fos expression in the brain may also include glial cells. In this review, we collect data showing that glial cells also express this proto-oncogene. We present evidence demonstrating that at least astrocytes, oligodendrocytes, and microglia express this immediate early gene (IEG). Unlike neurons, whose expression changes used to be associated with depolarization, glial cells seem to express the c-fos proto-oncogene under the influence of proliferation, differentiation, growth, inflammation, repair, damage, plasticity, and other conditions. The collected evidence provides a complementary view of c-fos as an activity marker and urges the introduction of the glial cell perspective into brain activity studies. This glial cell view may provide additional information related to the brain microenvironment that is difficult to obtain from the isolated neuron paradigm. Thus, it is highly recommended that detection techniques are improved in order to better differentiate the phenotypes expressing c-fos in the brain and to elucidate the specific roles of c-fos expression in glial cells.
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Innes JA, Lowe AS, Fonseca R, Aley N, El-Hassan T, Constantinou M, Lau J, Eddaoudi A, Marino S, Brandner S. Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment. J Transl Med 2022; 102:172-184. [PMID: 34782726 PMCID: PMC8784315 DOI: 10.1038/s41374-021-00695-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 11/09/2022] Open
Abstract
The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities.
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Affiliation(s)
- James A Innes
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Andrew S Lowe
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Raquel Fonseca
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Natasha Aley
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Tedani El-Hassan
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Myrianni Constantinou
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, E1 2AT, UK
| | - Joanne Lau
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK
| | - Ayad Eddaoudi
- Zayed Centre for Research Into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1DZ, UK
| | - Silvia Marino
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, E1 2AT, UK
| | - Sebastian Brandner
- Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK.
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35
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Tokumoto Y, Araki Y, Narizuka Y, Mizuno Y, Ohshima S, Mimura T. Induction of memory-like CD8+ T cells and CD4+ T cells from human naive T cells in culture. Clin Exp Immunol 2022; 207:95-103. [PMID: 35020828 PMCID: PMC8802181 DOI: 10.1093/cei/uxab012] [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: 05/29/2021] [Revised: 10/21/2021] [Accepted: 10/28/2021] [Indexed: 11/14/2022] Open
Abstract
Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here, we describe a method to produce human memory-like T cells from naive human T cells in culture. Using commercially available human T-cell differentiation kits, both purified naive CD8+ T cells and purified naive CD4+ T cells were activated via T-cell receptor signaling and appropriate cytokines for several days in culture. All the T-cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T-cell activators were added back. We could also induce memory-like T cells from naive human T cells without hypoxia, if we froze the activated T cells or prepared the naive T cells from chilled filter buffy coats.
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Affiliation(s)
| | - Yasuto Araki
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yusuke Narizuka
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Yosuke Mizuno
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Susumu Ohshima
- Biomedical Research Center, Saitama Medical University, Saitama, Japan
| | - Toshihide Mimura
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
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36
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Bloom MS, Orthmann-Murphy J, Grinspan JB. Motor Learning and Physical Exercise in Adaptive Myelination and Remyelination. ASN Neuro 2022; 14:17590914221097510. [PMID: 35635130 PMCID: PMC9158406 DOI: 10.1177/17590914221097510] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 11/17/2022] Open
Abstract
The idea that myelination is driven by both intrinsic and extrinsic cues has gained much traction in recent years. Studies have demonstrated that myelination occurs in an intrinsic manner during early development and continues through adulthood in an activity-dependent manner called adaptive myelination. Motor learning, the gradual acquisition of a specific novel motor skill, promotes adaptive myelination in both the healthy and demyelinated central nervous system (CNS). On the other hand, exercise, a physical activity that involves planned, structured and repetitive bodily movements that expend energy and benefits one's fitness, promotes remyelination in pathology, but it is less clear whether it promotes adaptive myelination in healthy subjects. Studies on these topics have also investigated whether the timing of motor learning or physical exercise is important for successful addition of myelin. Here we review our current understanding of the relationship of motor skill learning and physical exercise on myelination.
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Affiliation(s)
- Mara S. Bloom
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jennifer Orthmann-Murphy
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Judith B. Grinspan
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
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37
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Wilms C, Lepka K, Häberlein F, Edwards S, Felsberg J, Pudelko L, Lindenberg TT, Poschmann G, Qin N, Volbracht K, Prozorovski T, Meuth SG, Kahlert UD, Remke M, Aktas O, Reifenberger G, Bräutigam L, Odermatt B, Berndt C. Glutaredoxin 2 promotes SP-1-dependent CSPG4 transcription and migration of wound healing NG2 glia and glioma cells: Enzymatic Taoism. Redox Biol 2021; 49:102221. [PMID: 34952462 PMCID: PMC8715126 DOI: 10.1016/j.redox.2021.102221] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/04/2021] [Accepted: 12/20/2021] [Indexed: 01/11/2023] Open
Abstract
Redox regulation of specific cysteines via oxidoreductases of the thioredoxin family is increasingly being recognized as an important signaling pathway. Here, we demonstrate that the cytosolic isoform of the vertebrate-specific oxidoreductase Glutaredoxin 2 (Grx2c) regulates the redox state of the transcription factor SP-1 and thereby its binding affinity to both the promoter and an enhancer region of the CSPG4 gene encoding chondroitin sulfate proteoglycan nerve/glial antigen 2 (NG2). This leads to an increased number of NG2 glia during in vitro oligodendroglial differentiation and promotes migration of these wound healing cells. On the other hand, we found that the same mechanism also leads to increased invasion of glioma tumor cells. Using in vitro (human cell lines), ex vivo (mouse primary cells), and in vivo models (zebrafish), as well as glioblastoma patient tissue samples we provide experimental data highlighting the Yin and Yang of redox signaling in the central nervous system and the enzymatic Taoism of Grx2c.
CSPG4 promoter binding of the transcription factor SP-1 depends on glutaredoxin 2 Cytosolic glutaredoxin 2 promotes oligodendrocyte differentiation into NG2 glia Migration and wound healing capacity of NG2 glia is increased by glutaredoxin 2 Glutaredoxin 2 increases invasion of human glioblastoma cells in vitro and in vivo
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Affiliation(s)
- Christina Wilms
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Klaudia Lepka
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Felix Häberlein
- Institute for Anatomy, Medical Faculty, University Bonn, Germany
| | | | - Jörg Felsberg
- Institute of Neuropathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Linda Pudelko
- Zebrafish Core Facility, Karolinska Institute, Stockholm, Sweden
| | | | - Gereon Poschmann
- Institute of Molecular Medicine, Proteome Research, Medical Faculty and University Hospital Düsseldorf, HeinrichHeineUniversity Düsseldorf, Germany
| | - Nan Qin
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Pediatric Neuro-Oncogenomics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Katrin Volbracht
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Tim Prozorovski
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Sven G Meuth
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Ulf D Kahlert
- Molecular and Experimental Surgery, University Clinic for General, Visceral and Vascular Surgery, Otto-von-Guericke-University Magdeburg, Germany
| | - Marc Remke
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Pediatric Neuro-Oncogenomics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Orhan Aktas
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Guido Reifenberger
- Institute of Neuropathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Lars Bräutigam
- Zebrafish Core Facility, Karolinska Institute, Stockholm, Sweden
| | | | - Carsten Berndt
- Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.
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38
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Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease. Cells 2021; 10:cells10082045. [PMID: 34440814 PMCID: PMC8392301 DOI: 10.3390/cells10082045] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.
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Franklin RJM, Frisén J, Lyons DA. Revisiting remyelination: Towards a consensus on the regeneration of CNS myelin. Semin Cell Dev Biol 2021; 116:3-9. [PMID: 33082115 DOI: 10.1016/j.semcdb.2020.09.009] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022]
Abstract
The biology of CNS remyelination has attracted considerable interest in recent years because of its translational potential to yield regenerative therapies for the treatment of chronic and progressive demyelinating diseases such as multiple sclerosis (MS). Critical to devising myelin regenerative therapies is a detailed understanding of how remyelination occurs. The accepted dogma, based on animal studies, has been that the myelin sheaths of remyelination are made by oligodendrocytes newly generated from adult oligodendrocyte progenitor cells in a classical regenerative process of progenitor migration, proliferation and differentiation. However, recent human and a growing number of animal studies have revealed a second mode of remyelination in which mature oligodendrocytes surviving within an area of demyelination are able to regenerate new myelin sheaths. This discovery, while opening up new opportunities for therapeutic remyelination, has also raised the question of whether there are fundamental differences in myelin regeneration between humans and some of the species in which experimental remyelination studies are conducted. Here we review how this second mode of remyelination can be integrated into a wider and revised framework for understanding remyelination in which apparent species differences can be reconciled but that also raises important questions for future research.
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Affiliation(s)
- Robin J M Franklin
- Wellcome-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
| | - Jonas Frisén
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
| | - David A Lyons
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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40
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Hou J, Bi H, Ye Z, Huang W, Zou G, Zou X, Shi YS, Shen Y, Ma Q, Kirchhoff F, Hu Y, Chen G. Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System. J Neurosci 2021; 41:4976-4990. [PMID: 33972402 PMCID: PMC8197633 DOI: 10.1523/jneurosci.2455-19.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/30/2021] [Accepted: 04/28/2021] [Indexed: 11/21/2022] Open
Abstract
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.
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Affiliation(s)
- Jinxing Hou
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Huiru Bi
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Zhuoyang Ye
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Wenhui Huang
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany
| | - Gang Zou
- Department of General Surgery, Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Shenzhen, 518000, China
| | - Xiaochuan Zou
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Yun Stone Shi
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
| | - Ying Shen
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Quanhong Ma
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Second Affiliated Hospital, Soochow University, Suzhou, 215123, China
| | - Frank Kirchhoff
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany
| | - Yimin Hu
- Department of Anesthesiology, Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
| | - Guiquan Chen
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
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41
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Huang H, Rubenstein JL, Qiu M. Cracking the Codes of Cortical Glial Progenitors: Evidence for the Common Lineage of Astrocytes and Oligodendrocytes. Neurosci Bull 2021; 37:437-439. [PMID: 33847916 DOI: 10.1007/s12264-021-00675-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/25/2021] [Indexed: 11/30/2022] Open
Affiliation(s)
- Hao Huang
- Institute of Life Sciences, College of Life and Environmental Sciences, College of Basic Medical Science, Hangzhou Normal University, Hangzhou, 311121, China
| | - John L Rubenstein
- Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, 94158, USA.
| | - Mengsheng Qiu
- Institute of Life Sciences, College of Life and Environmental Sciences, College of Basic Medical Science, Hangzhou Normal University, Hangzhou, 311121, China.
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Zhang Y, Liu G, Guo T, Liang XG, Du H, Yang L, Bhaduri A, Li X, Xu Z, Zhang Z, Li Z, He M, Tsyporin J, Kriegstein AR, Rubenstein JL, Yang Z, Chen B. Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog. Cell Rep 2021; 30:4490-4504.e4. [PMID: 32234482 PMCID: PMC7197103 DOI: 10.1016/j.celrep.2020.03.027] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/07/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce γ-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs. Zhang et al. reveal that cortical radial glia-derived GSX2+ cells at the late embryonic stage are tri-potential intermediate progenitors, which give rise to a subset of cortical oligodendrocytes, astrocytes, and olfactory bulb interneurons. SHH signaling is crucial for the generation of GSX2+ cells by reducing GLI3R protein level.
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Affiliation(s)
- Yue Zhang
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Guoping Liu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Teng Guo
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaoyi G Liang
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Heng Du
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lin Yang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Aparna Bhaduri
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Xiaosu Li
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhejun Xu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhuangzhi Zhang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhenmeiyu Li
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Miao He
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jeremiah Tsyporin
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Arnold R Kriegstein
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - John L Rubenstein
- Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Zhengang Yang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Bin Chen
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
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Baldassarro VA, Flagelli A, Sannia M, Calzà L. Nuclear receptors and differentiation of oligodendrocyte precursor cells. VITAMINS AND HORMONES 2021; 116:389-407. [PMID: 33752826 DOI: 10.1016/bs.vh.2021.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Oligodendrocytes are the cells responsible for myelin formation during development and in adulthood, both for normal myelin turnover and myelin repair. These highly specialized cells derive from the oligodendrocyte precursor cells (OPCs), through a complex differentiation process involving genetic and epigenetic regulation mechanisms, which switch the phenotype from a migratory and replicative precursor to a mature post-mitotic cell. The process is regulated by a plethora of molecules, involving neurotransmitters, growth factors, hormones and other small molecules, and is mainly driven by nuclear receptors (NRs). NRs are transcription factors with heterogeneous ligand-dependent and independent actions which differ for the cell target, the responsive gene and the formation of NR homo- or heterodimers. This chapter highlights the role of NRs in regulating OPC differentiation, also in view of drug discovery strategies aimed at targeting pathological conditions which interfere with both developmental myelination and remyelination in adulthood.
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Affiliation(s)
- Vito Antonio Baldassarro
- Interdepartmental Center for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy.
| | - Alessandra Flagelli
- Interdepartmental Center for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
| | - Michele Sannia
- Interdepartmental Center for Industrial Research in Health Sciences and Technologies, University of Bologna, Bologna, Italy
| | - Laura Calzà
- Montecatone Rehabilitation Institute, Imola, Bologna, Italy; IRET Foundation, Ozzano Emilia, Bologna, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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44
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Akay LA, Effenberger AH, Tsai LH. Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function. Genes Dev 2021; 35:180-198. [PMID: 33526585 PMCID: PMC7849363 DOI: 10.1101/gad.344218.120] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Oligodendrocyte precursor cells (OPCs) are not merely a transitory progenitor cell type, but rather a distinct and heterogeneous population of glia with various functions in the developing and adult central nervous system. In this review, we discuss the fate and function of OPCs in the brain beyond their contribution to myelination. OPCs are electrically sensitive, form synapses with neurons, support blood-brain barrier integrity, and mediate neuroinflammation. We explore how sex and age may influence OPC activity, and we review how OPC dysfunction may play a primary role in numerous neurological and neuropsychiatric diseases. Finally, we highlight areas of future research.
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Affiliation(s)
- Leyla Anne Akay
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Audrey H Effenberger
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Li-Huei Tsai
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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45
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Zhang Z, Zhou H, Zhou J. Heterogeneity and Proliferative and Differential Regulators of NG2-glia in Physiological and Pathological States. Curr Med Chem 2021; 27:6384-6406. [PMID: 31333083 DOI: 10.2174/0929867326666190717112944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/12/2019] [Accepted: 06/20/2019] [Indexed: 12/16/2022]
Abstract
NG2-glia, also called Oligodendrocyte Precursor Cells (OPCs), account for approximately 5%-10% of the cells in the developing and adult brain and constitute the fifth major cell population in the central nervous system. NG2-glia express receptors and ion channels involved in rapid modulation of neuronal activities and signaling with neuronal synapses, which have functional significance in both physiological and pathological states. NG2-glia participate in quick signaling with peripheral neurons via direct synaptic touches in the developing and mature central nervous system. These distinctive glia perform the unique function of proliferating and differentiating into oligodendrocytes in the early developing brain, which is critical for axon myelin formation. In response to injury, NG2-glia can proliferate, migrate to the lesions, and differentiate into oligodendrocytes to form new myelin sheaths, which wrap around damaged axons and result in functional recovery. The capacity of NG2-glia to regulate their behavior and dynamics in response to neuronal activity and disease indicate their critical role in myelin preservation and remodeling in the physiological state and in repair in the pathological state. In this review, we provide a detailed summary of the characteristics of NG2-glia, including their heterogeneity, the regulators of their proliferation, and the modulators of their differentiation into oligodendrocytes.
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Affiliation(s)
- Zuo Zhang
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| | - Hongli Zhou
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
| | - Jiyin Zhou
- National Drug Clinical Trial Institution, the Second Affiliated Hospital, Army Medical University, Chongqing 400037, China
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46
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Du X, Zhang Z, Zhou H, Zhou J. Differential Modulators of NG2-Glia Differentiation into Neurons and Glia and Their Crosstalk. Cell Mol Neurobiol 2021; 41:1-15. [PMID: 32285247 PMCID: PMC11448640 DOI: 10.1007/s10571-020-00843-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/06/2020] [Indexed: 02/08/2023]
Abstract
As the fifth main cell population in the brain, NG2-glia are also known as oligodendrocyte precursor cells. NG2-glia express receptors and ion channels for fast modulation of neuronal activities and signaling with neuronal synapses, which are of functional significance in both physiological and pathological states. NG2-glia also participate in fast signaling with peripheral neurons via direct synaptic contacts in the brain. These distinctive glia have the unique capability of proliferating and differentiating into oligodendrocytes, which are critical for axonal myelination in the early developing brain. In neurodegenerative diseases, NG2-glia play an important role and undergo morphological modification, adapt the expression of their membrane receptors and ion channels, and display gene-modulated cell reprogramming and excitotoxicity-caused cell death. These modifications directly and indirectly influence populations of neurons and other glial cells. NG2-glia regulate their action and dynamics in response to neuronal behavior and disease, indicating a critical function to preserve and remodel myelin in physiological states and to repair it in pathological states. Here, we review in detail the differential modulators of NG2-glia into neurons and astrocytes, as well as interactions of NG2-glia with neurons, astrocytes, and microglia. We will also summarize a future potential exploitation of NG2-glia.
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Affiliation(s)
- Xiaohuang Du
- Department of Scientific Research, Army Medical University, Chongqing, 400037, China
| | - Zuo Zhang
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China
| | - Hongli Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China
| | - Jiyin Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, China.
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Gupta P, Furness SGB, Bittencourt L, Hare DL, Wookey PJ. Building the case for the calcitonin receptor as a viable target for the treatment of glioblastoma. Ther Adv Med Oncol 2020; 12:1758835920978110. [PMID: 33425026 PMCID: PMC7758865 DOI: 10.1177/1758835920978110] [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: 06/05/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022] Open
Abstract
Researchers are actively seeking novel targeted therapies for the brain tumour glioblastoma (GBM) as the mean survival is less than 15 months. Here we discuss the proposal that the calcitonin receptor (CT Receptor), expressed in 76-86% of patient biopsies, is expressed by both malignant glioma cells and putative glioma stem cells (GSCs), and therefore represents a potential therapeutic target. Forty-two per cent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines express CT Receptor protein. CT Receptors are widely expressed throughout the life cycle of organisms and in some instances promote apoptosis. Which of the common isoforms of the CT Receptor are predominantly expressed is currently unknown, but a functional response to cell stress of the insert-positive isoform is hypothesised. A model for resistant malignancies is one in which chemotherapy plays a direct role in activating quiescent stem cells for replacement of the tumour tissue hierarchy. The putative role that the CT Receptor plays in maintenance of quiescent cancer stem cells is discussed in view of the activation of the Notch-CT Receptor-collagen V axis in quiescent muscle (satellite) stem cells. The pharmacological CT response profiles of four of the HGG cell lines were reported. Both CT responders and non-responders were sensitive to an immunotoxin based on an anti-CT Receptor antibody. The CALCR mRNA exhibits alternative splicing commonly associated with cancer cells, which could result in the atypical pharmacology exhibited by CT non-responders and an explanation of tumour suppression. Due to the inherent instability of CALCR mRNA, analysis of CT Receptor protein in patient samples will lead to improved data for the expression of CT Receptor in GBM and other cancers, and an understanding of the role and activity of the splice variants. This knowledge will aid the effective targeting of this receptor for treatment of GBM.
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Affiliation(s)
- Pragya Gupta
- Department of Medicine (Austin Health, Heidelberg), University of Melbourne, Melbourne, Victoria, Australia
| | - Sebastian G B Furness
- Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University (Parkville), Victoria, Australia
| | - Lucas Bittencourt
- Department of Medicine (Austin Health, Heidelberg), University of Melbourne, Melbourne, Victoria, Australia
| | - David L Hare
- Department of Medicine (Austin Health, Heidelberg), University of Melbourne, Melbourne, Victoria, Australia
| | - Peter J Wookey
- Department of Medicine, University of Melbourne, Level 10, Lance Townsend Building, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia
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48
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Glioblastoma with a primitive neuroectodermal component: two cases with implications for glioblastoma cell-of-origin. Clin Imaging 2020; 73:139-145. [PMID: 33406475 DOI: 10.1016/j.clinimag.2020.10.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/22/2020] [Accepted: 10/17/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy, but much remains unknown about the histogenesis of these tumors. In the great majority of cases, GBM is a purely glial tumor but in rare cases the classic-appearing high-grade glioma component is admixed with regions of small round blue cells with neuronal immunophenotype, and these tumors have been defined in the WHO 2016 Classification as "glioblastoma with a primitive neuronal component." METHODS In this paper, we present two cases of GBM-PNC with highly divergent clinical courses, and review current theories for the GBM cell-of-origin. RESULTS AND CONCLUSIONS GBM-PNC likely arises from a cell type competent to give rise to glial or neuronal lineages. The thesis that GBM recapitulates to some extent normal neurodevelopmental cellular pathways is supported by molecular and clinical features of our two cases of GBM-PNC, but more work is needed to determine which cellular precursor gives rise to specific cases of GBM. GBM-PNC may have a dramatically altered clinical course compared to standard GBM and may benefit from specific lines of treatment.
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49
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Engrafted primary type-2 astrocytes improve the recovery of the nigrostriatal pathway in a rat model of Parkinson's disease. Mol Cell Biochem 2020; 476:619-631. [PMID: 33070275 DOI: 10.1007/s11010-020-03931-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/07/2020] [Indexed: 10/23/2022]
Abstract
Parkinson's disease (PD) is a disorder characterized by a progressive loss of the dopaminergic neurons in the substantia nigra and a depletion of the neurotransmitter dopamine in the striatum. Our published results indicate that fasciculation and elongation protein zeta-1 (FEZ1) plays a role in the astrocyte-mediated protection of dopamine neurons and regulation of the neuronal microenvironment during the progression of PD. In this study, we examined the effects of engrafted type-2 astrocytes (T2As) with high expression of FEZ1 on the improvement of the symptoms and functional reconstruction of PD rats. T2As were stereotactically transplanted into the striatum of rats with PD induced by 6-hydroxydopamine (6-OHDA). An examination of apomorphine (APO)-induced rotations was performed to evaluate dopamine neuron damage and motor functions. Remarkably, the grafted cells survived in the lesion environment for six weeks or longer after implantation. In addition, the transplantation of T2As decrease the average velocity and the duration time of the APO-induced rotations, and increase the actuation time, as measured in the rotation behavioural tests. In the substantia nigra, the transplantation of T2As reduced the PD-induced GFAP, TH and FEZ1 downregulation. The grafted cells exclusively migrated to other regions near the injection site in the striatum and differentiated into GFAP+ astrocytes or TH+ neurons. Furthermore, by detecting monoamine neurotransmitters through high-performance liquid chromatography, we found that the nigrostriatal pathway had been repaired to some extent. Taken together, these results suggest that engrafted T2As with high expression of FEZ1 improved the symptoms and functional reconstruction of PD rats, providing a theoretical basis for FEZ1 as a potential target and engraftment of T2As as a therapeutic strategy in the treatment of PD.
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50
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Martins-Macedo J, Lepore AC, Domingues HS, Salgado AJ, Gomes ED, Pinto L. Glial restricted precursor cells in central nervous system disorders: Current applications and future perspectives. Glia 2020; 69:513-531. [PMID: 33052610 DOI: 10.1002/glia.23922] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 12/27/2022]
Abstract
The crosstalk between glial cells and neurons represents an exceptional feature for maintaining the normal function of the central nervous system (CNS). Increasing evidence has revealed the importance of glial progenitor cells in adult neurogenesis, reestablishment of cellular pools, neuroregeneration, and axonal (re)myelination. Several types of glial progenitors have been described, as well as their potentialities for recovering the CNS from certain traumas or pathologies. Among these precursors, glial-restricted precursor cells (GRPs) are considered the earliest glial progenitors and exhibit tripotency for both Type I/II astrocytes and oligodendrocytes. GRPs have been derived from embryos and embryonic stem cells in animal models and have maintained their capacity for self-renewal. Despite the relatively limited knowledge regarding the isolation, characterization, and function of these progenitors, GRPs are promising candidates for transplantation therapy and reestablishment/repair of CNS functions in neurodegenerative and neuropsychiatric disorders, as well as in traumatic injuries. Herein, we review the definition, isolation, characterization and potentialities of GRPs as cell-based therapies in different neurological conditions. We briefly discuss the implications of using GRPs in CNS regenerative medicine and their possible application in a clinical setting. MAIN POINTS: GRPs are progenitors present in the CNS with differentiation potential restricted to the glial lineage. These cells have been employed in the treatment of a myriad of neurodegenerative and traumatic pathologies, accompanied by promising results, herein reviewed.
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Affiliation(s)
- Joana Martins-Macedo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Angelo C Lepore
- Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Helena S Domingues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Eduardo D Gomes
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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