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Snapyan M, Desmeules F, Munro J, Bérard M, Saikali S, Gould PV, Richer M, Pourcher E, Langlois M, Dufresne A, Prud'homme M, Cantin L, Parent A, Saghatelyan A, Parent M. Adult Neurogenesis in the Subventricular Zone of Patients with Huntington's and Parkinson's Diseases and following Long-Term Treatment with Deep Brain Stimulation. Ann Neurol 2025; 97:894-906. [PMID: 39829080 PMCID: PMC12010058 DOI: 10.1002/ana.27181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 01/22/2025]
Abstract
OBJECTIVE Parkinson's and Huntington's diseases are characterized by progressive neuronal loss. Previous studies using human postmortem tissues have shown the impact of neurodegenerative disorders on adult neurogenesis. The extent to which adult neural stem cells are activated in the subventricular zone and whether therapeutic treatments such as deep brain stimulation promote adult neurogenesis remains unclear. The goal of the present study is to assess adult neural stem cells activation and neurogenesis in the subventricular zone of patients with Huntington's and Parkinson's diseases who were treated or not by deep brain stimulation. METHODS Postmortem brain samples from Huntington's and Parkinson's disease patients who had received or not long-term deep brain stimulation of the subthalamic nucleus were used. RESULTS Our results indicate a significant increase in the thickness of the subventricular zone and in the density of proliferating cells and activated stem cells in the brain of Huntington's disease subjects and Parkinson's disease patients treated with deep brain stimulation. We also observed an increase in the density of immature neurons in the brain of these patients. INTERPRETATION Overall, our data indicate that long-term deep brain stimulation of the subthalamic nucleus promotes cell proliferation and neurogenesis in the subventricular zone that are reduced in Parkinson's disease. Taken together, our results also provide a detailed characterization of the cellular composition of the adult human subventricular zone and caudate nucleus in normal condition and in Parkinson's and Huntington's diseases and demonstrate the plasticity of these regions in response to neurodegeneration. ANN NEUROL 2025;97:894-906.
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Affiliation(s)
| | - Francis Desmeules
- CERVO Brain Research CentreQuebec CityQuebecCanada
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | | | | | - Stephan Saikali
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Peter V. Gould
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Maxime Richer
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Emmanuelle Pourcher
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Mélanie Langlois
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Anne‐Marie Dufresne
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Michel Prud'homme
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - Léo Cantin
- Hôpital de l'Enfant‐Jésus, CHU de Québec‐Université LavalQuebec CityQuebecCanada
| | - André Parent
- CERVO Brain Research CentreQuebec CityQuebecCanada
- Department of Psychiatry and NeuroscienceFaculty of Medicine, Université LavalQuebec CityQuebecCanada
| | - Armen Saghatelyan
- CERVO Brain Research CentreQuebec CityQuebecCanada
- Department of Psychiatry and NeuroscienceFaculty of Medicine, Université LavalQuebec CityQuebecCanada
- Department of Cellular and Molecular MedicineFaculty of Medicine, University of OttawaOttawaOntarioCanada
| | - Martin Parent
- CERVO Brain Research CentreQuebec CityQuebecCanada
- Department of Psychiatry and NeuroscienceFaculty of Medicine, Université LavalQuebec CityQuebecCanada
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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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Gecici NN, Habib A, Mallela AN, Rich JN, Drappatz J, Mantica M, Abdullah KG, Zinn PO. Ventricular Entry During Glioblastoma Resection is Associated With Reduced Survival and Increased Risk of Distant Recurrence. Neurosurgery 2025:00006123-990000000-01554. [PMID: 40178259 DOI: 10.1227/neu.0000000000003431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/10/2024] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Although subventricular zone (SVZ) involvement is known to correlate with more aggressive tumor behavior and reduced survival in glioblastoma (GBM), the role of ventricular entry (VE) on outcomes is less clear and remains debated. This study aims to investigate the impact of VE on outcomes and overall survival (OS) in GBM. METHODS A retrospective analysis of patients with newly diagnosed supratentorial GBMtreated between 2013 and 2023 at the University of Pittsburgh Medical Center was performed. SVZ involvement, size, and extent of resection were identified through preoperative and postoperative imaging. VE was identified through operative notes and postoperative imaging review. RESULTS A total of 282 patients met inclusion criteria. VE occurred in 38.3% (n = 108) of patients and was more common in those with SVZ-contacting tumors (P < .001). Patients who had VE had significantly lower median OS compared with non-VE (12 months vs 18 months, P < .001). VE was identified as an independent risk factor for decreased OS in patients with GBM, after adjusting for well-known prognostic factors and SVZ contact (hazard ratios: 1.62 [1.12-2.34], P = .001). Only patients who had VE developed postoperative hydrocephalus (n = 4, 1.4%, P = .021) and had external ventricular drain placed (n = 6, 2.1%, P = .003). Distant parenchymal recurrence and leptomeningeal dissemination (LMD) rates were significantly higher in the VE group compared with the non-VE group (63.9% vs 39.7%, P < .001, and 23.1% vs 13.2%, P = .035), and VE emerged as an independent predictor of distant recurrences/LMDs in multivariable logistic regression (odds ratio: 4.7 [2.11-10.4], P < .001). CONCLUSION Our data suggest that VE during GBM resection is a significant independent risk factor for decreased survival and increased distant recurrence/LMD. While maximizing tumor resection remains critical, neurosurgeons must consider the potential adverse outcomes associated with VE because it may diminish the survival benefits of gross-total resection. Prospective studies are warranted to better understand the risks and benefits of VE in GBM surgery.
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Affiliation(s)
- Neslihan Nisa Gecici
- Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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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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Jinnou H, Rosko LM, Yamashita S, Henmi S, Prasad J, Lam VK, Agaronyan A, Tu TW, Imamura Y, Kuboyama K, Sawamoto K, Hashimoto-Torii K, Ishibashi N, Gallo V. Outer radial glia promotes white matter regeneration after neonatal brain injury. Cell Rep Med 2025; 6:101986. [PMID: 40023165 PMCID: PMC11970391 DOI: 10.1016/j.xcrm.2025.101986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 11/27/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The developing gyrencephalic brain contains a large population of neural stem cells in the ventricular zone and outer subventricular zone (OSVZ), the latter populated by outer radial glia (oRG). The role of oRG during postnatal development is not well understood. We show that oRG cells increase proliferative capacity and contribute to oligodendrocyte precursor cell (OPC) production following brain injury in human infants and neonatal piglets, whose brains resemble the human brain in structure and development. RNA sequencing revealed oRG-specific transcriptional responses to injury in piglets and showed that the activating transcription factor 5 (ATF5) pathway positively regulates oRG proliferation. Intranasal activation of ATF5 using salubrinal enhanced OSVZ-derived oligodendrogenesis in the injured periventricular white matter and improved functional recovery. These results reveal a key role for postnatal oRG in brain injury recovery and identify ATF5 as a potential therapeutic target for treating white matter injury in infants.
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Affiliation(s)
- Hideo Jinnou
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics and Neonatology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Lauren M Rosko
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Satoshi Yamashita
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Soichiro Henmi
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Jaya Prasad
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Van K Lam
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA
| | - Artur Agaronyan
- Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC 20059, USA
| | - Tsang-Wei Tu
- Molecular Imaging Laboratory, Department of Radiology, Howard University, Washington, DC 20059, USA
| | - Yuka Imamura
- Departments of Pharmacology and Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Kazuya Kuboyama
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Kazue Hashimoto-Torii
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Nobuyuki Ishibashi
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
| | - Vittorio Gallo
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA; Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
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6
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Tsujimura K, Ortug A, Alatorre Warren JL, Shiohama T, McDougle CJ, Marcus RE, Tseng CEJ, Zürcher NR, Mercaldo ND, Faja S, Maunakea A, Hooker J, Takahashi E. Structural pathways related to the subventricular zone are decreased in volume with altered microstructure in young adult males with autism spectrum disorder. Cereb Cortex 2025; 35:bhaf041. [PMID: 40055911 DOI: 10.1093/cercor/bhaf041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/27/2025] [Accepted: 02/05/2025] [Indexed: 03/22/2025] Open
Abstract
Autism spectrum disorder is a neurodevelopmental condition characterized by reduced social communication and repetitive behaviors. Altered neurogenesis, including disturbed neuronal migration, has been implicated in autism spectrum disorder. Using diffusion MRI, we previously identified neuronal migration pathways in the human fetal brain and hypothesized that similar pathways persist into adulthood, with differences in volume and microstructural characteristics between individuals with autism spectrum disorder and controls. We analyzed diffusion MRI-based tractography of subventricular zone-related pathways in 15 young adult men with autism spectrum disorder and 18 controls at Massachusetts General Hospital, with validation through the Autism Imaging Data Exchange II dataset. Participants with autism spectrum disorder had reduced subventricular zone pathway volumes and fractional anisotropy compared to controls. Furthermore, subventricular zone pathway volume was positively correlated (r: 0.68; 95% CI: 0.25 to 0.88) with symptom severity, suggesting that individuals with more severe symptoms tended to have larger subventricular zone pathway volumes, normalized by brain size. Analysis of the Autism Imaging Data Exchange cohort confirmed these findings of reduced subventricular zone pathway volumes in autism spectrum disorder. While some of these pathways may potentially include inaccurately disconnected pathways that go through the subventricular zone, our results suggest that diffusion MRI-based tractography pathways anatomically linked to the periventricular region are associated with certain symptom types in adult males with autism spectrum disorder.
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Affiliation(s)
- Keita Tsujimura
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
- Group of Brain Function and Development, Neuroscience Institute of the Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan
- Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya 464-8601, Aichi, Japan
| | - Alpen Ortug
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - José Luis Alatorre Warren
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
- Center for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo 0317, Norway
| | - Tadashi Shiohama
- Department of Pediatrics, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
| | - Christopher J McDougle
- Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA 02421, United States
- Department of Psychiatry, Harvard Medical School, Boston, MA 02215, United States
| | - Rachel E Marcus
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
- Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA 02421, United States
| | - Chieh-En Jane Tseng
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - Nicole R Zürcher
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
- Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA 02421, United States
| | - Nathaniel D Mercaldo
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
| | - Susan Faja
- Division of Developmental Medicine, Department of Pediatrics, Harvard School of Medicine, Boston, MA 02215, United States
| | - Alika Maunakea
- Department of Anatomy, Biochemistry, and Physiology (ABP), John A. Burns School of Medicine (JABSOM), University of Hawaii, Manoa, Honolulu, HI 96813, United States
| | - Jacob Hooker
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
- Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA 02421, United States
| | - Emi Takahashi
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
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7
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Kuriakose D, Zhu HM, Zhao YL, Iraqi FA, Morahan G, Xiao ZC. Upstream regulation of microRNA-9 through a complex cellular machinery during neurogenesis. Brain Res 2025; 1848:149328. [PMID: 39547498 DOI: 10.1016/j.brainres.2024.149328] [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: 10/16/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 11/17/2024]
Abstract
While microRNAs (miRs) like miR-9 are crucial for neurogenesis and neuronal differentiation, their regulatory mechanisms are not well understood. miR-9 is highly expressed in the brain and plays a significant role in neurogenesis. Using the Collaborative Cross resource, we identified significant quantitative trait loci (QTL) through genetic analyses. We then characterized over 130 candidate genes within these QTL regions using RNA interference, qPCR, and neuronal differentiation assays, narrowing them down to 13 promising candidates. Among these, Panx2, Polr1c, and Mgea5 were found to colocalize in the neurogenic niches of the SVZ and DG regions, as shown by immunofluorescence. Further ChIP-seq and Co-IP analyses revealed their interaction and binding to the miR-9 locus, forming a DNA-protein regulatory complex we termed 'miRSome-9.' A 3C/ChIP-loop assay confirmed the chromatin organization of miRSome-9 at the miR-9 locus, shedding light on the upstream mechanisms regulating miR-9 expression during neurogenesis.
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Affiliation(s)
- Diji Kuriakose
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic 3800, Australia.
| | - Hong-Mei Zhu
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China
| | - Yi-Ling Zhao
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China
| | - Fuad A Iraqi
- Department of Human Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Grant Morahan
- Harry Perkins Institute of Medical Research, University of Western Australia of Medical Research, Perth, Australia
| | - Zhi-Cheng Xiao
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic 3800, Australia; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China.
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8
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Fattahi E, Kankam SB, Khoshnevisan A, Hashemi AP. Evaluating prognosis and survival in patients with glioblastoma in contact with subventricular zone: Tumor location and its correlation with prognosis. Med J Armed Forces India 2024; 80:S21-S28. [PMID: 39734827 PMCID: PMC11670616 DOI: 10.1016/j.mjafi.2022.06.012] [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: 01/23/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022] Open
Abstract
Background To explore the altered malignant behavior, prognosis and survival of glioblastoma in contact with Subventricular Zone (SVZ) and independent predictors on patients' overall survival. Method The records of 131 patients with supratentorial primary glioblastoma who underwent surgery at our hospital between 2012 and 2018 were reviewed retrospectively. The authors reviewed preoperative MRI images and divided patients into two groups: Glioblastoma not in contact with SVZ (G-SVZ) and glioblastoma in contact with SVZ (G + SVZ). They computed and compared the overall survival (OS) of these two groups using the Kaplan-Meier method. The correlation between G + SVZ and OS was investigated using the Cox Proportional Hazard Ratio Model. Results The median progression-free survival (PFS) of the patient was 10 months (Interquartile Range), and the median OS was 13 months. At six months and one year, the OS was 81 percent and 51.1 percent, respectively. Patients with G + SVZ and G-SVZ had a median OS of 12 months and 15 months, respectively (p = 0.0093). According to Cox Multivariate model, repeat surgery (p = 0.001), among other independent predictors, including age ≥60, Karnofsky Performance Score (KPS) < 70, and extent of resection (Subtotal/biopsy vs total resection), had the strongest associated decreased OS. G + SVZ independently correlated significantly with reduced patient survival (p = 0.014). Conclusion Repeat surgery had the strongest association with decreased OS among the independent predictors of survival in patients with G + SVZ lesions. Prospective studies about molecular mechanisms are needed to explain why G + SVZ lesions are thought to be aggressive and associated with a poor prognosis.
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Affiliation(s)
- Ehsan Fattahi
- Department of Neurosurgery, Zanjan University of Medical Sciences, Kesharvaz Street, Zanjan, Iran
- Department of Neurosurgery, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Kesharvaz Street, Tehran, Iran
| | - Samuel Berchi Kankam
- Department of Neurosurgery, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Kesharvaz Street, Tehran, Iran
| | - Alireza Khoshnevisan
- Department of Neurosurgery, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Kesharvaz Street, Tehran, Iran
| | - Amir Pajman Hashemi
- Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Kesharvaz Street, Tehran, Iran
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9
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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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10
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Ghanbari A, Rad F, Shahraki MH, Hosseini E, Barmak MJ, Zibara K. Human mesenchymal stem cells-derived microvesicles increase oligodendrogenesis and neurogenesis of cultured adult neural stem cells. Neurosci Lett 2024; 841:137951. [PMID: 39191299 DOI: 10.1016/j.neulet.2024.137951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024]
Abstract
Mesenchymal stem cells (MSCs) are involved in tissue repair and anti-inflammatory activities and have shown promising therapeutic efficiency in different animal models of neurodegenerative disorders. Microvesicles (MVs), implicated in cellular communication, are secreted from MSCs and play a key role in determining the fate of cell differentiation. Our study examines the effect of human umbilical cord MSC-derived MVs (hUC-MSC MVs) on the proliferation and differentiation potential of adult neural stem cells (NSCs). Results showed that 0.2 μg MSC derived MVs significantly increased the viability of NSCs and their proliferation, as demonstrated by an increase in the number of neurospheres and their derived cells, compared to controls. In addition, all hUC-MSC MVs concentrations (0.1, 0.2 and 0.4 µg) induced the differentiation of NSCs toward precursors (Olig2 + ) and mature oligodendrocytes (MBP+). This increase in mature oligodendrocytes was inversely proportional to the dose of MVs. Moreover, hUC-MSC MVs induced the differentiation of NSCs into neurons (β-tubulin + ), in a dose-dependent manner, but had no effect on astrocytes (GFAP+). Furthermore, treatment of NSCs with hUC-MSC MVs (0.1 and 0.2 μg) significantly increased the expression levels of the proliferation marker Ki67 gene, compared to controls. Finally, hUC-MSC MVs (0.1 μg) significantly increased the expression level of Sox10 transcripts; but not Pax6 gene, demonstrating an increased NSC ability to differentiate into oligodendrocytes. In conclusion, our study showed that hUC-MSC MVs increased NSC proliferation in vitro and induced NSC differentiation into oligodendrocytes and neurons, but not astrocytes.
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Affiliation(s)
- Amir Ghanbari
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fariba Rad
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | | | - Ebrahim Hosseini
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mehrzad Jafari Barmak
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Kazem Zibara
- PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
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11
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Toader C, Radoi MP, Dumitru A, Glavan LA, Covache-Busuioc RA, Popa AA, Costin HP, Corlatescu AD, Ciurea AV. High-Grade Thalamic Glioma: Case Report with Literature Review. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1667. [PMID: 39459454 PMCID: PMC11509817 DOI: 10.3390/medicina60101667] [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: 08/09/2024] [Revised: 09/24/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024]
Abstract
This case report delves into the case of a 56-year-old female patient presenting with progressive cephalalgia syndrome, nausea, vomiting, and gait disorders, diagnosed with a high-grade thalamic glioma. Glioma is the most common form of central nervous system (CNS) neoplasm that originates from glial cells. Gliomas are diffusely infiltrative tumors that affect the surrounding brain tissue. Glioblastoma is the most malignant type, while pilocytic astrocytomas are the least malignant brain tumors. In the past, these diffuse gliomas were classified into different subtypes and grades based on histopathologies such as a diffuse astrocytoma, oligodendrogliomas, or mixed gliomas/oligoastrocytomas. Currently, gliomas are classified based on molecular and genetic markers. After the gross total resection, a postoperative brain CT scan was conducted, which confirmed the quasi-complete resection of the tumor. The successful gross total resection of the tumor in this case, coupled with significant neurological improvement postoperatively, illustrates the potential benefits of aggressive surgical management for thalamic gliomas. This report advocates for further research to assess the efficacy of such interventions in malignant cases and to establish standardized treatment protocols, considering the heterogeneity in prognostic outcomes and the advancements in molecular diagnostics that offer deeper insights into glioma oncogenesis and progression.
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Affiliation(s)
- Corneliu Toader
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
- Department of Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 020021 Bucharest, Romania
| | - Mugurel Petrinel Radoi
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
- Department of Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 020021 Bucharest, Romania
| | - Adrian Dumitru
- Department of Pathology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Pathology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania
| | - Luca-Andrei Glavan
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
| | - Razvan-Adrian Covache-Busuioc
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
| | - Andrei Adrian Popa
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
| | - Horia-Petre Costin
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
| | - Antonio-Daniel Corlatescu
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
| | - Alexandru Vladimir Ciurea
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.T.); (L.-A.G.); (R.-A.C.-B.); (A.A.P.); (H.-P.C.); (A.-D.C.); (A.V.C.)
- Department of Neurosurgery, Sanador Clinical Hospital, 011038 Bucharest, Romania
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12
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Ashraf M, Abdelsadg M, Grivas A. Relationship between molecular characteristics of glioblastoma multiforme and the subventricular zone. Br J Neurosurg 2024; 38:1100-1107. [PMID: 35038937 DOI: 10.1080/02688697.2021.2024144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/13/2021] [Accepted: 12/24/2021] [Indexed: 11/02/2022]
Abstract
OBJECTIVE This study aims to assess the relationship between the molecular characteristics of glioblastoma multiforme (GBM) and the subventricular zone (SVZ). MATERIAL AND METHODS Eligible patients had their data anonymously collected from an institutional database, including age, sex, preoperative performance status, the extent of tumour resection, anatomical location, IDH mutation and MGMT methylation status. An Institutional picture archiving and communications system was used for volumetric and morphometric analysis. All measurements were made on T1-weighted magnetic resonance images with gadolinium contrast enhancement. IDH wild-type and mutant GBMs were stratified by MGMT methylation status. The relationship between tumour volume, distance from the tumour's enhancing edge and the tumour's geometric centre to the SVZ and their molecular characteristics were assessed. RESULTS Fifty IDH wild-type GBMs were studied. Twenty-three were MGMT methylated, Twenty-seven were unmethylated. IDH wild-type MGMT methylated GBMs were significantly associated with a tumour's enhancing boundary being contiguous to the SVZ (P < 0.001). Ninety percent of tumours contiguous to the SVZ were wild-type methylated (n = 18) and 10% were unmethylated (n = 2). Mean GBM geometric centre distance to SVZ was significantly less for methylated wild-type GBMs compared to unmethylated (P = 0.025) and median GBM distance from the tumour's edge of enhancement to the SVZ was significantly shorter in methylated tumours compared to unmethylated (P < 0.001). Mean and median distances to SVZ from the edge of enhancement was 3.8 millimetres (mm) and 0 mm, respectively, for wild-type methylated GBMs, while for unmethylated wild-types, 14.6 mm, and 12.5 mm. There was no anatomical localisation of IDH wild-type GBMs by MGMT methylation status to a cerebral hemisphere or lobe. CONCLUSION IDH wild-type GBMs contiguous to the SVZ are highly likely to be MGMT methylated. Replication by further studies is required to affirm our results and conclusion.
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Affiliation(s)
- Mohammad Ashraf
- Department of Neurosurgery, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
- Medical Student, Wolfson School of Medicine, University of Glasgow, Scotland, UK
| | - Mohamed Abdelsadg
- Department of Neurosurgery, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
| | - Athanasios Grivas
- Department of Neurosurgery, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK
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13
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Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. SCIENCE ADVANCES 2024; 10:eadn1607. [PMID: 39110807 PMCID: PMC11305394 DOI: 10.1126/sciadv.adn1607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
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Affiliation(s)
- Emily S. Norton
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
- Regenerative Sciences Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Lauren A. Whaley
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Vanessa K. Jones
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Mieu M. Brooks
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Marissa N. Russo
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Dmytro Morderer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Erik Jessen
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | | | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Anna Carrano
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Wilfried Rossoll
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Yan W. Asmann
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | - TuKiet T. Lam
- Keck MS and Proteomics Resource, Yale School of Medicine, New Haven, CT 06510, USA
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06510, USA
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14
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Alonso M, Petit AC, Lledo PM. The impact of adult neurogenesis on affective functions: of mice and men. Mol Psychiatry 2024; 29:2527-2542. [PMID: 38499657 DOI: 10.1038/s41380-024-02504-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 02/22/2024] [Accepted: 02/27/2024] [Indexed: 03/20/2024]
Abstract
In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome was recognized with more difficulty. This review covers hypes and hopes of discovering the influence of newly-generated neurons on brain circuits devoted to affective functions. If the possibility of integrating new neurons into the adult brain is a commonly accepted faculty in the realm of mammals, the reluctance is strong when it comes to translating this concept to humans. Compiling data suggest now that new neurons are derived not only from stem cells, but also from a population of neuroblasts displaying a protracted maturation and ready to be engaged in adult brain circuits, under specific signals. Here, we discuss the significance of recruiting new neurons in the adult brain circuits, specifically in the context of affective outcomes. We also discuss the fact that adult neurogenesis could be the ultimate cellular process that integrates elements from both the internal and external environment to adjust brain functions. While we must be critical and beware of the unreal promises that Science could generate sometimes, it is important to continue exploring the potential of neural recruitment in adult primates. Reporting adult neurogenesis in humankind contributes to a new vision of humans as mammals whose brain continues to develop throughout life. This peculiar faculty could one day become the target of treatment for mental health, cognitive disorders, and elderly-associated diseases. The vision of an adult brain which never stops integrating new neurons is a real game changer for designing new therapeutic interventions to treat mental disorders associated with substantial morbidity, mortality, and social costs.
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Affiliation(s)
- Mariana Alonso
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Action Unit, F-75015, Paris, France
| | - Anne-Cécile Petit
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Action Unit, F-75015, Paris, France
- Pôle Hospitalo-Universitaire Psychiatrie Paris 15, GHU Paris Psychiatry and Neurosciences, Hôpital Sainte-Anne, Paris, France
| | - Pierre-Marie Lledo
- Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Perception and Action Unit, F-75015, Paris, France.
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15
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Herman J, Rittenhouse N, Mandino F, Majid M, Wang Y, Mezger A, Kump A, Kadian S, Lake EMR, Verardi PH, Conover JC. Ventricular-subventricular zone stem cell niche adaptations in a mouse model of post-infectious hydrocephalus. Front Neurosci 2024; 18:1429829. [PMID: 39145299 PMCID: PMC11322059 DOI: 10.3389/fnins.2024.1429829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 07/02/2024] [Indexed: 08/16/2024] Open
Abstract
Congenital post-infectious hydrocephalus (PIH) is a condition characterized by enlargement of the ventricular system, consequently imposing a burden on the associated stem cell niche, the ventricular-subventricular zone (V-SVZ). To investigate how the V-SVZ adapts in PIH, we developed a mouse model of influenza virus-induced PIH based on direct intracerebroventricular injection of mouse-adapted influenza virus at two distinct time points: embryonic day 16 (E16), when stem cells line the ventricle, and postnatal day 4 (P4), when an ependymal monolayer covers the ventricle surface and stem cells retain only a thin ventricle-contacting process. Global hydrocephalus with associated regions of astrogliosis along the lateral ventricle was found in 82% of the mice infected at P4. Increased ependymogenesis was observed at gliotic borders and throughout areas exhibiting intact ependyma based on tracking of newly divided cells. Additionally, in areas of intact ependyma, stem cell numbers were reduced; however, we found no significant reduction in new neurons reaching the olfactory bulb following onset of ventriculomegaly. At P4, injection of only the non-infectious viral component neuraminidase resulted in limited, region-specific ventriculomegaly due to absence of cell-to-cell transmission. In contrast, at E16 intracerebroventricular injection of influenza virus resulted in death at birth due to hypoxia and multiorgan hemorrhage, suggesting an age-dependent advantage in neonates, while the viral component neuraminidase resulted in minimal, or no, ventriculomegaly. In summary, we tracked acute adaptations of the V-SVZ stem cell niche following onset of ventriculomegaly and describe developmental changes that help mitigate the severity of congenital PIH.
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Affiliation(s)
- Julianna Herman
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Nicole Rittenhouse
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Francesca Mandino
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States
| | - Mushirah Majid
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Yuxiang Wang
- Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT, United States
| | - Amelia Mezger
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Aidan Kump
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Sumeet Kadian
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
| | - Evelyn M. R. Lake
- Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States
- Department of Biomedical Engineering, Yale University, New Haven, CT, United States
- Wu Tsai Institute, Yale University, New Haven, CT, United States
| | - Paulo H. Verardi
- Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT, United States
| | - Joanne C. Conover
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, United States
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16
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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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17
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Baig S, Nadaf J, Allache R, Le PU, Luo M, Djedid A, Nkili-Meyong A, Safisamghabadi M, Prat A, Antel J, Guiot MC, Petrecca K. Identity and nature of neural stem cells in the adult human subventricular zone. iScience 2024; 27:109342. [PMID: 38495819 PMCID: PMC10940989 DOI: 10.1016/j.isci.2024.109342] [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: 10/03/2023] [Revised: 12/26/2023] [Accepted: 02/22/2024] [Indexed: 03/19/2024] Open
Abstract
The existence of neural stem cells (NSCs) in adult human brain neurogenic regions remains unresolved. To address this, we created a cell atlas of the adult human subventricular zone (SVZ) derived from fresh neurosurgical samples using single-cell transcriptomics. We discovered 2 adult radial glia (RG)-like populations, aRG1 and aRG2. aRG1 shared features with fetal early RG (eRG) and aRG2 were transcriptomically similar to fetal outer RG (oRG). We also captured early neuronal and oligodendrocytic NSC states. We found that the biological programs driven by their transcriptomes support their roles as early lineage NSCs. Finally, we show that these NSCs have the potential to transition between states and along lineage trajectories. These data reveal that multipotent NSCs reside in the adult human SVZ.
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Affiliation(s)
- Salma Baig
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Javad Nadaf
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Redouane Allache
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Phuong U. Le
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Michael Luo
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Annisa Djedid
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Andriniaina Nkili-Meyong
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Maryam Safisamghabadi
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Alex Prat
- Neuroimmunology Research Lab, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X0A9, Canada
| | - Jack Antel
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Marie-Christine Guiot
- Department of Neuropathology, Montreal Neurological Institute-Hospital, McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
| | - Kevin Petrecca
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital McGill University, 3801 University Avenue, Montreal QC H3A2B4, Canada
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18
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Basaia S, Zavarella M, Rugarli G, Sferruzza G, Cividini C, Canu E, Cacciaguerra L, Bacigaluppi M, Martino G, Filippi M, Agosta F. Caudate functional networks influence brain structural changes with aging. Brain Commun 2024; 6:fcae116. [PMID: 38665962 PMCID: PMC11043654 DOI: 10.1093/braincomms/fcae116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/22/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Neurogenesis decline with aging may be associated with brain atrophy. Subventricular zone neuron precursor cells possibly modulate striatal neuronal activity via the release of soluble molecules. Neurogenesis decay in the subventricular zone may result in structural alterations of brain regions connected to the caudate, particularly to its medial component. The aim of this study was to investigate how the functional organization of caudate networks relates to structural brain changes with aging. One hundred and fifty-two normal subjects were recruited: 52 young healthy adults (≤35 years old), 42 middle-aged (36 ≤ 60 years old) and 58 elderly subjects (≥60 years old). In young adults, stepwise functional connectivity was used to characterize regions that connect to the medial and lateral caudate at different levels of link-step distances. A statistical comparison between the connectivity of medial and lateral caudate in young subjects was useful to define medial and lateral caudate connected regions. Atrophy of medial and lateral caudate connected regions was estimated in young, middle-aged and elderly subjects using T1-weighted images. Results showed that middle-aged and elderly adults exhibited decreased stepwise functional connectivity at one-link step from the caudate, particularly in the frontal, parietal, temporal and occipital brain regions, compared to young subjects. Elderly individuals showed increased stepwise functional connectivity in frontal, parietal, temporal and occipital lobes compared to both young and middle-aged adults. Additionally, elderly adults displayed decreased stepwise functional connectivity compared to middle-aged subjects in specific parietal and subcortical areas. Moreover, in young adults, the medial caudate showed higher direct connectivity to the basal ganglia (left thalamus), superior, middle and inferior frontal and inferior parietal gyri (medial caudate connected region) relative to the lateral caudate. Considering the opposite contrast, lateral caudate showed stronger connectivity to the basal ganglia (right pallidum), orbitofrontal, rostral anterior cingulate and insula cortices (lateral caudate connected region) compared to medial caudate. In elderly subjects, the medial caudate connected region showed greater atrophy relative to the lateral caudate connected region. Brain regions linked to the medial caudate appear to be more vulnerable to aging than lateral caudate connected areas. The adjacency to the subventricular zone may, at least partially, explain these findings. Stepwise functional connectivity analysis can be useful to evaluate the role of the subventricular zone in network disruptions in age-related neurodegenerative disorders.
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Affiliation(s)
- Silvia Basaia
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Matteo Zavarella
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Giulia Rugarli
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Giacomo Sferruzza
- Vita-Salute San Raffaele University, 20132 Milan, Italy
- Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Camilla Cividini
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Elisa Canu
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Laura Cacciaguerra
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marco Bacigaluppi
- Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Gianvito Martino
- Vita-Salute San Raffaele University, 20132 Milan, Italy
- Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Massimo Filippi
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
- Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Neurophysiology Service, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Federica Agosta
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
- Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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Al-Dalahmah O, Sosunov AA, Sun Y, Liu Y, Madden N, Connolly ES, Troy CM, McKhann GM, Goldman JE. The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures. Cells 2024; 13:129. [PMID: 38247821 PMCID: PMC10814649 DOI: 10.3390/cells13020129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 11/20/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024] Open
Abstract
In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial "interlaminar" astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease.
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Affiliation(s)
- Osama Al-Dalahmah
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - Alexander A. Sosunov
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - Yu Sun
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - Yang Liu
- Department of Pathology, Albany Medical Center, Albany, NY 12208, USA
| | - Nacoya Madden
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
| | - E. Sander Connolly
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - Carol M. Troy
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- The Taub Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Guy M. McKhann
- Department of Neurosurgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA (E.S.C.)
| | - James E. Goldman
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY 10032, USA
- The Taub Institute, Columbia University Irving Medical Center, New York, NY 10032, USA
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20
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Yoshida K, Chambers JK, Nibe K, Kagawa Y, Uchida K. Immunohistochemical analyses of neural stem cell lineage markers in normal feline brains and glial tumors. Vet Pathol 2024; 61:46-57. [PMID: 37358305 DOI: 10.1177/03009858231182337] [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: 06/27/2023]
Abstract
Neural stem cell (NSC) lineage cells have not been fully identified in feline brains, and the NSC-like nature of feline glial tumors has not been determined. In this study, 6 normal cat brains (3 newborn and 3 older cats) and 13 feline glial tumors were analyzed using immunohistochemical NSC lineage markers. The feline glial tumors were subjected to immunohistochemical scoring followed by hierarchical cluster analysis. In newborn brains, glial acidic fibrillary protein (GFAP)/nestin/sex-determining region Y-box transcription factor 2 (SOX2)-immunopositive NSCs, SOX2-immunopositive intermediate progenitor cells, oligodendrocyte transcription factor 2 (OLIG2)/platelet-derived growth factor receptor-α (PDGFR-α)-immunopositive oligodendrocyte precursor cells (OPCs), OLIG2/GFAP-immunopositive immature astrocytes, and neuronal nuclear (NeuN)/β-3 tubulin-immunopositive mature neuronal cells were observed. The apical membrane of NSCs was also immunopositive for Na+/H+ exchanger regulatory factor 1 (NHERF1). In mature brains, the NSC lineage cells were similar to those of the newborn brains. A total of 13 glial tumors consisted of 2 oligodendrogliomas, 4 astrocytomas, 3 subependymomas, and 4 ependymomas. Astrocytomas, subependymomas, and ependymomas were immunopositive for GFAP, nestin, and SOX2. Subependymomas and ependymomas showed dot-like or apical membrane immunolabeling for NHERF1, respectively. Astrocytomas were immunopositive for OLIG2. Oligodendrogliomas and subependymomas were immunopositive for OLIG2 and PDGFR-α. Feline glial tumors also showed variable immunolabeling for β-3 tubulin, NeuN, and synaptophysin. Based on these results, feline astrocytomas, subependymomas, and ependymomas appear to have an NSC-like immunophenotype. In addition, astrocytomas, subependymomas, and ependymomas have the characteristics of glial, oligodendrocyte precursor, and ependymal cells, respectively. Feline oligodendrogliomas likely have an OPC-like immunophenotype. In addition, feline glial tumors may have multipotential stemness for differentiation into neuronal cells. These preliminary results should be validated by gene expression analyses in future studies with larger case numbers.
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Affiliation(s)
| | | | - Kazumi Nibe
- FUJIFILM VET Systems Co., Ltd., Tokyo, Japan
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21
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Riley VA, Shankar V, Holmberg JC, Sokolov AM, Neckles VN, Williams K, Lyman R, Mackay TF, Feliciano DM. Tsc2 coordinates neuroprogenitor differentiation. iScience 2023; 26:108442. [PMID: 38107199 PMCID: PMC10724693 DOI: 10.1016/j.isci.2023.108442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/22/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate numerous cell types. The uncoupling of mRNA transcript availability and translation occurs during the progression from stem to differentiated states. The mTORC1 kinase pathway acutely controls proteins that regulate mRNA translation. Inhibiting mTORC1 during differentiation is hypothesized to be critical for brain development since somatic mutations of mTORC1 regulators perturb brain architecture. Inactivating mutations of TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC). TSC patients have growths near the striatum and ventricles. Here, it is demonstrated that V-SVZ NSC Tsc2 inactivation causes striatal hamartomas. Tsc2 removal altered translation factors, translatomes, and translational efficiency. Single nuclei RNA sequencing following in vivo loss of Tsc2 revealed changes in NSC activation states. The inability to decouple mRNA transcript availability and translation delayed differentiation leading to the retention of immature phenotypes in hamartomas. Taken together, Tsc2 is required for translational repression and differentiation.
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Affiliation(s)
- Victoria A. Riley
- Department of Biological Sciences, Clemson University, Clemson, SC, USA
| | - Vijay Shankar
- Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA
- Center for Human Genetics, Clemson University, Greenwood, SC, USA
| | | | - Aidan M. Sokolov
- Department of Biological Sciences, Clemson University, Clemson, SC, USA
| | | | - Kaitlyn Williams
- Clemson University Genomics and Bioinformatics Facility (CUGBF), Clemson University, Clemson, SC, USA
| | - Rachel Lyman
- Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA
- Center for Human Genetics, Clemson University, Greenwood, SC, USA
| | - Trudy F.C. Mackay
- Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA
- Center for Human Genetics, Clemson University, Greenwood, SC, USA
| | - David M. Feliciano
- Department of Biological Sciences, Clemson University, Clemson, SC, USA
- Center for Human Genetics, Clemson University, Greenwood, SC, USA
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22
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Washausen S, Knabe W. Patterns of senescence and apoptosis during development of branchial arches, epibranchial placodes, and pharyngeal pouches. Dev Dyn 2023; 252:1189-1223. [PMID: 37345578 DOI: 10.1002/dvdy.637] [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: 02/03/2022] [Revised: 04/27/2023] [Accepted: 05/31/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Many developmental processes are coregulated by apoptosis and senescence. However, there is a lack of data on the development of branchial arches, epibranchial placodes, and pharyngeal pouches, which harbor epibranchial signaling centers. RESULTS Using immunohistochemical, histochemical, and 3D reconstruction methods, we show that in mice, senescence and apoptosis together may contribute to the invagination of the branchial clefts and the deepening of the cervical sinus floor, in antagonism to the proliferation acting in the evaginating branchial arches. The concomitant apoptotic elimination of lateral line rudiments occurs in the absence of senescence. In the epibranchial placodes, senescence and apoptosis appear to (1) support invagination or at least indentation by immobilizing the margins of the centrally proliferating pit, (2) coregulate the number and fate of Pax8+ precursors, (3) progressively narrow neuroblast delamination sites, and (4) contribute to placode regression. Putative epibranchial signaling centers in the pharyngeal pouches are likely deactivated by rostral senescence and caudal apoptosis. CONCLUSIONS Our results reveal a plethora of novel patterns of apoptosis and senescence, some overlapping, some complementary, whose functional contributions to the development of the branchial region, including the epibranchial placodes and their signaling centers, can now be tested experimentally.
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Affiliation(s)
- Stefan Washausen
- Prosektur Anatomie, Westfälische Wilhelms-Universität Münster, Münster, Germany
| | - Wolfgang Knabe
- Prosektur Anatomie, Westfälische Wilhelms-Universität Münster, Münster, Germany
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23
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Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553966. [PMID: 37662251 PMCID: PMC10473635 DOI: 10.1101/2023.08.19.553966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. Highlights Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.GBM stalls neurogenesis and promotes NPC senescence via CTSB.
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24
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Jiménez-Madrona E, Morado-Díaz CJ, Talaverón R, Tabernero A, Pastor AM, Sáez JC, Matarredona ER. Antiproliferative effect of boldine on neural progenitor cells and on glioblastoma cells. Front Neurosci 2023; 17:1211467. [PMID: 37655012 PMCID: PMC10467274 DOI: 10.3389/fnins.2023.1211467] [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: 04/24/2023] [Accepted: 08/02/2023] [Indexed: 09/02/2023] Open
Abstract
Introduction The subventricular zone (SVZ) is a brain region that contains neural stem cells and progenitor cells (NSCs/NPCs) from which new neurons and glial cells are formed during adulthood in mammals. Recent data indicate that SVZ NSCs are the cell type that acquires the initial tumorigenic mutation in glioblastoma (GBM), the most aggressive form of malignant glioma. NSCs/NPCs of the SVZ present hemichannel activity whose function has not yet been fully elucidated. In this work, we aimed to analyze whether hemichannel-mediated communication affects proliferation of SVZ NPCs and GBM cells. Methods and Results For that purpose, we used boldine, an alkaloid derived from the boldo tree (Peumus boldus), that inhibits connexin and pannexin hemichannels, but without affecting gap junctional communication. Boldine treatment (50 μM) of rat SVZ NPCs grown as neurospheres effectively inhibited dye uptake through hemichannels and induced a significant reduction in neurosphere diameter and in bromodeoxyuridine (BrdU) incorporation. However, the differentiation pattern was not modified by the treatment. Experiments with specific blockers for hemichannels formed by connexin subunits (D4) or pannexin 1 (probenecid) revealed that probenecid, but not D4, produced a decrease in BrdU incorporation similar to that obtained with boldine. These results suggest that inhibition of pannexin 1 hemichannels could be partially responsible for the antiproliferative effect of boldine on SVZ NPCs. Analysis of the effect of boldine (25-600 μM) on different types of primary human GBM cells (GBM59, GBM96, and U87-MG) showed a concentration-dependent decrease in GBM cell growth. Boldine treatment also induced a significant inhibition of hemichannel activity in GBM cells. Discussion Altogether, we provide evidence of an antimitotic action of boldine in SVZ NPCs and in GBM cells which may be due, at least in part, to its hemichannel blocking function. These results could be of relevance for future possible strategies in GBM aimed to suppress the proliferation of mutated NSCs or glioma stem cells that might remain in the brain after tumor resection.
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Affiliation(s)
- Enrique Jiménez-Madrona
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca, Spain
| | - Camilo J. Morado-Díaz
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Rocío Talaverón
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain
| | - Arantxa Tabernero
- Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca, Spain
| | - Angel M. Pastor
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Juan C. Sáez
- Instituto de Neurociencia, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
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25
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García-Montaño LA, Licón-Muñoz Y, Martinez FJ, Keddari YR, Ziemke MK, Chohan MO, Piccirillo SG. Dissecting Intra-tumor Heterogeneity in the Glioblastoma Microenvironment Using Fluorescence-Guided Multiple Sampling. Mol Cancer Res 2023; 21:755-767. [PMID: 37255362 PMCID: PMC10390891 DOI: 10.1158/1541-7786.mcr-23-0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/25/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023]
Abstract
The treatment of the most aggressive primary brain tumor in adults, glioblastoma (GBM), is challenging due to its heterogeneous nature, invasive potential, and poor response to chemo- and radiotherapy. As a result, GBM inevitably recurs and only a few patients survive 5 years post-diagnosis. GBM is characterized by extensive phenotypic and genetic heterogeneity, creating a diversified genetic landscape and a network of biological interactions between subclones, ultimately promoting tumor growth and therapeutic resistance. This includes spatial and temporal changes in the tumor microenvironment, which influence cellular and molecular programs in GBM and therapeutic responses. However, dissecting phenotypic and genetic heterogeneity at spatial and temporal levels is extremely challenging, and the dynamics of the GBM microenvironment cannot be captured by analysis of a single tumor sample. In this review, we discuss the current research on GBM heterogeneity, in particular, the utility and potential applications of fluorescence-guided multiple sampling to dissect phenotypic and genetic intra-tumor heterogeneity in the GBM microenvironment, identify tumor and non-tumor cell interactions and novel therapeutic targets in areas that are key for tumor growth and recurrence, and improve the molecular classification of GBM.
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Affiliation(s)
- Leopoldo A. García-Montaño
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Yamhilette Licón-Muñoz
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Frank J. Martinez
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
| | - Yasine R. Keddari
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of California, Merced, California
| | - Michael K. Ziemke
- Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Muhammad O. Chohan
- Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Sara G.M. Piccirillo
- The Brain Tumor Translational Laboratory, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico
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26
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Nonoguchi HA, Jin M, Narreddy R, Kouo TWS, Nayak M, Trenet W, Mandyam CD. Progenitor Cells Play a Role in Reinstatement of Ethanol Seeking in Adult Male and Female Ethanol Dependent Rats. Int J Mol Sci 2023; 24:12233. [PMID: 37569609 PMCID: PMC10419311 DOI: 10.3390/ijms241512233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Female and male glial fibrillary acidic protein-thymidine kinase (GFAP-TK) transgenic rats were made ethanol dependent via a six-week chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. During the last week of CIE, a subset of male and female TK rats was fed valcyte to ablate dividing progenitor cells and continued the diet until the end of this study. Following week six, all CIE rats experienced two weeks of forced abstinence from CIE-ED, after which they experienced relapse to drinking, extinction, and reinstatement of ethanol seeking sessions. CIE increased ED in female and male rats, with females having higher ethanol consumption during CIE and relapse sessions compared with males. In both sexes, valcyte reduced the levels of Ki-67-labeled progenitor cells in the subgranular zone of the dentate gyrus and did not alter the levels in the medial prefrontal cortex (mPFC). Valcyte increased ED during relapse, increased lever responses during extinction and, interestingly, enhanced latency to extinguish ethanol-seeking behaviors in males. Valcyte reduced the reinstatement of ethanol-seeking behaviors triggered by ethanol cues in females and males. Reduced seeking by valcyte was associated with the normalization of cytokines and chemokines in plasma isolated from trunk blood, indicating a role for progenitor cells in peripheral inflammatory responses. Reduced seeking by valcyte was associated with increases in tight junction protein claudin-5 and oligodendrogenesis in the dentate gyrus and reduction in microglial activity in the dentate gyrus and mPFC in females and males, demonstrating a role for progenitor cells in the dentate gyrus in dependence-induced endothelial and microglial dysfunction. These data suggest that progenitor cells born during withdrawal and abstinence from CIE in the dentate gyrus are aberrant and could play a role in strengthening ethanol memories triggered by ethanol cues via central and peripheral immune responses.
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Affiliation(s)
| | - Michael Jin
- VA San Diego Healthcare System, San Diego, CA 92161, USA
| | | | | | | | - Wulfran Trenet
- VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Chitra D. Mandyam
- VA San Diego Healthcare System, San Diego, CA 92161, USA
- Department of Anesthesiology, University of California San Diego, San Diego, CA 92161, USA
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Blasco-Chamarro L, Fariñas I. Fine-tuned rest: unveiling the regulatory landscape of adult quiescent neural stem cells. Neuroscience 2023:S0306-4522(23)00298-1. [PMID: 37437796 DOI: 10.1016/j.neuroscience.2023.07.003] [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: 06/09/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/14/2023]
Abstract
Cell quiescence is an essential mechanism that allows cells to temporarily halt proliferation while preserving the potential to resume it at a later time. The molecular mechanisms underlying cell quiescence are complex and involve the regulation of various signaling pathways, transcription factors and epigenetic modifications. The importance of unveiling the mechanisms regulating the quiescent state is undeniable, as its long-term maintenance is key to sustain tissue homeostasis throughout life. Neural stem cells (NSCs) are maintained in the subependymal zone (SEZ) niche of adult mammalian brains mostly as long-lasting quiescent cells, owing to multiple intrinsic and extrinsic cues that actively regulate this state. Differently from other non-proliferative states, quiescence is a reversible and tightly regulated condition that can re-activate to support the formation of new neurons throughout adult lifespan. Decoding its regulatory mechanisms in homeostasis and unveiling how it is modulated in the context of the aged brain or during tumorigenesis, could bring us closer to the development of new potential strategies to intervene in adult neurogenesis with therapeutic purposes. Starting with a general conceptualization of the quiescent state in different stem cell niches, we here review what we have learned about NSC quiescence in the SEZ, encompassing the experimental strategies used for its study, to end up discussing the modulation of quiescence in the context of a physiology or pathological NSC dysregulation.
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Affiliation(s)
- Laura Blasco-Chamarro
- Biomedical Research Network on Neurodegenerative Diseases (CIBERNED); Department of Cell Biology; Biotechnology and Biomedicine Institute (BioTecMed), University of Valencia, Spain
| | - Isabel Fariñas
- Biomedical Research Network on Neurodegenerative Diseases (CIBERNED); Department of Cell Biology; Biotechnology and Biomedicine Institute (BioTecMed), University of Valencia, Spain.
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Visser VL, Caçoilo A, Rusinek H, Weickenmeier J. Mechanical loading of the ventricular wall as a spatial indicator for periventricular white matter degeneration. J Mech Behav Biomed Mater 2023; 143:105921. [PMID: 37269602 PMCID: PMC10266836 DOI: 10.1016/j.jmbbm.2023.105921] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 06/05/2023]
Abstract
Progressive white matter degeneration in periventricular and deep white matter regions appears as white matter hyperintensities (WMH) on MRI scans. To date, periventricular WMHs are often associated with vascular dysfunction. Here, we demonstrate that ventricular inflation resulting from cerebral atrophy and hemodynamic pulsation with every heartbeat leads to a mechanical loading state of periventricular tissues that significantly affects the ventricular wall. Specifically, we present a physics-based modeling approach that provides a rationale for ependymal cell involvement in periventricular WMH formation. Building on eight previously created 2D finite element brain models, we introduce novel mechanomarkers for ependymal cell loading and geometric measures that characterize lateral ventricular shape. We show that our novel mechanomarkers, such as maximum ependymal cell deformations and maximum curvature of the ventricular wall, spatially overlap with periventricular WMH locations and are sensitive predictors for WMH formation. We also explore the role of the septum pellucidum in mitigating mechanical loading of the ventricular wall by constraining the radial expansion of the lateral ventricles during loading. Our models consistently show that ependymal cells are stretched thin only in the horns of the ventricles irrespective of ventricular shape. We therefore pose that periventricular WMH etiology is strongly linked to the deterioration of the over-stretched ventricular wall resulting in CSF leakage into periventricular white matter. Subsequent secondary damage mechanisms, including vascular degeneration, exacerbate lesion formation and lead to progressive growth into deep white matter regions.
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Affiliation(s)
- Valery L Visser
- Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States of America; Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
| | - Andreia Caçoilo
- Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States of America
| | - Henry Rusinek
- Department of Radiology, New York University Grossman School of Medicine, New York, NY 10016, United States of America
| | - Johannes Weickenmeier
- Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, United States of America.
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Russo MN, Whaley LA, Norton ES, Zarco N, Guerrero-Cázares H. Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective. Mol Aspects Med 2023; 91:101167. [PMID: 36577547 PMCID: PMC10073317 DOI: 10.1016/j.mam.2022.101167] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.
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Affiliation(s)
- Marissa N Russo
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Biology Graduate Program, University of North Florida, Jacksonville, FL, USA
| | - Emily S Norton
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, 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
| | - Natanael Zarco
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA
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Loras A, Gonzalez-Bonet LG, Gutierrez-Arroyo JL, Martinez-Cadenas C, Marques-Torrejon MA. Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life (Basel) 2023; 13:life13040905. [PMID: 37109434 PMCID: PMC10145968 DOI: 10.3390/life13040905] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults and it remains incurable. These tumors are very heterogeneous, resistant to cytotoxic therapies, and they show high rates of invasiveness. Therefore, patients face poor prognosis, and the survival rates remain very low. Previous research states that GBM contains a cell population with stem cell characteristics called glioma stem cells (GSCs). These cells are able to self-renew and regenerate the tumor and, therefore, they are partly responsible for the observed resistance to therapies and tumor recurrence. Recent data indicate that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells of origin of GBM, that is, the cell type acquiring the initial tumorigenic mutation. The involvement of SVZ-NSCs is also associated with GBM progression and recurrence. Identifying the cellular origin of GBM is important for the development of early detection techniques and the discovery of early disease markers. In this review, we analyze the SVZ-NSC population as a potential GBM cell of origin, and its potential role for GBM therapies.
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Affiliation(s)
- Alba Loras
- Department of Medicine, University of Valencia, 46010 Valencia, Spain
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
| | - Luis G. Gonzalez-Bonet
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon de la Plana, Spain
| | - Julia L. Gutierrez-Arroyo
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
- Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon de la Plana, Spain
| | | | - Maria Angeles Marques-Torrejon
- Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
- Correspondence: ; Tel.: +34-964-387-478
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Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy. Int J Mol Sci 2023; 24:ijms24065665. [PMID: 36982740 PMCID: PMC10055343 DOI: 10.3390/ijms24065665] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/12/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, “Reprogramming Therapy”, which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.
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Ohno Y, Nakajima C, Ajioka I, Muraoka T, Yaguchi A, Fujioka T, Akimoto S, Matsuo M, Lotfy A, Nakamura S, Herranz-Pérez V, García-Verdugo JM, Matsukawa N, Kaneko N, Sawamoto K. Amphiphilic peptide-tagged N-cadherin forms radial glial-like fibers that enhance neuronal migration in injured brain and promote sensorimotor recovery. Biomaterials 2023; 294:122003. [PMID: 36736095 DOI: 10.1016/j.biomaterials.2023.122003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 12/05/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)3-(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy.
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Affiliation(s)
- Yuya Ohno
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan; Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Chikako Nakajima
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Itsuki Ajioka
- Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510, Japan; Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa, 243-0435, Japan
| | - Takahiro Muraoka
- Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa, 243-0435, Japan; Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo, 184-8588, Japan
| | - Atsuya Yaguchi
- Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo, 184-8588, Japan
| | - Teppei Fujioka
- Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Saori Akimoto
- Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510, Japan; Kanagawa Institute of Industrial Science and Technology (KISTEC), Kanagawa, 243-0435, Japan
| | - Misaki Matsuo
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Ahmed Lotfy
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Sayuri Nakamura
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Vicente Herranz-Pérez
- Laboratory of Comparative Neurobiology, Cavanilles Institute, University of Valencia, CIBERNED, Valencia, 46980, Spain
| | - José Manuel García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute, University of Valencia, CIBERNED, Valencia, 46980, Spain
| | - Noriyuki Matsukawa
- Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan
| | - Naoko Kaneko
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan; Laboratory of Neuronal Regeneration, Graduate School of Brain Science, Doshisha University, Kyotanabe, Kyoto, 610-0394, Japan.
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, 467-8601, Japan; Division of Neural Development and Regeneration, National Institute of Physiological Sciences, Okazaki, Aichi, 444-8585, Japan.
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Takahashi E, Allan N, Peres R, Ortug A, van der Kouwe AJW, Valli B, Ethier E, Levman J, Baumer N, Tsujimura K, Vargas-Maya NI, McCracken TA, Lee R, Maunakea AK. Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study. Front Neurosci 2023; 16:1023665. [PMID: 36817099 PMCID: PMC9935943 DOI: 10.3389/fnins.2022.1023665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 12/20/2022] [Indexed: 02/05/2023] Open
Abstract
Introduction Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain. Methods We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR. Results Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens. Conclusion These findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.
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Affiliation(s)
- Emi Takahashi
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Nina Allan
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Rafael Peres
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Alpen Ortug
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Andre J. W. van der Kouwe
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Briana Valli
- Department of Behavioral Neuroscience, Northeastern University, Boston, MA, United States
| | - Elizabeth Ethier
- Department of Behavioral Neuroscience, Northeastern University, Boston, MA, United States
| | - Jacob Levman
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Mathematics, Statistics and Computer Science, St. Francis Xavier University, Antigonish, NS, Canada
| | - Nicole Baumer
- Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Keita Tsujimura
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Nauru Idalia Vargas-Maya
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Trevor A. McCracken
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Rosa Lee
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
| | - Alika K. Maunakea
- Epigenomics Research Program, Department of Anatomy, Institute for Biogenesis Research, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai’i at Mānoa, Honolulu, HI, United States
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Elias AE, Nuñez TA, Kun B, Kreiling JA. primiReference: a reference for analysis of primary-microRNA expression in single-nucleus sequencing data. J Genet Genomics 2023; 50:108-121. [PMID: 36371075 PMCID: PMC9974815 DOI: 10.1016/j.jgg.2022.10.003] [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: 06/28/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022]
Abstract
Single-nucleus RNA-sequencing technology has revolutionized understanding of nuanced changes in gene expression between cell types within tissues. Unfortunately, our understanding of regulatory RNAs, such as microRNAs (miRNAs), is limited through both single-cell and single-nucleus techniques due to the short length of miRNAs in the cytoplasm and the incomplete reference of longer primary miRNA (pri-miRNA) transcripts in the nucleus. We build a custom reference to align and count pri-miRNA sequences in single-nucleus data. Using young and aged subventricular zone (SVZ) nuclei, we show differential expression of pri-miRNAs targeting genes involved in neural stem cells (NSC) differentiation in the aged SVZ. Furthermore, using wild-type and 5XFAD mouse model cortex nuclei, to validate the use of primiReference, we find cell-type-specific expression of pri-miRNAs known to be involved in Alzheimer's disease (AD). pri-miRNAs likely contribute to NSC dysregulation with age and AD pathology. primiReference is paramount in capturing a global profile of gene expression and regulation in single-nucleus data and can provide key insights into cell-type-specific expression of pri-miRNAs, paving the way for future studies of regulation and pathway dysregulation. By looking at pri-miRNA abundance and transcriptional differences, regulation of gene expression by miRNAs in disease and aging can be further explored.
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Affiliation(s)
- Amy E Elias
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Thomas A Nuñez
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Bianca Kun
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA
| | - Jill A Kreiling
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA.
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Ghibaudi M, Amenta A, Agosti M, Riva M, Graïc JM, Bifari F, Bonfanti L. Consistency and Variation in Doublecortin and Ki67 Antigen Detection in the Brain Tissue of Different Mammals, including Humans. Int J Mol Sci 2023; 24:2514. [PMID: 36768845 PMCID: PMC9916846 DOI: 10.3390/ijms24032514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
Recently, a population of "immature" neurons generated prenatally, retaining immaturity for long periods and finally integrating in adult circuits has been described in the cerebral cortex. Moreover, comparative studies revealed differences in occurrence/rate of different forms of neurogenic plasticity across mammals, the "immature" neurons prevailing in gyrencephalic species. To extend experimentation from laboratory mice to large-brained mammals, including humans, it is important to detect cell markers of neurogenic plasticity in brain tissues obtained from different procedures (e.g., post-mortem/intraoperative specimens vs. intracardiac perfusion). This variability overlaps with species-specific differences in antigen distribution or antibody species specificity, making it difficult for proper comparison. In this work, we detect the presence of doublecortin and Ki67 antigen, markers for neuronal immaturity and cell division, in six mammals characterized by widely different brain size. We tested seven commercial antibodies in four selected brain regions known to host immature neurons (paleocortex, neocortex) and newly born neurons (hippocampus, subventricular zone). In selected human brains, we confirmed the specificity of DCX antibody by performing co-staining with fluorescent probe for DCX mRNA. Our results indicate that, in spite of various types of fixations, most differences were due to the use of different antibodies and the existence of real interspecies variation.
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Affiliation(s)
- Marco Ghibaudi
- Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, Italy
- Department of Veterinary Sciences, University of Turin, 10095 Torino, Italy
| | - Alessia Amenta
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Miriam Agosti
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Marco Riva
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Jean-Marie Graïc
- Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro, Italy
| | - Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
| | - Luca Bonfanti
- Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, Italy
- Department of Veterinary Sciences, University of Turin, 10095 Torino, Italy
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Medina S, Ihrie RA, Irish JM. Learning cell identity in immunology, neuroscience, and cancer. Semin Immunopathol 2023; 45:3-16. [PMID: 36534139 PMCID: PMC9762661 DOI: 10.1007/s00281-022-00976-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/19/2022] [Indexed: 12/23/2022]
Abstract
Suspension and imaging cytometry techniques that simultaneously measure hundreds of cellular features are powering a new era of cell biology and transforming our understanding of human tissues and tumors. However, a central challenge remains in learning the identities of unexpected or novel cell types. Cell identification rubrics that could assist trainees, whether human or machine, are not always rigorously defined, vary greatly by field, and differentially rely on cell intrinsic measurements, cell extrinsic tissue measurements, or external contextual information such as clinical outcomes. This challenge is especially acute in the context of tumors, where cells aberrantly express developmental programs that are normally time, location, or cell-type restricted. Well-established fields have contrasting practices for cell identity that have emerged from convention and convenience as much as design. For example, early immunology focused on identifying minimal sets of protein features that mark individual, functionally distinct cells. In neuroscience, features including morphology, development, and anatomical location were typical starting points for defining cell types. Both immunology and neuroscience now aim to link standardized measurements of protein or RNA to informative cell functions such as electrophysiology, connectivity, lineage potential, phospho-protein signaling, cell suppression, and tumor cell killing ability. The expansion of automated, machine-driven methods for learning cell identity has further created an urgent need for a harmonized framework for distinguishing cell identity across fields and technology platforms. Here, we compare practices in the fields of immunology and neuroscience, highlight concepts from each that might work well in the other, and propose ways to implement these ideas to study neural and immune cell interactions in brain tumors and associated model systems.
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Affiliation(s)
- Stephanie Medina
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rebecca A Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan M Irish
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
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Bartkowska K, Tepper B, Turlejski K, Djavadian R. Postnatal and Adult Neurogenesis in Mammals, Including Marsupials. Cells 2022; 11:cells11172735. [PMID: 36078144 PMCID: PMC9455070 DOI: 10.3390/cells11172735] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 12/11/2022] Open
Abstract
In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area.
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Affiliation(s)
- Katarzyna Bartkowska
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Beata Tepper
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Krzysztof Turlejski
- Faculty of Biology and Environmental Sciences, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland
| | - Ruzanna Djavadian
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
- Correspondence:
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Akindona FA, Frederico SC, Hancock JC, Gilbert MR. Exploring the origin of the cancer stem cell niche and its role in anti-angiogenic treatment for glioblastoma. Front Oncol 2022; 12:947634. [PMID: 36091174 PMCID: PMC9454306 DOI: 10.3389/fonc.2022.947634] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/08/2022] [Indexed: 11/21/2022] Open
Abstract
Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.
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Affiliation(s)
- Funto A. Akindona
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
| | - Stephen C. Frederico
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - John C. Hancock
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Mark R. Gilbert
- Neuro-Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Mark R. Gilbert,
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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: 13] [Impact Index Per Article: 4.3] [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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Yan Y, Dai W, Mei Q. Multicentric Glioma: An Ideal Model to Reveal the Mechanism of Glioma. Front Oncol 2022; 12:798018. [PMID: 35747806 PMCID: PMC9209746 DOI: 10.3389/fonc.2022.798018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
As a special type of glioma, multicentric glioma provides an ideal pathological model for glioma research. According to the stem-cell-origin theory, multiple lesions of multicentric glioma share the same neuro-oncological origin, both in gene level and in cell level. Although the number of studies focusing on genetic evolution in gliomas with the model of multicentric gliomas were limited, some mutations, including IDH1 mutations, TERTp mutations and PTEN deletions, are found to be at an early stage in the process of genetic aberrance during glioma evolution based on the results of these studies. This article reviews the clinical reports and genetic studies of multicentric glioma, and intends to explain the various clinical phenomena of multicentric glioma from the perspective of genetic aberrance accumulation and tumor cell evolution. The malignant degree of a glioma is determined by both the tumorigenicity of early mutant genes, and the stemness of early suffered cells.
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Affiliation(s)
- Yong Yan
- Departmentof Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Wei Dai
- Departmentof Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Qiyong Mei
- Departmentof Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
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Corell A, Gomez Vecchio T, Ferreyra Vega S, Dénes A, Neimantaite A, Hagerius A, Barchéus H, Solheim O, Lindskog C, Olsson Bontell T, Carén H, Jakola AS, Smits A. Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma; an exploratory study. Neurooncol Adv 2022; 4:vdac074. [PMID: 35795469 PMCID: PMC9248775 DOI: 10.1093/noajnl/vdac074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grades 2–3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
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Affiliation(s)
- Alba Corell
- Department of Neurosurgery, Sahlgrenska University Hospital , Gothenburg, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Tomás Gomez Vecchio
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Sandra Ferreyra Vega
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Anna Dénes
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Alice Neimantaite
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Alexander Hagerius
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Hanna Barchéus
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Ole Solheim
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology , Trondheim, Norway
- Department of Neurosurgery, St. Olavs University Hospital , Trondheim, Norway
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Uppsala University , Uppsala, Sweden
| | - Thomas Olsson Bontell
- Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital , Gothenburg, Sweden
- Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Helena Carén
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
| | - Asgeir S Jakola
- Department of Neurosurgery, Sahlgrenska University Hospital , Gothenburg, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology , Trondheim, Norway
| | - Anja Smits
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden
- Department of Medicine, Neurology, Uppsala University , Uppsala, Sweden
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Beiriger J, Habib A, Jovanovich N, Kodavali CV, Edwards L, Amankulor N, Zinn PO. The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling. Front Oncol 2022; 12:790976. [PMID: 35359410 PMCID: PMC8960165 DOI: 10.3389/fonc.2022.790976] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.
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Affiliation(s)
- Jamison Beiriger
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Ahmed Habib
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nicolina Jovanovich
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Chowdari V. Kodavali
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Lincoln Edwards
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Nduka Amankulor
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
| | - Pascal O. Zinn
- Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh PA, United States
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43
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Dausinas Ni P, Basile C, Junge C, Hartman M, O’Leary HA. Hypoxia and Hematopoiesis. CURRENT STEM CELL REPORTS 2022. [DOI: 10.1007/s40778-021-00203-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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44
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Bhargav AG, Domino JS, Chamoun R, Thomas SM. Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities. Front Oncol 2022; 11:805628. [PMID: 35127517 PMCID: PMC8813748 DOI: 10.3389/fonc.2021.805628] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/29/2021] [Indexed: 12/30/2022] Open
Abstract
Gliomas represent the most common malignant primary brain tumors, and a high-grade subset of these tumors including glioblastoma are particularly refractory to current standard-of-care therapies including maximal surgical resection and chemoradiation. The prognosis of patients with these tumors continues to be poor with existing treatments and understanding treatment failure is required. The dynamic interplay between the tumor and its microenvironment has been increasingly recognized as a key mechanism by which cellular adaptation, tumor heterogeneity, and treatment resistance develops. Beyond ongoing lines of investigation into the peritumoral cellular milieu and microenvironmental architecture, recent studies have identified the growing role of mechanical properties of the microenvironment. Elucidating the impact of these biophysical factors on disease heterogeneity is crucial for designing durable therapies and may offer novel approaches for intervention and disease monitoring. Specifically, pharmacologic targeting of mechanical signal transduction substrates such as specific ion channels that have been implicated in glioma progression or the development of agents that alter the mechanical properties of the microenvironment to halt disease progression have the potential to be promising treatment strategies based on early studies. Similarly, the development of technology to measure mechanical properties of the microenvironment in vitro and in vivo and simulate these properties in bioengineered models may facilitate the use of mechanical properties as diagnostic or prognostic biomarkers that can guide treatment. Here, we review current perspectives on the influence of mechanical properties in glioma with a focus on biophysical features of tumor-adjacent tissue, the role of fluid mechanics, and mechanisms of mechanical signal transduction. We highlight the implications of recent discoveries for novel diagnostics, therapeutic targets, and accurate preclinical modeling of glioma.
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Affiliation(s)
- Adip G. Bhargav
- Department of Neurological Surgery, University of Kansas Medical Center, Kansas City, KS, United States
| | - Joseph S. Domino
- Department of Neurological Surgery, University of Kansas Medical Center, Kansas City, KS, United States
| | - Roukoz Chamoun
- Department of Neurological Surgery, University of Kansas Medical Center, Kansas City, KS, United States
| | - Sufi M. Thomas
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS, United States
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Ricca A, Cascino F, Gritti A. Isolation and Culture of Neural Stem/Progenitor Cells from the Postnatal Periventricular Region. Methods Mol Biol 2022; 2389:11-31. [PMID: 34557998 DOI: 10.1007/978-1-0716-1783-0_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Due to the complexity of the neural stem cell (NSC) niche organization, the lack of specific NSC markers, and the difficulty of long-term tracking these cells and their progeny in vivo, the functional properties of the endogenous NSCs remain largely unexplored. These limitations have led to the development of methodologies to efficiently isolate, expand, and differentiate NSCs ex vivo. We describe here the peculiarities of the neurosphere assay (NSA) as a methodology that allows to efficiently isolate, expand, and differentiate somatic NSCs derived from the postnatal and adult forebrain periventricular region while preserving proliferation, self-renewal, and multipotency, the main attributes that provide their functional identification.
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Affiliation(s)
- Alessandra Ricca
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Cascino
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Gritti
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.
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North HF, Weissleder C, Fullerton JM, Sager R, Webster MJ, Weickert CS. A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone. Transl Psychiatry 2021; 11:635. [PMID: 34911938 PMCID: PMC8674325 DOI: 10.1038/s41398-021-01742-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 09/18/2021] [Accepted: 10/01/2021] [Indexed: 12/27/2022] Open
Abstract
Inflammation regulates neurogenesis, and the brains of patients with schizophrenia and bipolar disorder have reduced expression of neurogenesis markers in the subependymal zone (SEZ), the birthplace of inhibitory interneurons. Inflammation is associated with cortical interneuron deficits, but the relationship between inflammation and reduced neurogenesis in schizophrenia and bipolar disorder remains unexplored. Therefore, we investigated inflammation in the SEZ by defining those with low and high levels of inflammation using cluster analysis of IL6, IL6R, IL1R1 and SERPINA3 gene expression in 32 controls, 32 schizophrenia and 29 bipolar disorder cases. We then determined whether mRNAs for markers of glia, immune cells and neurogenesis varied with inflammation. A significantly greater proportion of schizophrenia (37%) and bipolar disorder cases (32%) were in high inflammation subgroups compared to controls (10%, p < 0.05). Across the high inflammation subgroups of psychiatric disorders, mRNAs of markers for phagocytic microglia were reduced (P2RY12, P2RY13), while mRNAs of markers for perivascular macrophages (CD163), pro-inflammatory macrophages (CD64), monocytes (CD14), natural killer cells (FCGR3A) and adhesion molecules (ICAM1) were increased. Specific to high inflammation schizophrenia, quiescent stem cell marker mRNA (GFAPD) was reduced, whereas neuronal progenitor (ASCL1) and immature neuron marker mRNAs (DCX) were decreased compared to low inflammation control and schizophrenia subgroups. Thus, a heightened state of inflammation may dampen microglial response and recruit peripheral immune cells in psychiatric disorders. The findings elucidate differential neurogenic responses to inflammation within psychiatric disorders and highlight that inflammation may impair neuronal differentiation in the SEZ in schizophrenia.
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Affiliation(s)
- Hayley F North
- Neuroscience Research Australia, Sydney, NSW, Australia
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
| | | | - Janice M Fullerton
- Neuroscience Research Australia, Sydney, NSW, Australia
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Rachel Sager
- Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
| | - Maree J Webster
- Laboratory of Brain Research, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD, USA
| | - Cynthia Shannon Weickert
- Neuroscience Research Australia, Sydney, NSW, Australia.
- School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.
- Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA.
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Nuninga JO, Mandl RCW, Siero J, Nieuwdorp W, Heringa SM, Boks MP, Somers M, Sommer IEC. Shape and volume changes of the superior lateral ventricle after electroconvulsive therapy measured with ultra-high field MRI. Psychiatry Res Neuroimaging 2021; 317:111384. [PMID: 34537602 DOI: 10.1016/j.pscychresns.2021.111384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/11/2021] [Accepted: 08/31/2021] [Indexed: 11/18/2022]
Abstract
The subventricular zone (SVZ) of the lateral ventricles harbors neuronal stem cells in adult mammals. Rodent studies report neurogenic effects in the SVZ of electroconvulsive stimulation. We hypothesize that if this finding translates to depressed patients undergoing electroconvulsive therapy (ECT), this would be reflected in shape changes at the SVZ. Using T1-weighted MR images acquired at ultra-high field strength (7T), the shape and volume of the ventricles were compared from pre to post ECT after 10 ECT sessions (in patients twice weekly) or 5 weeks apart (controls) using linear mixed models with age and gender as covariates. Ventricle shape significantly changed and volume significantly decreased over time in patients for the left ventricle, but not in controls. The decrease in volume of the ventricles was associated to a decrease in depression scores, and an increase in the left dentate gyrus, However, the shape changes of the ventricles were not restricted to the neurogenic niche in the lateral walls of the ventricles, providing no clear evidence for neurogenesis as sole explanation of volume changes in the ventricles after ECT.
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Affiliation(s)
- Jasper O Nuninga
- University Groningen, University Medical Center Groningen, Department of Biomedical Sciences of Cells and Systems, Groningen, the Netherlands; Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands.
| | - René C W Mandl
- Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands
| | - Jeroen Siero
- Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands; Spinoza Centre for Neuroimaging, Amsterdam, the Netherlands
| | - Wendy Nieuwdorp
- Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands
| | - Sophie M Heringa
- Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands
| | - Marco P Boks
- Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands
| | - Metten Somers
- Department of Psychiatry, UMC Utrecht Brain Center, University Utrecht, Utrecht, the Netherlands
| | - Iris E C Sommer
- University Groningen, University Medical Center Groningen, Department of Biomedical Sciences of Cells and Systems, Groningen, the Netherlands
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Visser VL, Rusinek H, Weickenmeier J. Peak ependymal cell stretch overlaps with the onset locations of periventricular white matter lesions. Sci Rep 2021; 11:21956. [PMID: 34753951 PMCID: PMC8578319 DOI: 10.1038/s41598-021-00610-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/14/2021] [Indexed: 12/30/2022] Open
Abstract
Deep and periventricular white matter hyperintensities (dWMH/pvWMH) are bright appearing white matter tissue lesions in T2-weighted fluid attenuated inversion recovery magnetic resonance images and are frequent observations in the aging human brain. While early stages of these white matter lesions are only weakly associated with cognitive impairment, their progressive growth is a strong indicator for long-term functional decline. DWMHs are typically associated with vascular degeneration in diffuse white matter locations; for pvWMHs, however, no unifying theory exists to explain their consistent onset around the horns of the lateral ventricles. We use patient imaging data to create anatomically accurate finite element models of the lateral ventricles, white and gray matter, and cerebrospinal fluid, as well as to reconstruct their WMH volumes. We simulated the mechanical loading of the ependymal cells forming the primary brain-fluid interface, the ventricular wall, and its surrounding tissues at peak ventricular pressure during the hemodynamic cycle. We observe that both the maximum principal tissue strain and the largest ependymal cell stretch consistently localize in the anterior and posterior horns. Our simulations show that ependymal cells experience a loading state that causes the ventricular wall to be stretched thin. Moreover, we show that maximum wall loading coincides with the pvWMH locations observed in our patient scans. These results warrant further analysis of white matter pathology in the periventricular zone that includes a mechanics-driven deterioration model for the ventricular wall.
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Affiliation(s)
- Valery L Visser
- Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ, 07030, USA
- Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands
- Institute for Regenerative Medicine, University of Zurich, Zurich, 8006, Switzerland
| | - Henry Rusinek
- Department of Radiology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Johannes Weickenmeier
- Department of Mechanical Engineering, Stevens Institute of Technology, Hoboken, NJ, 07030, USA.
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Gault N, Szele FG. Immunohistochemical evidence for adult human neurogenesis in health and disease. WIREs Mech Dis 2021; 13:e1526. [PMID: 34730290 DOI: 10.1002/wsbm.1526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 01/19/2023]
Abstract
Postnatal and adult neurogenesis in the subventricular zone and subgranular zone of animals such as rodents and non-human primates has been observed with many different technical approaches. Since most techniques used in animals cannot be used in humans, the majority of human neurogenesis studies rely on postmortem immunohistochemistry. This technique is difficult in human tissue, due to poor and variable preservation of antigens and samples. Nevertheless, a survey of the literature reveals that most published studies provide evidence for childhood and adult neurogenesis in the human brain stem cell niches. There are some conflicting results even when assessing the same markers and when using the same antibodies. Focusing on immunohistochemical studies on post-mortem human sections, we discuss the relative robustness of the literature on adult neurogenesis. We also discuss the response of the subventricular and subgranular zones to human disease, showing that the two niches can respond differently and that the stage of disease impacts neurogenesis levels. Thus, we highlight strong evidence for adult human neurogenesis, discuss other work that did not find it, describe obstacles in analysis, and offer other approaches to evaluate the neurogenic potential of the subventricular and subgranular zones of Homo sapiens. This article is categorized under: Neurological Diseases > Stem Cells and Development Reproductive System Diseases > Stem Cells and Development.
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Affiliation(s)
| | - Francis G Szele
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
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Roth JG, Huang MS, Li TL, Feig VR, Jiang Y, Cui B, Greely HT, Bao Z, Paşca SP, Heilshorn SC. Advancing models of neural development with biomaterials. Nat Rev Neurosci 2021; 22:593-615. [PMID: 34376834 PMCID: PMC8612873 DOI: 10.1038/s41583-021-00496-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2021] [Indexed: 12/12/2022]
Abstract
Human pluripotent stem cells have emerged as a promising in vitro model system for studying the brain. Two-dimensional and three-dimensional cell culture paradigms have provided valuable insights into the pathogenesis of neuropsychiatric disorders, but they remain limited in their capacity to model certain features of human neural development. Specifically, current models do not efficiently incorporate extracellular matrix-derived biochemical and biophysical cues, facilitate multicellular spatio-temporal patterning, or achieve advanced functional maturation. Engineered biomaterials have the capacity to create increasingly biomimetic neural microenvironments, yet further refinement is needed before these approaches are widely implemented. This Review therefore highlights how continued progression and increased integration of engineered biomaterials may be well poised to address intractable challenges in recapitulating human neural development.
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Affiliation(s)
- Julien G Roth
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Michelle S Huang
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Thomas L Li
- Department of Chemistry, Stanford University, Stanford, CA, USA
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Vivian R Feig
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
| | - Yuanwen Jiang
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Bianxiao Cui
- Department of Chemistry, Stanford University, Stanford, CA, USA
| | - Henry T Greely
- Stanford Law School, Stanford University, Stanford, CA, USA
| | - Zhenan Bao
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
| | - Sergiu P Paşca
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Sarah C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.
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