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Li K, Zheng Y, Cai S, Fan Z, Yang J, Liu Y, Liang S, Song M, Du S, Qi L. The subventricular zone structure, function and implications for neurological disease. Genes Dis 2025; 12:101398. [PMID: 39935607 PMCID: PMC11810716 DOI: 10.1016/j.gendis.2024.101398] [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: 09/06/2023] [Revised: 05/28/2024] [Accepted: 07/28/2024] [Indexed: 02/13/2025] Open
Abstract
The subventricular zone (SVZ) is a region surrounding the lateral ventricles that contains neural stem cells and neural progenitor cells, which can proliferate and differentiate into various neural and glial cells. SVZ cells play important roles in neurological diseases like neurodegeneration, neural injury, and glioblastoma multiforme. Investigating the anatomy, structure, composition, physiology, disease associations, and related mechanisms of SVZ is significant for neural stem cell therapy and treatment/prevention of neurological disorders. However, challenges remain regarding the mechanisms regulating SVZ cell proliferation, differentiation, and migration, delivering cells to damaged areas, and immune responses. In-depth studies of SVZ functions and related therapeutic developments may provide new insights and approaches for treating brain injuries and degenerative diseases, as well as a scientific basis for neural stem cell therapy. This review summarizes research findings on SVZ and neurological diseases to provide references for relevant therapies.
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Affiliation(s)
- Kaishu Li
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Yin Zheng
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Shubing Cai
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Zhiming Fan
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Junyi Yang
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Yuanrun Liu
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Shengqi Liang
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Meihui Song
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Siyuan Du
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Ling Qi
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
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Cebrian-Silla A, Nascimento MA, Mancia W, Gonzalez-Granero S, Romero-Rodriguez R, Obernier K, Steffen DM, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Neural stem cell relay from B1 to B2 cells in the adult mouse ventricular-subventricular zone. Cell Rep 2025; 44:115264. [PMID: 40019835 PMCID: PMC11979704 DOI: 10.1016/j.celrep.2025.115264] [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: 08/05/2024] [Revised: 11/27/2024] [Accepted: 01/13/2025] [Indexed: 03/05/2025] Open
Abstract
Neurogenesis and gliogenesis continue in the ventricular-subventricular zone (V-SVZ) of the adult rodent brain. V-SVZ astroglial cells with apical contact with the ventricle (B1 cells) function as neural stem cells (NSCs). B1 cells sharply decline during early postnatal life; in contrast, neurogenesis decreases at a slower rate. Here, we show that a second population of astroglia (B2 cells) that do not contact the ventricle also function as NSCs in the adult mouse brain. B2 cell numbers increase postnatally, are sustained in adults, and decrease with aging. We reveal the transcriptomic profile of B1 and B2 cells and show that, like B1 cells, B2 cells can be quiescent or activated. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals that NSC function is progressively relayed from B1 to B2 progenitors helping explain how neurogenesis is maintained into adult life.
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Affiliation(s)
- Arantxa Cebrian-Silla
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
| | - Marcos Assis Nascimento
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Walter Mancia
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Susana Gonzalez-Granero
- BTELab, Research Foundation of the General University Hospital of Valencia, Valencia 46014, Spain
| | - Ricardo Romero-Rodriguez
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Kirsten Obernier
- Quantitative Biosciences Institute, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - David M Steffen
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Daniel A Lim
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Jose Manuel Garcia-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Paterna, 46980 Valencia, Spain
| | - Arturo Alvarez-Buylla
- Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
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3
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Marymonchyk A, Rodriguez-Aller R, Willis A, Beaupré F, Warsi S, Snapyan M, Clavet-Fournier V, Lavoie-Cardinal F, Kaplan DR, Miller FD, Saghatelyan A. Neural stem cell quiescence and activation dynamics are regulated by feedback input from their progeny under homeostatic and regenerative conditions. Cell Stem Cell 2025; 32:445-462.e9. [PMID: 39919748 DOI: 10.1016/j.stem.2025.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 11/03/2024] [Accepted: 01/02/2025] [Indexed: 02/09/2025]
Abstract
Life-long maintenance of stem cells implies that feedback mechanisms from the niche regulate their quiescence/activation dynamics. Here, in the mouse adult subventricular neural stem cell (NSC) niche, we charted a precise spatiotemporal map of functional responses in NSCs induced by multiple niche cells and used machine learning to predict NSC interactions with specific niche cell types. We revealed a feedback mechanism whereby the NSC proliferative state is directly repressed by transient amplifying cells (TAPs), their rapidly dividing progeny. NSC processes wrap around TAPs and display hotspots of Ca2+ activity at their points of contact, mediated by ephrin (Efn) signaling. The modulation of Efn signaling or TAP ablation altered the Ca2+ signature of NSCs, leading to their activation. In vivo optogenetic modulation of Ca2+ dynamics abrogated NSC activation and prevented niche replenishment. Thus, TAP-to-NSC feedback signaling controls stem cell quiescence and activation, providing a mechanism to maintain stem cell pools throughout life.
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Affiliation(s)
- Alina Marymonchyk
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Université Laval, Quebec City, QC, Canada
| | - Raquel Rodriguez-Aller
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Université Laval, Quebec City, QC, Canada
| | - Ashleigh Willis
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
| | - Frédéric Beaupré
- Université Laval, Quebec City, QC, Canada; CERVO Brain Research Center, Quebec City, QC, Canada
| | - Sareen Warsi
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Marina Snapyan
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Valérie Clavet-Fournier
- Université Laval, Quebec City, QC, Canada; CERVO Brain Research Center, Quebec City, QC, Canada
| | - Flavie Lavoie-Cardinal
- Université Laval, Quebec City, QC, Canada; CERVO Brain Research Center, Quebec City, QC, Canada
| | - David R Kaplan
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Program for Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Freda D Miller
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Program for Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Armen Saghatelyan
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
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Jaiswal C, Singh AK. Particulate matter exposure and its consequences on hippocampal neurogenesis and cognitive function in experimental models. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 363:125275. [PMID: 39515570 DOI: 10.1016/j.envpol.2024.125275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/30/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Exposure to air pollution is thought to cause millions of deaths globally each year. According to the Who 2018, approximately 7 million deaths annually are caused predominantly by noncommunicable diseases due to air pollution. Exposure to air particulate matter 2.5 (PM2.5) has been strongly associated with increased mortality and has significant effects on brain health. Air pollution, particularly ultrafine particulate matter, has emerged as a serious environmental concern with profound implications for human health. Studies in animal models have indicated that exposure to these pollutants during gestational development impacts prenatal and postnatal brain development. In particular, air pollution has been increasingly identified as a potential causative factor, as it affects neurogenesis in the brain's hippocampal region. The hippocampus is highly vulnerable to PM exposure, and any alteration in the structure or function of this region leads to various neurodevelopmental defects and neurodegenerative disorders via oxidative stress, microglial activation, neuronal death, and differential expression of genes. The neurogenesis process involves several steps, such as proliferation, differentiation, migration, synaptogenesis, and neuritogenesis. If any step of the neurogenesis process is hampered by environmental exposure or other factors, it can lead to neurodevelopmental defects, neurodegenerative disorders, and cognitive decline. One significant contributor to these alterations is air pollution, which ranks as the leading environmental risk factor worldwide. Some of the most common effects include oxidative stress, neuroinflammation, depressive behavior, altered cognitive processes, and microglial activation. This review explores how prenatal and postnatal PM exposure affects the hippocampal regions of the brain and the defects associated with exposure.
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Affiliation(s)
- Charu Jaiswal
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India
| | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576 104, India.
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Hillerer KM, Gimsa U. Adult neurogenesis and the microbiota-gut-brain axis in farm animals: underestimated and understudied parameters for improving welfare in livestock farming. Front Neurosci 2024; 18:1493605. [PMID: 39664450 PMCID: PMC11631930 DOI: 10.3389/fnins.2024.1493605] [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: 09/09/2024] [Accepted: 11/05/2024] [Indexed: 12/13/2024] Open
Abstract
Welfare in commercial livestock farming is becoming increasingly important in current agriculture research. Unfortunately, there is a lack of understanding about the neuronal mechanisms that underlie well-being on an individual level. Neuroplasticity in the hippocampus, the subventricular zone (SVZ), the olfactory bulb (OB) and the hypothalamus may be essential regulatory components in the context of farm animal behaviour and welfare that may be altered by providing environmental enrichment (EE). The importance of pre-and probiotics as a form of EE and the microbiota-gut-brain axis (MGBA) has come under the spotlight in the last 20 years, particularly in the contexts of research into stress and of stress resilience. However, it could also be an important regulatory system for animal welfare in livestock farming. This review aims to present a brief overview of the effects of EE on physiology and behaviour in farm animals and briefly discusses literature on behavioural flexibility, as well as inter-individual stress-coping styles and their relationship to animal welfare. Most importantly, we will summarise the literature on different forms of neural plasticity in farm animals, focusing on neurogenesis in various relevant brain regions. Furthermore, we will provide a brief outlook connecting these forms of neuroplasticity, stress, EE, the MGBA and welfare measures in modern livestock farming, concentrating on pigs.
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Affiliation(s)
- Katharina M. Hillerer
- Research Institute for Farm Animal Biology (FBN), Dummerstorf, Mecklenburg-Vorpommern, Germany
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6
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Chaker Z, Makarouni E, Doetsch F. The Organism as the Niche: Physiological States Crack the Code of Adult Neural Stem Cell Heterogeneity. Annu Rev Cell Dev Biol 2024; 40:381-406. [PMID: 38985883 DOI: 10.1146/annurev-cellbio-120320-040213] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Neural stem cells (NSCs) persist in the adult mammalian brain and are able to give rise to new neurons and glia throughout life. The largest stem cell niche in the adult mouse brain is the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles. Adult NSCs in the V-SVZ coexist in quiescent and actively proliferating states, and they exhibit a regionalized molecular identity. The importance of such spatial diversity is just emerging, as depending on their position within the niche, adult NSCs give rise to distinct subtypes of olfactory bulb interneurons and different types of glia. However, the functional relevance of stem cell heterogeneity in the V-SVZ is still poorly understood. Here, we put into perspective findings highlighting the importance of adult NSC diversity for brain plasticity, and how the body signals to brain stem cells in different physiological states to regulate their behavior.
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Affiliation(s)
- Zayna Chaker
- Biozentrum, University of Basel, Basel, Switzerland; , ,
| | | | - Fiona Doetsch
- Biozentrum, University of Basel, Basel, Switzerland; , ,
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Shen Y, Li T, Sun C, Cheng X, Chen Z, Wang G, Yang X. Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine. Cell Death Differ 2024; 31:1375-1388. [PMID: 38898232 PMCID: PMC11445561 DOI: 10.1038/s41418-024-01330-5] [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: 10/26/2023] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024] Open
Abstract
A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.
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Affiliation(s)
- Yao Shen
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Tingting Li
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Chengyang Sun
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xin Cheng
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhi Chen
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Guang Wang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Guangdong Second Provincial General Hospital, School of Medicine, Jinan University, Guangzhou, 510220, China.
| | - Xuesong Yang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, 510632, China.
- Clinical Research Center, Clifford Hospital, Guangzhou, 511496, China.
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8
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Vermaercke B, Iwata R, Wierda K, Boubakar L, Rodriguez P, Ditkowska M, Bonin V, Vanderhaeghen P. SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo. Neuron 2024; 112:3058-3068.e8. [PMID: 39111306 PMCID: PMC11446607 DOI: 10.1016/j.neuron.2024.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/31/2024] [Accepted: 07/10/2024] [Indexed: 09/28/2024]
Abstract
Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny is thought to be essential for the acquisition of advanced cognitive functions, which are typically altered in intellectual disability (ID) and autism spectrum disorders (ASDs). Human neuronal neoteny could be disrupted in some forms of ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation of human cortical neurons into the mouse brain to model SYNGAP1 haploinsufficiency, one of the most prevalent genetic causes of ID/ASDs. We find that SYNGAP1-deficient human neurons display strong acceleration of morphological and functional synaptic formation and maturation alongside disrupted synaptic plasticity. At the circuit level, SYNGAP1-haploinsufficient neurons display precocious acquisition of responsiveness to visual stimulation months ahead of time. Our findings indicate that SYNGAP1 is required cell autonomously for human neuronal neoteny, providing novel links between human-specific developmental mechanisms and ID/ASDs.
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Affiliation(s)
- Ben Vermaercke
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences & Leuven Brain Institute, 3000 Leuven, Belgium
| | - Ryohei Iwata
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences & Leuven Brain Institute, 3000 Leuven, Belgium
| | - Keimpe Wierda
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Electrophysiology Unit, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | - Leïla Boubakar
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences & Leuven Brain Institute, 3000 Leuven, Belgium
| | - Paula Rodriguez
- Neuro-Electronics Research Flanders, Kapeldreef 75, 3001 Leuven, Belgium; Electrophysiology Unit, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; imec, 3001 Leuven, Belgium
| | - Martyna Ditkowska
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences & Leuven Brain Institute, 3000 Leuven, Belgium
| | - Vincent Bonin
- Neuro-Electronics Research Flanders, Kapeldreef 75, 3001 Leuven, Belgium; Department of Biology, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium; imec, 3001 Leuven, Belgium.
| | - Pierre Vanderhaeghen
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences & Leuven Brain Institute, 3000 Leuven, Belgium.
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Yoshida R, Mori T. Morphological classification of radial glia-like cells in the postnatal mouse subventricular zone. Eur J Neurosci 2024; 60:5156-5168. [PMID: 39126378 DOI: 10.1111/ejn.16503] [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: 02/12/2024] [Revised: 06/04/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024]
Abstract
The subventricular zone (SVZ) is one of the neurogenic regions of the adult mammalian brain. Neural stem cells (NSCs) in the SVZ have certain key features: they express glial fibrillary acidic protein (GFAP), proliferate slowly, have a radial glia-like (RG-L) morphology, and are in contact with the cerebrospinal fluid (CSF). NSCs have been isolated by FACS to analyse them, but their morphology has not been systematically examined. To address this knowledge gap, we sparsely labelled RG-L cells in the SVZ of neonatal mice by introducing via electroporation a plasmid expressing fluorescent protein under the control of the GFAP promoter. We then classified RG-L cells into three types (RG-L1, 2, and 3) based on their morphologies. RG-L1 cells had a basal process with some branches and numerous fine processes. RG-L2 cells had a basal process, but fewer branches and fine processes than RG-L1 cells. RG-L3 cells had one basal process that was almost free of branches and fine processes. Importantly, regardless of the cell type, about half of their somata resided on the basal side of the SVZ. Based on changes in their proportions during postnatal development and their expression of GFAP and cell proliferation markers at the adult stage, we speculated that NSCs change their morphologies during development/maturation and not all NSCs must always be in the apical SVZ or in contact with the CSF. Our results indicate that in addition to expression of markers for NSCs, the morphology is a critical feature to identify NSCs.
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Affiliation(s)
- Ryota Yoshida
- Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Tetsuji Mori
- Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan
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10
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Cebrian-Silla A, Assis Nascimento M, Mancia W, Gonzalez-Granero S, Romero-Rodriguez R, Obernier K, Steffen DM, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Neural Stem Cell Relay from B1 to B2 cells in the adult mouse Ventricular-Subventricular Zone. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.28.600695. [PMID: 39005355 PMCID: PMC11244865 DOI: 10.1101/2024.06.28.600695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Neurogenesis and gliogenesis continue in the Ventricular-Subventricular Zone (V-SVZ) of the adult rodent brain. B1 cells are astroglial cells derived from radial glia that function as primary progenitors or neural stem cells (NSCs) in the V-SVZ. B1 cells, which have a small apical contact with the ventricle, decline in numbers during early postnatal life, yet neurogenesis continues into adulthood. Here we found that a second population of V-SVZ astroglial cells (B2 cells), that do not contact the ventricle, function as NSCs in the adult brain. B2 cell numbers increase postnatally, remain constant in 12-month-old mice and decrease by 18 months. Transcriptomic analysis of ventricular-contacting and non-contacting B cells revealed key molecular differences to distinguish B1 from B2 cells. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals how NSC function is relayed from B1 to B2 progenitors to maintain adult neurogenesis.
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11
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Garone C, De Giorgio F, Carli S. Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases. J Transl Med 2024; 22:238. [PMID: 38438847 PMCID: PMC10910780 DOI: 10.1186/s12967-024-05041-w] [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: 12/29/2023] [Accepted: 02/25/2024] [Indexed: 03/06/2024] Open
Abstract
Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during neural development and maintenance.During embryonic and adult neurogenesis, NSCs undergo a metabolic switch from glycolytic to oxidative phosphorylation with a rise in mitochondrial DNA (mtDNA) content, changes in mitochondria shape and size, and a physiological augmentation of mitochondrial reactive oxygen species which together drive NSCs to proliferate and differentiate. Genetic and epigenetic modifications of proteins involved in cellular differentiation (Mechanistic Target of Rapamycin), proliferation (Wingless-type), and hypoxia (Mitogen-activated protein kinase)-and all connected by the common key regulatory factor Hypoxia Inducible Factor-1A-are deemed to be responsible for the metabolic shift and, consequently, NSC fate in physiological and pathological conditions.Both primary mitochondrial dysfunction due to mutations in nuclear DNA or mtDNA or secondary mitochondrial dysfunction in oxidative phosphorylation (OXPHOS) metabolism, mitochondrial dynamics, and organelle interplay pathways can contribute to the development of neurodevelopmental or progressive neurodegenerative disorders.This review analyses the physiology and pathology of neural development starting from the available in vitro and in vivo models and highlights the current knowledge concerning key mitochondrial pathways involved in this process.
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Affiliation(s)
- C Garone
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
- IRCCS Istituto Delle Scienze Neurologiche di Bologna, UO Neuropsichiatria Dell'età Pediatrica, Bologna, Italy.
| | - F De Giorgio
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - S Carli
- Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy
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12
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Mahmoudi N, Wang Y, Moriarty N, Ahmed NY, Dehorter N, Lisowski L, Harvey AR, Parish CL, Williams RJ, Nisbet DR. Neuronal Replenishment via Hydrogel-Rationed Delivery of Reprogramming Factors. ACS NANO 2024; 18:3597-3613. [PMID: 38221746 DOI: 10.1021/acsnano.3c11337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
The central nervous system's limited capacity for regeneration often leads to permanent neuronal loss following injury. Reprogramming resident reactive astrocytes into induced neurons at the site of injury is a promising strategy for neural repair, but challenges persist in stabilizing and accurately targeting viral vectors for transgene expression. In this study, we employed a bioinspired self-assembling peptide (SAP) hydrogel for the precise and controlled release of a hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1 neural reprogramming transgene. This method effectively mitigates the issues of high viral dosage at the target site, off-target delivery, and immunogenic reactions, enhancing the vector's targeting and reprogramming efficiency. In vitro, this vector successfully induced neuron formation, as confirmed by morphological, histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation of reactive host astrocytes into induced neurons, concurrently reducing glial scarring. Our findings introduce a safe and effective method for treating central nervous system injuries, marking a significant advancement in regenerative neuroscience.
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Affiliation(s)
- Negar Mahmoudi
- Laboratory of Advanced Biomaterials, the John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
- ANU College of Engineering & Computer Science, Acton, ACT 2601, Australia
| | - Yi Wang
- The Graeme Clark Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Niamh Moriarty
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
| | - Noorya Y Ahmed
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia
- The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Nathalie Dehorter
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia
- The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Leszek Lisowski
- Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
- Vector and Genome Engineering Facility, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
- Australian Genome Therapeutics Centre, Children's Medical Research Institute and Sydney Children's Hospitals Network, Westmead, NSW 2145, Australia
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland
| | - Alan R Harvey
- School of Human Sciences, The University of Western Australia, and Perron Institute for Neurological and Translational Science, Perth, WA 6009, Australia
| | - Clare L Parish
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
| | - Richard J Williams
- The Graeme Clark Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
- IMPACT, School of Medicine, Deakin University, Geelong, VIC 3217, Australia
| | - David R Nisbet
- Laboratory of Advanced Biomaterials, the John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia
- The Graeme Clark Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC 3010, Australia
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13
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Salmina AB, Alexandrova OP, Averchuk AS, Korsakova SA, Saridis MR, Illarioshkin SN, Yurchenko SO. Current progress and challenges in the development of brain tissue models: How to grow up the changeable brain in vitro? J Tissue Eng 2024; 15:20417314241235527. [PMID: 38516227 PMCID: PMC10956167 DOI: 10.1177/20417314241235527] [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: 09/25/2023] [Accepted: 02/12/2024] [Indexed: 03/23/2024] Open
Abstract
In vitro modeling of brain tissue is a promising but not yet resolved problem in modern neurobiology and neuropharmacology. Complexity of the brain structure and diversity of cell-to-cell communication in (patho)physiological conditions make this task almost unachievable. However, establishment of novel in vitro brain models would ultimately lead to better understanding of development-associated or experience-driven brain plasticity, designing efficient approaches to restore aberrant brain functioning. The main goal of this review is to summarize the available data on methodological approaches that are currently in use, and to identify the most prospective trends in development of neurovascular unit, blood-brain barrier, blood-cerebrospinal fluid barrier, and neurogenic niche in vitro models. The manuscript focuses on the regulation of adult neurogenesis, cerebral microcirculation and fluids dynamics that should be reproduced in the in vitro 4D models to mimic brain development and its alterations in brain pathology. We discuss approaches that are critical for studying brain plasticity, deciphering the individual person-specific trajectory of brain development and aging, and testing new drug candidates in the in vitro models.
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Affiliation(s)
- Alla B Salmina
- Brain Science Institute, Research Center of Neurology, Moscow, Russia
- Bauman Moscow State Technical University, Moscow, Russia
| | - Olga P Alexandrova
- Brain Science Institute, Research Center of Neurology, Moscow, Russia
- Bauman Moscow State Technical University, Moscow, Russia
| | - Anton S Averchuk
- Brain Science Institute, Research Center of Neurology, Moscow, Russia
- Bauman Moscow State Technical University, Moscow, Russia
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14
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Benedetti B, Reisinger M, Hochwartner M, Gabriele G, Jakubecova D, Benedetti A, Bonfanti L, Couillard‐Despres S. The awakening of dormant neuronal precursors in the adult and aged brain. Aging Cell 2023; 22:e13974. [PMID: 37649323 PMCID: PMC10726842 DOI: 10.1111/acel.13974] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023] Open
Abstract
Beyond the canonical neurogenic niches, there are dormant neuronal precursors in several regions of the adult mammalian brain. Dormant precursors maintain persisting post-mitotic immaturity from birth to adulthood, followed by staggered awakening, in a process that is still largely unresolved. Strikingly, due to the slow rate of awakening, some precursors remain immature until old age, which led us to question whether their awakening and maturation are affected by aging. To this end, we studied the maturation of dormant precursors in transgenic mice (DCX-CreERT2 /flox-EGFP) in which immature precursors were labelled permanently in vivo at different ages. We found that dormant precursors are capable of awakening at young age, becoming adult-matured neurons (AM), as well as of awakening at old age, becoming late AM. Thus, protracted immaturity does not prevent late awakening and maturation. However, late AM diverged morphologically and functionally from AM. Moreover, AM were functionally most similar to neonatal-matured neurons (NM). Conversely, late AM were endowed with high intrinsic excitability and high input resistance, and received a smaller amount of spontaneous synaptic input, implying their relative immaturity. Thus, late AM awakening still occurs at advanced age, but the maturation process is slow.
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Affiliation(s)
- Bruno Benedetti
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Maximilian Reisinger
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Marie Hochwartner
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Gabriele Gabriele
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Dominika Jakubecova
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Ariane Benedetti
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Luca Bonfanti
- Neuroscience Institute Cavalieri Ottolenghi (NICO)OrbassanoItaly
- Department of Veterinary SciencesUniversity of TurinTorinoItaly
| | - Sebastien Couillard‐Despres
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
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15
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Zaki ZMM, Kuroda A, Morimura N, Hayashi Y, Hitoshi S. Depletion of transit amplifying cells in the adult brain does not affect quiescent neural stem cell pool size. J Physiol Sci 2023; 73:19. [PMID: 37704979 PMCID: PMC10717051 DOI: 10.1186/s12576-023-00876-2] [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: 06/15/2023] [Accepted: 09/04/2023] [Indexed: 09/15/2023]
Abstract
Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal's lifespan. NSCs in the subependymal zone infrequently divide and generate transit amplifying cells, which are destined to become olfactory bulb neurons. When transit amplifying cells are depleted, they are replenished by the quiescent NSC pool. However, the cellular basis for this recovery process remains largely unknown. In this study, we traced NSCs and their progeny after transit amplifying cells were eliminated by intraventricular infusion of cytosine β-D-arabinofuranoside. We found that although the number of neurosphere-forming NSCs decreased shortly after the treatment, they were restored to normal levels 3 weeks after the cessation of treatment. More importantly, the depletion of transit amplifying cells did not induce a significant expansion of the NSC pool by symmetric divisions. Our data suggest that the size of the NSC pool is hardly affected by brain damage due to antimitotic drug treatment.
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Affiliation(s)
- Zakiyyah Munirah Mohd Zaki
- Department of Integrative Physiology, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Anri Kuroda
- Department of Integrative Physiology, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
- Department of Ophthalmology, Shiga University of Medical Science, Otsu, Japan
| | - Naoko Morimura
- Department of Integrative Physiology, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Yoshitaka Hayashi
- Department of Integrative Physiology, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Seiji Hitoshi
- Department of Integrative Physiology, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan.
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16
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Echeverria V, Mendoza C, Iarkov A. Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases. Front Neurosci 2023; 17:1179611. [PMID: 37255751 PMCID: PMC10225599 DOI: 10.3389/fnins.2023.1179611] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/07/2023] [Indexed: 06/01/2023] Open
Abstract
Animal survival depends on cognitive abilities such as learning and memory to adapt to environmental changes. Memory functions require an enhanced activity and connectivity of a particular arrangement of engram neurons, supported by the concerted action of neurons, glia, and vascular cells. The deterioration of the cholinergic system is a common occurrence in neurological conditions exacerbated by aging such as traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), Alzheimer's disease (AD), and Parkinson's disease (PD). Cotinine is a cholinergic modulator with neuroprotective, antidepressant, anti-inflammatory, antioxidant, and memory-enhancing effects. Current evidence suggests Cotinine's beneficial effects on cognition results from the positive modulation of the α7-nicotinic acetylcholine receptors (nAChRs) and the inhibition of the toll-like receptors (TLRs). The α7nAChR affects brain functions by modulating the function of neurons, glia, endothelial, immune, and dendritic cells and regulates inhibitory and excitatory neurotransmission throughout the GABA interneurons. In addition, Cotinine acting on the α7 nAChRs and TLR reduces neuroinflammation by inhibiting the release of pro-inflammatory cytokines by the immune cells. Also, α7nAChRs stimulate signaling pathways supporting structural, biochemical, electrochemical, and cellular changes in the Central nervous system during the cognitive processes, including Neurogenesis. Here, the mechanisms of memory formation as well as potential mechanisms of action of Cotinine on memory preservation in aging and neurological diseases are discussed.
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Affiliation(s)
- Valentina Echeverria
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile
- Research and Development Department, Bay Pines VAHCS, Bay Pines, FL, United States
| | - Cristhian Mendoza
- Facultad de Odontologia y Ciencias de la Rehabilitacion, Universidad San Sebastián, Concepción, Chile
| | - Alex Iarkov
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Concepción, Chile
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17
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Danciu DP, Hooli J, Martin-Villalba A, Marciniak-Czochra A. Mathematics of neural stem cells: Linking data and processes. Cells Dev 2023; 174:203849. [PMID: 37179018 DOI: 10.1016/j.cdev.2023.203849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
Adult stem cells are described as a discrete population of cells that stand at the top of a hierarchy of progressively differentiating cells. Through their unique ability to self-renew and differentiate, they regulate the number of end-differentiated cells that contribute to tissue physiology. The question of how discrete, continuous, or reversible the transitions through these hierarchies are and the precise parameters that determine the ultimate performance of stem cells in adulthood are the subject of intense research. In this review, we explain how mathematical modelling has improved the mechanistic understanding of stem cell dynamics in the adult brain. We also discuss how single-cell sequencing has influenced the understanding of cell states or cell types. Finally, we discuss how the combination of single-cell sequencing technologies and mathematical modelling provides a unique opportunity to answer some burning questions in the field of stem cell biology.
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Affiliation(s)
- Diana-Patricia Danciu
- Heidelberg University, Institute of Mathematics (IMA), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany; Interdisciplinary Center for Scientific Computing (IWR), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany
| | - Jooa Hooli
- Heidelberg University, Institute of Mathematics (IMA), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany; Interdisciplinary Center for Scientific Computing (IWR), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany; Heidelberg University, Faculty of Biosciences, Im Neuenheimer Feld 234, 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Ana Martin-Villalba
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Anna Marciniak-Czochra
- Heidelberg University, Institute of Mathematics (IMA), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany; Interdisciplinary Center for Scientific Computing (IWR), Im Neuenheimer Feld 205, 69120 Heidelberg, Germany.
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18
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Genet N, Genet G, Chavkin NW, Paila U, Fang JS, Vasavada HH, Goldberg JS, Acharya BR, Bhatt NS, Baker K, McDonnell SP, Huba M, Sankaranarayanan D, Ma GZM, Eichmann A, Thomas JL, Ffrench-Constant C, Hirschi KK. Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone. Cell Rep 2023; 42:112371. [PMID: 37043357 PMCID: PMC10564973 DOI: 10.1016/j.celrep.2023.112371] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 02/20/2023] [Accepted: 03/22/2023] [Indexed: 04/13/2023] Open
Abstract
The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and in vitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders.
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Affiliation(s)
- Nafiisha Genet
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
| | - Gael Genet
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Nicholas W Chavkin
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Umadevi Paila
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Jennifer S Fang
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Hema H Vasavada
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Joshua S Goldberg
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Bipul R Acharya
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Neha S Bhatt
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Kasey Baker
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Stephanie P McDonnell
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Mahalia Huba
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Danya Sankaranarayanan
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Gerry Z M Ma
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | - Anne Eichmann
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Jean-Leon Thomas
- Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Charles Ffrench-Constant
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | - Karen K Hirschi
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
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19
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Otsuka K, Iwasaki T. Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. Int J Radiat Biol 2023; 99:1503-1521. [PMID: 36971595 DOI: 10.1080/09553002.2023.2194398] [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: 05/05/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. METHODS We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. RESULTS Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. CONCLUSIONS We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
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Affiliation(s)
- Kensuke Otsuka
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
| | - Toshiyasu Iwasaki
- Strategy and Planning Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
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20
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Xing YL, Poh J, Chuang BH, Moradi K, Mitew S, Richardson WD, Kilpatrick TJ, Osanai Y, Merson TD. High-efficiency pharmacogenetic ablation of oligodendrocyte progenitor cells in the adult mouse CNS. CELL REPORTS METHODS 2023; 3:100414. [PMID: 36936074 PMCID: PMC10014347 DOI: 10.1016/j.crmeth.2023.100414] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 10/11/2022] [Accepted: 01/30/2023] [Indexed: 03/02/2023]
Abstract
Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent CNS have limitations in the extent and duration of OPC depletion. We have developed a pharmacogenetic approach for conditional OPC ablation, eliminating >98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+ cells with the capacity to proliferate and migrate extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease.
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Affiliation(s)
- Yao Lulu Xing
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
| | - Jasmine Poh
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
| | - Bernard H.A. Chuang
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
| | - Kaveh Moradi
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Stanislaw Mitew
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
| | - William D. Richardson
- Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK
| | - Trevor J. Kilpatrick
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia
| | - Yasuyuki Osanai
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
| | - Tobias D. Merson
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
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21
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Norton ES, Whaley LA, Ulloa-Navas MJ, García-Tárraga P, Meneses KM, Lara-Velazquez M, Zarco N, Carrano A, Quiñones-Hinojosa A, García-Verdugo JM, Guerrero-Cázares H. Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone. Fluids Barriers CNS 2022; 19:58. [PMID: 35821139 PMCID: PMC9277938 DOI: 10.1186/s12987-022-00354-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/27/2022] [Indexed: 12/04/2022] Open
Abstract
Background Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer. Methods Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. Results We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells. Conclusions Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM. Supplementary Information The online version contains supplementary material available at 10.1186/s12987-022-00354-8.
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Affiliation(s)
- Emily S Norton
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.,Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA.,Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.,Department of Biology, University of North Florida, Jacksonville, FL, USA
| | - María José Ulloa-Navas
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain.,Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Patricia García-Tárraga
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain
| | - Kayleah M Meneses
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.,Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | | | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Anna Carrano
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | | | - José Manuel García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain
| | - Hugo Guerrero-Cázares
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
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22
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Endogenous Neural Stem Cell Mediated Oligodendrogenesis in the Adult Mammalian Brain. Cells 2022; 11:cells11132101. [PMID: 35805185 PMCID: PMC9265817 DOI: 10.3390/cells11132101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 02/08/2023] Open
Abstract
Oligodendrogenesis is essential for replacing worn-out oligodendrocytes, promoting myelin plasticity, and for myelin repair following a demyelinating injury in the adult mammalian brain. Neural stem cells are an important source of oligodendrocytes in the adult brain; however, there are considerable differences in oligodendrogenesis from neural stem cells residing in different areas of the adult brain. Amongst the distinct niches containing neural stem cells, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are considered the principle areas of adult neurogenesis. In addition to these areas, radial glia-like cells, which are the precursors of neural stem cells, are found in the lining of the third ventricle, where they are called tanycytes, and in the cerebellum, where they are called Bergmann glia. In this review, we will describe the contribution and regulation of each of these niches in adult oligodendrogenesis.
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23
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Gujar MR, Wang H. A fly's eye view of quiescent neural stem cells. OXFORD OPEN NEUROSCIENCE 2022; 1:kvac001. [PMID: 38596705 PMCID: PMC10913722 DOI: 10.1093/oons/kvac001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 04/11/2024]
Abstract
The balance between proliferation and quiescence of stem cells is crucial in maintaining tissue homeostasis. Neural stem cells (NSCs) in the brain have the ability to be reactivated from a reversible quiescent state to generate new neurons. However, how NSCs transit between quiescence and reactivation remains largely elusive. Drosophila larval brain NSCs, also known as neuroblasts, have emerged as an excellent in vivo model to study molecular mechanisms underlying NSC quiescence and reactivation. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs in Drosophila. We review the most recent advances on epigenetic regulations and microtubule cytoskeleton in Drosophila quiescent NSCs and their cross-talk with signaling pathways that are required in regulating NSC reactivation.
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Affiliation(s)
- Mahekta R Gujar
- Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, 8 College Road, 169857, Singapore
| | - Hongyan Wang
- Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, 8 College Road, 169857, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, 117456, Singapore
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24
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Iruzubieta P, Cantarero I, Monzón M, Lahoz M, Junquera C. Supporting Evidence of Human Enteric Nervous System Adult Neurogenesis: Presence of Primary Cilia and Adult Neurogenesis Markers. Cell Mol Neurobiol 2022; 42:473-481. [PMID: 33237455 PMCID: PMC11441200 DOI: 10.1007/s10571-020-01017-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 11/18/2020] [Indexed: 11/26/2022]
Abstract
Adult neurogenesis has been profusely studied in central nervous system. However, its presence in enteric nervous system remains elusive although it has been recently demonstrated in mice and intimately linked to glial cells. Moreover, primary cilium is an important organelle in central adult neurogenesis. In the present study, we analysed some parallelisms between central and enteric nervous system (ENS) in humans based on ultrastructural and immunohistochemical techniques. Thus, we described the presence of primary cilia in some subtypes of glial cells and Interstitial Cells of Cajal (ICCs) and we performed 3-D reconstructions to better characterise their features. Besides, we studied the expression of several adult neurogenesis-related proteins. Immature neuron markers were found in human ENS, supporting the existence of adult neurogenesis. However, only ICCs showed proliferation markers. Hence, we propose a new paradigm where ICCs would constitute the original neural stem cells which, through asymmetrical cell division, would generate the new-born neurons.
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Affiliation(s)
- Pablo Iruzubieta
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain.
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain.
| | - Irene Cantarero
- Dpto. Biología Celular, Fisiología e Inmunología. Facultad de Medicina, Instituto Maimonides de Investigación Biomédica (IMIBIC), Universidad de Córdoba, Córdoba, Spain
| | - Marta Monzón
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain
| | - Manuel Lahoz
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
| | - Concepción Junquera
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
- Institute for Health Research Aragón (IIS), Domingo Miral s/n, 50009, Zaragoza, Spain
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25
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Penning A, Tosoni G, Abiega O, Bielefeld P, Gasperini C, De Pietri Tonelli D, Fitzsimons CP, Salta E. Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications. Front Cell Neurosci 2022; 15:781434. [PMID: 35058752 PMCID: PMC8764185 DOI: 10.3389/fncel.2021.781434] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/09/2021] [Indexed: 01/11/2023] Open
Abstract
The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.
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Affiliation(s)
- Amber Penning
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Giorgia Tosoni
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Oihane Abiega
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Pascal Bielefeld
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Caterina Gasperini
- Neurobiology of miRNAs Lab, Istituto Italiano di Tecnologia, Genova, Italy
| | | | - Carlos P. Fitzsimons
- Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, Netherlands
| | - Evgenia Salta
- Laboratory of Neurogenesis and Neurodegeneration, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
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26
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Velloso FJ, Shankar S, Parpura V, Rakic P, Levison SW. Neural Stem Cells in Adult Mammals are not Astrocytes. ASN Neuro 2022; 14:17590914221134739. [PMID: 36330653 PMCID: PMC9638700 DOI: 10.1177/17590914221134739] [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: 06/22/2022] [Revised: 09/27/2022] [Accepted: 10/01/2022] [Indexed: 11/06/2022] Open
Abstract
At the turn of the 21st century studies of the cells that resided in the adult mammalian subventricular zone (SVZ) characterized the neural stem cells (NSCs) as a subtype of astrocyte. Over the ensuing years, numerous studies have further characterized the properties of these NSCs and compared them to parenchymal astrocytes. Here we have evaluated the evidence collected to date to establish whether classifying the NSCs as astrocytes is appropriate and useful. We also performed a meta-analysis with 4 previously published datasets that used cell sorting and unbiased single-cell RNAseq to highlight the distinct gene expression profiles of adult murine NSCs and niche astrocytes. On the basis of our understanding of the properties and functions of astrocytes versus the properties and functions of NSCs, and from our comparative transcriptomic analyses we conclude that classifying the adult mammalian NSC as an astrocyte is potentially misleading. From our vantage point, it is more appropriate to refer to the cells in the adult mammalian SVZ that retain the capacity to produce new neurons and macroglia as NSCs without attaching the term "astrocyte-like."
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Affiliation(s)
- Fernando Janczur Velloso
- Department of Pharmacology, Physiology & Neuroscience, New
Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Sandhya Shankar
- Department of Pharmacology, Physiology & Neuroscience, New
Jersey Medical School, Rutgers University, Newark, NJ, USA
| | - Vladimir Parpura
- Department of Neurobiology, The University of Alabama at Birmingham,
Birmingham, AL, USA
| | - Pasko Rakic
- Department of Neuroscience, Yale School of Medicine, New Haven, CT,
USA
- Kavli Institute for Neuroscience, Yale School of Medicine, New
Haven, CT, USA
| | - Steven W. Levison
- Department of Pharmacology, Physiology & Neuroscience, New
Jersey Medical School, Rutgers University, Newark, NJ, USA
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27
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Austin SHL, Gabarró-Solanas R, Rigo P, Paun O, Harris L, Guillemot F, Urbán N. Wnt/β-catenin signalling is dispensable for adult neural stem cell homeostasis and activation. Development 2021; 148:272521. [PMID: 34557919 PMCID: PMC8572000 DOI: 10.1242/dev.199629] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 09/17/2021] [Indexed: 12/26/2022]
Abstract
Adult mouse hippocampal neural stem cells (NSCs) generate new neurons that integrate into existing hippocampal networks and modulate mood and memory. These NSCs are largely quiescent and are stimulated by niche signals to activate and produce neurons. Wnt/β-catenin signalling acts at different steps along the hippocampal neurogenic lineage, but whether it has a direct role in the regulation of NSCs remains unclear. Here, we used Wnt/β-catenin reporters and transcriptomic data from in vivo and in vitro models to show that adult NSCs respond to Wnt/β-catenin signalling. Wnt/β-catenin stimulation instructed the neuronal differentiation of proliferating NSCs and promoted the activation or differentiation of quiescent NSCs in a dose-dependent manner. However, deletion of β-catenin in NSCs did not affect either their activation or maintenance of their stem cell characteristics. Together, these results indicate that, although NSCs do respond to Wnt/β-catenin stimulation in a dose-dependent and state-specific manner, Wnt/β-catenin signalling is not cell-autonomously required to maintain NSC homeostasis, which reconciles some of the contradictions in the literature as to the role of Wnt/β-catenin signalling in adult hippocampal NSCs. Summary: Wnt/β-catenin signalling stimulation promotes the exit from quiescence and differentiation of adult hippocampal neural stem cells but is dispensable for homeostatic neurogenesis in the dentate gyrus of young mice.
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Affiliation(s)
| | - Rut Gabarró-Solanas
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter Campus (VBC), Dr. Bohr Gasse 3, 1030 Vienna, Austria.,Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna A-1030, Austria
| | - Piero Rigo
- The Francis Crick Institute, London NW1 1AT, UK
| | - Oana Paun
- The Francis Crick Institute, London NW1 1AT, UK
| | | | | | - Noelia Urbán
- The Francis Crick Institute, London NW1 1AT, UK.,Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter Campus (VBC), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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28
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Wooden JI, Thompson KR, Guerin SP, Nawarawong NN, Nixon K. Consequences of adolescent alcohol use on adult hippocampal neurogenesis and hippocampal integrity. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2021; 160:281-304. [PMID: 34696876 DOI: 10.1016/bs.irn.2021.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol is the most commonly used drug among adolescents. Their decreased sensitivity to self-regulating cues to stop drinking coincides with an enhanced vulnerability to negative outcomes of excessive drinking. In adolescents, the hippocampus is one brain region that is particularly susceptible to alcohol-induced neurodegeneration. While cell death is causal, alcohol effects on adult neurogenesis also impact hippocampal structure and function. This review describes what little is known about adolescent-specific effects of alcohol on adult neurogenesis and its relationship to hippocampal integrity. For example, alcohol intoxication inhibits neurogenesis persistently in adolescents but produces aberrant neurogenesis after alcohol dependence. Little is known, however, about the role of adolescent-born neurons in hippocampal integrity or the mechanisms of these effects. Understanding the role of neurogenesis in adolescent alcohol use and misuse is critical to our understanding of adolescent susceptibility to alcohol pathology and increased likelihood of developing alcohol problems in adulthood.
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Affiliation(s)
- J I Wooden
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - K R Thompson
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - S P Guerin
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - N N Nawarawong
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States
| | - K Nixon
- Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, United States.
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29
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Marymonchyk A, Malvaut S, Saghatelyan A. In vivo live imaging of postnatal neural stem cells. Development 2021; 148:271820. [PMID: 34383894 DOI: 10.1242/dev.199778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Neural stem cells (NSCs) are maintained in specific regions of the postnatal brain and contribute to its structural and functional plasticity. However, the long-term renewal potential of NSCs and their mode of division remain elusive. The use of advanced in vivo live imaging approaches may expand our knowledge of NSC physiology and provide new information for cell replacement therapies. In this Review, we discuss the in vivo imaging methods used to study NSC dynamics and recent live-imaging results with respect to specific intracellular pathways that allow NSCs to integrate and decode different micro-environmental signals. Lastly, we discuss future directions that may provide answers to unresolved questions regarding NSC physiology.
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Affiliation(s)
- Alina Marymonchyk
- CERVO Brain Research Center, Quebec City, QC, CanadaG1J 2G3.,Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, CanadaG1V 0A6
| | - Sarah Malvaut
- CERVO Brain Research Center, Quebec City, QC, CanadaG1J 2G3.,Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, CanadaG1V 0A6
| | - Armen Saghatelyan
- CERVO Brain Research Center, Quebec City, QC, CanadaG1J 2G3.,Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC, CanadaG1V 0A6
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30
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Deng Q, Tan YS, Chew LY, Wang H. Msps governs acentrosomal microtubule assembly and reactivation of quiescent neural stem cells. EMBO J 2021; 40:e104549. [PMID: 34368973 PMCID: PMC8488572 DOI: 10.15252/embj.2020104549] [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: 01/23/2020] [Revised: 07/05/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The ability of stem cells to switch between quiescence and proliferation is crucial for tissue homeostasis and regeneration. Drosophila quiescent neural stem cells (NSCs) extend a primary cellular protrusion from the cell body prior to their reactivation. However, the structure and function of this protrusion are not well established. Here, we show that in the protrusion of quiescent NSCs, microtubules are predominantly acentrosomal and oriented plus‐end‐out toward the tip of the primary protrusion. We have identified Mini Spindles (Msps)/XMAP215 as a key microtubule regulator in quiescent NSCs that governs NSC reactivation via regulating acentrosomal microtubule growth and orientation. We show that quiescent NSCs form membrane contact with the neuropil and E‐cadherin, a cell adhesion molecule, localizes to these NSC‐neuropil junctions. Msps and a plus‐end directed motor protein Kinesin‐2 promote NSC cell cycle re‐entry and target E‐cadherin to NSC‐neuropil contact during NSC reactivation. Together, this work establishes acentrosomal microtubule organization in the primary protrusion of quiescent NSCs and the Msps‐Kinesin‐2 pathway that governs NSC reactivation, in part, by targeting E‐cad to NSC‐neuropil contact sites.
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Affiliation(s)
- Qiannan Deng
- Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Ye Sing Tan
- Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Liang Yuh Chew
- Temasek Life Sciences Laboratory, Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Hongyan Wang
- Neuroscience & Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.,NUS Graduate School - Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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31
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Brockman AA, Mobley BC, Ihrie RA. Histological Studies of the Ventricular-Subventricular Zone as Neural Stem Cell and Glioma Stem Cell Niche. J Histochem Cytochem 2021; 69:819-834. [PMID: 34310246 DOI: 10.1369/00221554211032003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The neural stem cell niche of the ventricular-subventricular zone supports the persistence of stem and progenitor cells in the mature brain. This niche has many notable cytoarchitectural features that affect the activity of stem cells and may also support the survival and growth of invading tumor cells. Histochemical studies of the niche have revealed many proteins that, in combination, can help to reveal stem-like cells in the normal or cancer context, although many caveats persist in the quest to consistently identify these cells in the human brain. Here, we explore the complex relationship between the persistent proliferative capacity of the neural stem cell niche and the malignant proliferation of brain tumors, with a special focus on histochemical identification of stem cells and stem-like tumor cells and an eye toward the potential application of high-dimensional imaging approaches to the field.
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Affiliation(s)
- Asa A Brockman
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Bret C Mobley
- Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rebecca A Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.,Departments of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
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32
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Baudry M, Su W, Seinfeld J, Sun J, Bi X. Role of Calpain-1 in Neurogenesis. Front Mol Biosci 2021; 8:685938. [PMID: 34212005 PMCID: PMC8239220 DOI: 10.3389/fmolb.2021.685938] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/01/2021] [Indexed: 12/25/2022] Open
Abstract
While calpains have been implicated in neurogenesis for a long time, there is still little information regarding the specific contributions of various isoforms in this process. We took advantage of the availability of mutant mice with complete deletion of calpain-1 to analyze its contribution to neurogenesis. We first used the incorporation of BrdU in newly-generated cells in the subgranular zone of the dentate gyrus to determine the role of calpain-1 deletion in neuronal proliferation. Our results showed that the lack of calpain-1 decreased the rate of cell proliferation in adult hippocampus. As previously shown, it also decreased the long-term survival of newly-generated neurons. We also used data from previously reported RNA and miRNA sequencing analyses to identify differentially expressed genes in brain of calpain-1 knock-out mice related to cell division, cell migration, cell proliferation and cell survival. A number of differentially expressed genes were identified, which could play a significant role in the changes in neurogenesis in calpain-1 knock out mice. The results provide new information regarding the role of calpain-1 in neurogenesis and have implications for better understanding the pathologies associated with calpain-1 mutations in humans.
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Affiliation(s)
- Michel Baudry
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Wenyue Su
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Jeffrey Seinfeld
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Jiandong Sun
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Xiaoning Bi
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
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33
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Delgado AC, Maldonado-Soto AR, Silva-Vargas V, Mizrak D, von Känel T, Tan KR, Paul A, Madar A, Cuervo H, Kitajewski J, Lin CS, Doetsch F. Release of stem cells from quiescence reveals gliogenic domains in the adult mouse brain. Science 2021; 372:1205-1209. [PMID: 34112692 DOI: 10.1126/science.abg8467] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022]
Abstract
Quiescent neural stem cells (NSCs) in the adult mouse ventricular-subventricular zone (V-SVZ) undergo activation to generate neurons and some glia. Here we show that platelet-derived growth factor receptor beta (PDGFRβ) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia. Selective deletion of PDGFRβ in adult V-SVZ NSCs leads to their release from quiescence, uncovering gliogenic domains for different glial cell types. These domains are also recruited upon injury. We identify an intraventricular oligodendrocyte progenitor derived from NSCs inside the brain ventricles that contacts supraependymal axons. Together, our findings reveal that the adult V-SVZ contains spatial domains for gliogenesis, in addition to those for neurogenesis. These gliogenic NSC domains tend to be quiescent under homeostasis and may contribute to brain plasticity.
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Affiliation(s)
| | | | | | - Dogukan Mizrak
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
- Department of Systems Biology, Columbia University, New York, NY, USA
| | | | - Kelly R Tan
- Biozentrum, University of Basel, Basel, Switzerland
| | - Alex Paul
- Department of Genetics and Development, Columbia University, New York, NY, USA
| | - Aviv Madar
- Department of Biology, Center for Genomics and Systems Biology, New York University, New York, NY, USA
| | - Henar Cuervo
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Jan Kitajewski
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Chyuan-Sheng Lin
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA
| | - Fiona Doetsch
- Biozentrum, University of Basel, Basel, Switzerland.
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Differentiation of human adult-derived stem cells towards a neural lineage involves a dedifferentiation event prior to differentiation to neural phenotypes. Sci Rep 2021; 11:12034. [PMID: 34103613 PMCID: PMC8187441 DOI: 10.1038/s41598-021-91566-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 05/27/2021] [Indexed: 01/09/2023] Open
Abstract
Although it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension. In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy. We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs. Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a dedifferentiation step followed by differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.
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Huang J, Gujar MR, Deng Q, Y Chia S, Li S, Tan P, Sung W, Wang H. Histone lysine methyltransferase Pr-set7/SETD8 promotes neural stem cell reactivation. EMBO Rep 2021; 22:e50994. [PMID: 33565211 PMCID: PMC8024890 DOI: 10.15252/embr.202050994] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 01/07/2023] Open
Abstract
The ability of neural stem cells (NSCs) to switch between quiescence and proliferation is crucial for brain development and homeostasis. Increasing evidence suggests that variants of histone lysine methyltransferases including KMT5A are associated with neurodevelopmental disorders. However, the function of KMT5A/Pr-set7/SETD8 in the central nervous system is not well established. Here, we show that Drosophila Pr-Set7 is a novel regulator of NSC reactivation. Loss of function of pr-set7 causes a delay in NSC reactivation and loss of H4K20 monomethylation in the brain. Through NSC-specific in vivo profiling, we demonstrate that Pr-set7 binds to the promoter region of cyclin-dependent kinase 1 (cdk1) and Wnt pathway transcriptional co-activator earthbound1/jerky (ebd1). Further validation indicates that Pr-set7 is required for the expression of cdk1 and ebd1 in the brain. Similar to Pr-set7, Cdk1 and Ebd1 promote NSC reactivation. Finally, overexpression of Cdk1 and Ebd1 significantly suppressed NSC reactivation defects observed in pr-set7-depleted brains. Therefore, Pr-set7 promotes NSC reactivation by regulating Wnt signaling and cell cycle progression. Our findings may contribute to the understanding of mammalian KMT5A/PR-SET7/SETD8 during brain development.
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Affiliation(s)
- Jiawen Huang
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
| | - Mahekta R Gujar
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
| | - Qiannan Deng
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
| | - Sook Y Chia
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
- Present address:
National Neuroscience InstituteSingaporeSingapore
| | - Song Li
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
| | - Patrick Tan
- Genome Institute of SingaporeSingaporeSingapore
- Cancer & Stem Cell Biology ProgramDuke‐NUS Medical SchoolSingaporeSingapore
- Cellular and Molecular ResearchNational Cancer CentreSingaporeSingapore
- Cancer Science Institute of SingaporeNational University of SingaporeSingaporeSingapore
| | - Wing‐Kin Sung
- Genome Institute of SingaporeSingaporeSingapore
- Department of Computer ScienceNational University of SingaporeSingaporeSingapore
| | - Hongyan Wang
- Neuroscience & Behavioral Disorders ProgrammeDuke‐NUS Medical SchoolSingaporeSingapore
- Department of PhysiologyYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Integrative Sciences and Engineering ProgrammeNational University of SingaporeSingaporeSingapore
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Luongo C, Butruille L, Sébillot A, Le Blay K, Schwaninger M, Heuer H, Demeneix BA, Remaud S. Absence of Both Thyroid Hormone Transporters MCT8 and OATP1C1 Impairs Neural Stem Cell Fate in the Adult Mouse Subventricular Zone. Stem Cell Reports 2021; 16:337-353. [PMID: 33450189 PMCID: PMC7878696 DOI: 10.1016/j.stemcr.2020.12.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Adult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed Mct8/Oatp1c1 double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.
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Affiliation(s)
- Cristina Luongo
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France
| | - Lucile Butruille
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France
| | - Anthony Sébillot
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France
| | - Karine Le Blay
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany
| | - Heike Heuer
- Department of Endocrinology, Diabetes and Metabolism, University of Duisburg-Essen, 45122 Essen, Germany
| | - Barbara A Demeneix
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France
| | - Sylvie Remaud
- UMR 7221 Phyma, CNRS/Muséum National d'Histoire Naturelle, 75005 Paris, France.
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Abstract
Quiescence is a cellular state in which a cell remains out of the cell cycle but retains the capacity to divide. The unique ability of adult stem cells to maintain quiescence is crucial for life-long tissue homeostasis and regenerative capacity. Quiescence has long been viewed as an inactive state but recent studies have shown that it is in fact an actively regulated process and that adult stem cells are highly reactive to extrinsic stimuli. This has fuelled hopes of boosting the reactivation potential of adult stem cells to improve tissue function during ageing. In this Review, we provide a perspective of the quiescent state and discuss how quiescent adult stem cells transition into the cell cycle. We also discuss current challenges in the field, highlighting recent technical advances that could help overcome some of these challenges.
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Affiliation(s)
- Noelia Urbán
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter Campus (VBC), Dr. Bohr Gasse 3, 1030 Vienna, Austria
| | - Tom H Cheung
- Division of Life Science, Center for Stem Cell Research, Center of Systems Biology and Human Health, State Key Laboratory of Molecular Neuroscience, and Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China
- Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, The Hong Kong University of Science and Technology Shenzhen Research Institute, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, Guangdong 518057, China
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Tanycytes in the infundibular nucleus and median eminence and their role in the blood-brain barrier. HANDBOOK OF CLINICAL NEUROLOGY 2021; 180:253-273. [PMID: 34225934 DOI: 10.1016/b978-0-12-820107-7.00016-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The blood-brain barrier is generally attributed to endothelial cells. However, in circumventricular organs, such as the median eminence, tanycytes take over the barrier function. These ependymoglial cells form the wall of the third ventricle and send long extensions into the parenchyma to contact blood vessels and hypothalamic neurons. The shape and location of tanycytes put them in an ideal position to connect the periphery with central nervous compartments. In line with this, tanycytes control the transport of hormones and key metabolites in and out of the hypothalamus. They function as sensors of peripheral homeostasis for central regulatory networks. This chapter discusses current evidence that tanycytes play a key role in regulating glucose balance, food intake, endocrine axes, seasonal changes, reproductive function, and aging. The understanding of how tanycytes perform these diverse tasks is only just beginning to emerge and will probably lead to a more differentiated view of how the brain and the periphery interact.
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Ortiz-Álvarez G, Spassky N. One progenitor to generate them all: new evidence for multi-fated neural progenitors. Curr Opin Neurobiol 2020; 66:186-194. [PMID: 33276241 DOI: 10.1016/j.conb.2020.10.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/13/2020] [Accepted: 10/21/2020] [Indexed: 12/30/2022]
Abstract
The past two decades have left behind the old conception of early fate-restricted neural progenitors. The new paradigm is that of a more plastic brain, in which the cellular potential of multi-fated progenitors is progressively restricted. This is observed in the switch from neurogenesis to gliogenesis, but also in the generation of different types of glial cells and neurons at later stages. The mechanisms that establish brain cell diversity or heterogeneity within a single population are starting to be elucidated. The role of cell cycle regulators and dynamics and the asymmetric distribution of cell cargoes during cell division are attracting more attention. Understanding these mechanisms could open the way for new treatments against brain pathologies such as brain tumors or neurodegenerative disorders.
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Affiliation(s)
- Gonzalo Ortiz-Álvarez
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, UMR8197, INSERM U1024, PSL Université Paris, 75005 Paris, France
| | - Nathalie Spassky
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, UMR8197, INSERM U1024, PSL Université Paris, 75005 Paris, France.
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The art of lineage tracing: From worm to human. Prog Neurobiol 2020; 199:101966. [PMID: 33249090 DOI: 10.1016/j.pneurobio.2020.101966] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/03/2020] [Accepted: 11/22/2020] [Indexed: 12/20/2022]
Abstract
Reconstructing the genealogy of every cell that makes up an organism remains a long-standing challenge in developmental biology. Besides its relevance for understanding the mechanisms underlying normal and pathological development, resolving the lineage origin of cell types will be crucial to create these types on-demand. Multiple strategies have been deployed towards the problem of lineage tracing, ranging from direct observation to sophisticated genetic approaches. Here we discuss the achievements and limitations of past and current technology. Finally, we speculate about the future of lineage tracing and how to reach the next milestones in the field.
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Coronas V, Terrié E, Déliot N, Arnault P, Constantin B. Calcium Channels in Adult Brain Neural Stem Cells and in Glioblastoma Stem Cells. Front Cell Neurosci 2020; 14:600018. [PMID: 33281564 PMCID: PMC7691577 DOI: 10.3389/fncel.2020.600018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/06/2020] [Indexed: 12/12/2022] Open
Abstract
The brain of adult mammals, including humans, contains neural stem cells (NSCs) located within specific niches of which the ventricular-subventricular zone (V-SVZ) is the largest one. Under physiological conditions, NSCs proliferate, self-renew and produce new neurons and glial cells. Several recent studies established that oncogenic mutations in adult NSCs of the V-SVZ are responsible for the emergence of malignant primary brain tumors called glioblastoma. These aggressive tumors contain a small subpopulation of cells, the glioblastoma stem cells (GSCs), that are endowed with proliferative and self-renewal abilities like NSCs from which they may arise. GSCs are thus considered as the cells that initiate and sustain tumor growth and, because of their resistance to current treatments, provoke tumor relapse. A growing body of studies supports that Ca2+ signaling controls a variety of processes in NSCs and GSCs. Ca2+ is a ubiquitous second messenger whose fluctuations of its intracellular concentrations are handled by channels, pumps, exchangers, and Ca2+ binding proteins. The concerted action of the Ca2+ toolkit components encodes specific Ca2+ signals with defined spatio-temporal characteristics that determine the cellular responses. In this review, after a general overview of the adult brain NSCs and GSCs, we focus on the multiple roles of the Ca2+ toolkit in NSCs and discuss how GSCs hijack these mechanisms to promote tumor growth. Extensive knowledge of the role of the Ca2+ toolkit in the management of essential functions in healthy and pathological stem cells of the adult brain should help to identify promising targets for clinical applications.
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Affiliation(s)
- Valérie Coronas
- Laboratoire STIM, Université de Poitiers-CNRS ERL 7003, Poitiers, France
| | - Elodie Terrié
- Laboratoire STIM, Université de Poitiers-CNRS ERL 7003, Poitiers, France
| | - Nadine Déliot
- Laboratoire STIM, Université de Poitiers-CNRS ERL 7003, Poitiers, France
| | - Patricia Arnault
- Laboratoire STIM, Université de Poitiers-CNRS ERL 7003, Poitiers, France
| | - Bruno Constantin
- Laboratoire STIM, Université de Poitiers-CNRS ERL 7003, Poitiers, France
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Xia SH, Hu SW, Ge DG, Liu D, Wang D, Zhang S, Zhang Q, Yuan L, Li YQ, Yang JX, Wu P, Zhang H, Han MH, Ding HL, Cao JL. Chronic Pain Impairs Memory Formation via Disruption of Neurogenesis Mediated by Mesohippocampal Brain-Derived Neurotrophic Factor Signaling. Biol Psychiatry 2020; 88:597-610. [PMID: 32307038 DOI: 10.1016/j.biopsych.2020.02.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 01/30/2020] [Accepted: 02/14/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Chronic pain patients often complain of their poor memory. The mechanisms underlying chronic pain-related memory impairment remain elusive, and there are few clinical therapeutic strategies available for this condition. METHODS In a neuropathic pain model induced by chronic constrictive injury of the sciatic nerve in male mice, we used circuit-specific electrophysiological recording, combined with chemogenetic, molecular, and pharmacologic methods, to examine the circuit and molecular mechanisms underlying chronic pain-related memory impairment. RESULTS Our current results show that chronic neuropathic pain impaired the acquisition of spatial memory and, meanwhile, reduced adult neurogenesis in the dentate gyrus. Experimentally reducing dentate gyrus neurogenesis mimicked this pain-induced effect on spatial memory formation in naïve mice. Furthermore, pain-associated impairments of both hippocampal neurogenesis and memory formation were rescued or mimicked by chemogenetic activation or deactivation, respectively, of the ventral tegmental area dopaminergic projection, through which ventral tegmental area-released brain-derived neurotrophic factor was required. Importantly, we found that chronic, but not acute, systematic administration of subanesthetic doses of ketamine, while without relieving pain, ameliorated chronic pain-related impairment of spatial memory formation, potentially by rescuing brain-derived neurotrophic factor-mediated dentate gyrus neurogenesis. CONCLUSIONS These findings provide a novel, circuit-based mechanistic link between chronic pain and memory formation deficit, and potential new therapeutic options for chronic pain-related learning deficit and memory impairment.
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Affiliation(s)
- Sun-Hui Xia
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Su-Wan Hu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - De-Gao Ge
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Di Liu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Di Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Song Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Qi Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Ling Yuan
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Yan-Qiang Li
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Jun-Xia Yang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Peng Wu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Hongxing Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China
| | - Ming-Hu Han
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York; Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hai-Lei Ding
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China.
| | - Jun-Li Cao
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, China; Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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Parmigiani E, Taylor V, Giachino C. Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma. Cells 2020; 9:cells9102304. [PMID: 33076453 PMCID: PMC7602630 DOI: 10.3390/cells9102304] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/18/2022] Open
Abstract
Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.
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Farmer BC, Walsh AE, Kluemper JC, Johnson LA. Lipid Droplets in Neurodegenerative Disorders. Front Neurosci 2020; 14:742. [PMID: 32848541 PMCID: PMC7403481 DOI: 10.3389/fnins.2020.00742] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/23/2020] [Indexed: 12/13/2022] Open
Abstract
Knowledge of lipid droplets (LDs) has evolved from simple depots of lipid storage to dynamic and functionally active organelles involved in a variety of cellular functions. Studies have now informed significant roles for LDs in cellular signaling, metabolic disease, and inflammation. While lipid droplet biology has been well explored in peripheral organs such as the liver and heart, LDs within the brain are relatively understudied. The presence and function of these dynamic organelles in the central nervous system has recently gained attention, especially in the context of neurodegeneration. In this review, we summarize the current understanding of LDs within the brain, with an emphasis on their relevance in neurodegenerative diseases.
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Affiliation(s)
- Brandon C Farmer
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Adeline E Walsh
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Jude C Kluemper
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Lance A Johnson
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, United States
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Frankel BM, Cachia D, Patel SJ, Das A. Targeting Subventricular Zone Progenitor Cells with Intraventricular Liposomal Encapsulated Cytarabine in Patients with Secondary Glioblastoma : A Report of Two Cases. ACTA ACUST UNITED AC 2020; 2:836-843. [PMID: 32704621 DOI: 10.1007/s42399-020-00322-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Current treatments for glioblastoma (GB), the most common and malignant primary brain tumor are inadequate and as such, the median survival for most patients with GB is on the order of months, even after cytoreductive surgery, radiation and chemotherapy. Case Description Current study reports two cases of glioblastoma (GB) with subventricular zone (SVZ) involvement. SVZ biopsies demonstrated the presence of hypercellularity, nestin immunoreactivity, and a Ki-67 labeling index (LI) of 1-2%. Interestingly, tumor morphology and proliferative indices are different in the SVZ specimens than the hemispheric recurrences, which displayed similar nestin immunoreactivity, but a greater LI of 10%. Biopsy specimens demonstrated both intense nestin immunoreactivity and GFAP immunoreactivity in and around the GB recurrence. Nestin positive cells were more abundant closer to the SVZ nearest to the dorsolateral horn of the left lateral ventricle, while GFAP immunoreactivity was more intense closer to the center of the tumor recurrence. Additionally, co-labeling of cells with Ki67 and several different progenitor markers (CD133, CD140, TUJ-1, and nestin) demonstrated that these cells found in and around the GB recurrence were actively dividing. Having failed standard therapy with evidence of bi-hemispheric spread and progression to GB, we report a novel approach of using intraventricular liposomal encapsulated cytarabine (DepoCyt) for the treatment for GB by suppressing glial progenitor cells that surround the ventricular system in patients with GB. Conclusions MRI and immunohistochemistry demonstrated that the SVZ is the incubator for future recurrences of GB and propose targeting SVZ progenitor cells with intraventricular liposomal encapsulated Ara-C. Two patients treated using this novel regimen have demonstrated partial radiographic responses warranting further studies looking at targeting the subventricular zone.
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Affiliation(s)
- Bruce M Frankel
- Department of Neurosurgery, Medical University of South Carolina
| | - David Cachia
- Department of Neurosurgery, Medical University of South Carolina
| | - Sunil J Patel
- Department of Neurosurgery, Medical University of South Carolina
| | - Arabinda Das
- Department of Neurosurgery, Medical University of South Carolina
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Joppé SE, Cochard LM, Levros LC, Hamilton LK, Ameslon P, Aumont A, Barnabé-Heider F, Fernandes KJ. Genetic targeting of neurogenic precursors in the adult forebrain ventricular epithelium. Life Sci Alliance 2020; 3:3/7/e202000743. [PMID: 32482782 PMCID: PMC7266992 DOI: 10.26508/lsa.202000743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/16/2020] [Accepted: 05/18/2020] [Indexed: 01/31/2023] Open
Abstract
In vivo evidence for precursors that produce neurons independent of neurosphere-forming neural stem cells suggests the adult forebrain, like the developing brain, has two distinct neurogenic pathways. The ventricular epithelium of the adult forebrain is a heterogeneous cell population that is a source of both quiescent and activated neural stem cells (qNSCs and aNSCs, respectively). We genetically targeted a subset of ventricle-contacting, glial fibrillary acidic protein (GFAP)-expressing cells, to study their involvement in qNSC/aNSC–mediated adult neurogenesis. Ventricle-contacting GFAP+ cells were lineage-traced beginning in early adulthood using adult brain electroporation and produced small numbers of olfactory bulb neuroblasts until at least 21 mo of age. Notably, electroporated GFAP+ neurogenic precursors were distinct from both qNSCs and aNSCs: they did not give rise to neurosphere-forming aNSCs in vivo or after extended passaging in vitro and they were not recruited during niche regeneration. GFAP+ cells with these properties included a FoxJ1+GFAP+ subset, as they were also present in an inducible FoxJ1 transgenic lineage-tracing model. Transiently overexpressing Mash1 increased the neurogenic output of electroporated GFAP+ cells in vivo, identifying them as a potentially recruitable population. We propose that the qNSC/aNSC lineage of the adult forebrain coexists with a distinct, minimally expanding subset of GFAP+ neurogenic precursors.
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Affiliation(s)
- Sandra E Joppé
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada.,Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Montreal, Canada
| | - Loïc M Cochard
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada.,Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
| | - Louis-Charles Levros
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada.,Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
| | - Laura K Hamilton
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada.,Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
| | - Pierre Ameslon
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada.,Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
| | - Anne Aumont
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada
| | - Fanie Barnabé-Heider
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada
| | - Karl Jl Fernandes
- Research Center of the University of Montreal Hospital (CRCHUM), Montreal, Canada .,Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
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47
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Jurisch-Yaksi N, Yaksi E, Kizil C. Radial glia in the zebrafish brain: Functional, structural, and physiological comparison with the mammalian glia. Glia 2020; 68:2451-2470. [PMID: 32476207 DOI: 10.1002/glia.23849] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/07/2020] [Accepted: 05/13/2020] [Indexed: 02/01/2023]
Abstract
The neuroscience community has witnessed a tremendous expansion of glia research. Glial cells are now on center stage with leading roles in the development, maturation, and physiology of brain circuits. Over the course of evolution, glia have highly diversified and include the radial glia, astroglia or astrocytes, microglia, oligodendrocytes, and ependymal cells, each having dedicated functions in the brain. The zebrafish, a small teleost fish, is no exception to this and recent evidences point to evolutionarily conserved roles for glia in the development and physiology of its nervous system. Due to its small size, transparency, and genetic amenability, the zebrafish has become an increasingly prominent animal model for brain research. It has enabled the study of neural circuits from individual cells to entire brains, with a precision unmatched in other vertebrate models. Moreover, its high neurogenic and regenerative potential has attracted a lot of attention from the research community focusing on neural stem cells and neurodegenerative diseases. Hence, studies using zebrafish have the potential to provide fundamental insights about brain development and function, and also elucidate neural and molecular mechanisms of neurological diseases. We will discuss here recent discoveries on the diverse roles of radial glia and astroglia in neurogenesis, in modulating neuronal activity and in regulating brain homeostasis at the brain barriers. By comparing insights made in various animal models, particularly mammals and zebrafish, our goal is to highlight the similarities and differences in glia biology among species, which could set new paradigms relevant to humans.
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Affiliation(s)
- Nathalie Jurisch-Yaksi
- Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Neurology and Clinical Neurophysiology, St Olav University Hospital, Trondheim, Norway
| | - Emre Yaksi
- Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway
| | - Caghan Kizil
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Dresden, Germany.,Center for Molecular and Cellular Bioengineering (CMCB), TU Dresden, Dresden, Germany
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48
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Nam HS, Capecchi MR. Lrig1 expression prospectively identifies stem cells in the ventricular-subventricular zone that are neurogenic throughout adult life. Neural Dev 2020; 15:3. [PMID: 32183906 PMCID: PMC7077007 DOI: 10.1186/s13064-020-00139-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) regulates stem cell quiescence. As a marker, it identifies stem cells in multiple organs of the mouse. We had detected Lrig1 expression in cultured Id1high neural stem cells obtained from the lateral walls lining the lateral ventricles of the adult mouse brain. Thus, we investigated whether Lrig1 expression also identifies stem cells in that region in vivo. METHODS Publicly available single cell RNA sequencing datasets were analyzed with Seurat and Monocle. The Lrig1+ cells were lineage traced in vivo with a novel non-disruptive co-translational Lrig1T2A-iCreERT2 reporter mouse line. RESULTS Analysis of single cell RNA sequencing datasets suggested Lrig1 was highly expressed in the most primitive stem cells of the neurogenic lineage in the lateral wall of the adult mouse brain. In support of their neurogenic stem cell identity, cell cycle entry was only observed in two morphologically distinguishable Lrig1+ cells that could also be induced into activation by Ara-C infusion. The Lrig1+ neurogenic stem cells were observed throughout the lateral wall. Neuroblasts and neurons were lineage traced from Lrig1+ neurogenic stem cells at 1 year after labeling. CONCLUSIONS We identified Lrig1 as a marker of long-term neurogenic stem cells in the lateral wall of the mouse brain. Lrig1 expression revealed two morphotypes of the Lrig1+ cells that function as long-term neurogenic stem cells. The spatial distribution of the Lrig1+ neurogenic stem cells suggested all subtypes of the adult neurogenic stem cells were labeled.
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Affiliation(s)
- Hyung-Song Nam
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112-5331, USA.
| | - Mario R Capecchi
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112-5331, USA
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49
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Iemolo A, Montilla-Perez P, Lai IC, Meng Y, Nolan S, Wen J, Rusu I, Dulcis D, Telese F. A cell type-specific expression map of NCoR1 and SMRT transcriptional co-repressors in the mouse brain. J Comp Neurol 2020; 528:2218-2238. [PMID: 32072640 DOI: 10.1002/cne.24886] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 12/12/2019] [Accepted: 02/12/2020] [Indexed: 12/11/2022]
Abstract
The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid-hormone receptors (SMRT) are the best characterized transcriptional co-repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type-specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type-specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain.
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Affiliation(s)
- Attilio Iemolo
- Department of Medicine, University of California San Diego, La Jolla, California
| | | | - I-Chi Lai
- Department of Psychiatry, University of California San Diego, La Jolla, California
| | - Yinuo Meng
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Syreeta Nolan
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Junneng Wen
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Iulia Rusu
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Davide Dulcis
- Department of Psychiatry, University of California San Diego, La Jolla, California
| | - Francesca Telese
- Department of Medicine, University of California San Diego, La Jolla, California
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50
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Wu J, Tian WJ, Liu Y, Wang HJ, Zheng J, Wang X, Pan H, Li J, Luo J, Yang X, Lau LF, Ghashghaei HT, Shen Q. Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone. EMBO J 2020; 39:e101679. [PMID: 32009252 DOI: 10.15252/embj.2019101679] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 11/19/2019] [Accepted: 12/12/2019] [Indexed: 12/17/2022] Open
Abstract
Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
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Affiliation(s)
- Jun Wu
- School of Medicine, Tsinghua University, Beijing, China.,IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wen-Jia Tian
- IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yang Liu
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China.,MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Huanhuan J Wang
- IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jiangli Zheng
- School of Medicine, Tsinghua University, Beijing, China.,IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xin Wang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Han Pan
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Ji Li
- School of Medicine, Tsinghua University, Beijing, China
| | - Junyu Luo
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xuerui Yang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Lester F Lau
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - H Troy Ghashghaei
- WM Keck Center for Behavioral Biology, Program in Genetics, Program in Comparative Biomedical Sciences, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Qin Shen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tongji University Brain and Spinal Cord Clinical Research Center, Shanghai, China
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