|
1
|
Sun Z, Li X, Li G, Xu Y, Meng J, Meng W, He S. Potential application value of pigment epithelium-derived factor in sensorineural hearing loss. Front Neurosci 2023; 17:1302124. [PMID: 38164244 PMCID: PMC10757943 DOI: 10.3389/fnins.2023.1302124] [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: 09/26/2023] [Accepted: 11/17/2023] [Indexed: 01/03/2024] Open
Abstract
The inner ear is a complex and precise auditory perception system responsible for receiving and converting sound signals into neural signals, enabling us to perceive and understand sound. However, the occurrence and development of inner ear diseases and auditory disorders, such as sensorineural hearing loss, remain a global problem. In recent years, there has been increasing research on the treatment of inner ear diseases and auditory regeneration. Among these treatments, pigment epithelium-derived factor (PEDF), as a multifunctional secretory protein, exhibits diverse biological activities and functions through various mechanisms, and has shown potential applications in the inner ear. This minireview comprehensively evaluates the performance of PEDF in sensorineural hearing loss in inner ear and its potential targets and therapeutic prospects.
Collapse
Affiliation(s)
- Zihui Sun
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| | - Xiaoguang Li
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| | - Guangfei Li
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| | - Ying Xu
- Department of Stomatology, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jie Meng
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| | - Wei Meng
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| | - Shuangba He
- Department of Otolaryngology Head and Neck Surgery, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
- Nanjing Tongren ENT Hospital, Nanjing, China
| |
Collapse
|
|
2
|
Gil-Gas C, Sánchez-Díez M, Honrubia-Gómez P, Sánchez-Sánchez JL, Alvarez-Simón CB, Sabater S, Sánchez-Sánchez F, Ramírez-Castillejo C. Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer. Cancers (Basel) 2023; 15:5422. [PMID: 38001682 PMCID: PMC10670784 DOI: 10.3390/cancers15225422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Breast cancer is the leading cause of death among females in developed countries. Although the implementation of screening tests and the development of new therapies have increased the probability of remission, relapse rates remain high. Numerous studies have indicated the connection between cancer-initiating cells and slow cellular cycle cells, identified by their capacity to retain long labeling (LT+). In this study, we perform new assays showing how stem cell self-renewal modulating proteins, such as PEDF, can modify the properties, percentage of biomarker-expressing cells, and carcinogenicity of cancer stem cells. The PEDF signaling pathway could be a useful tool for controlling cancer stem cells' self-renewal and therefore control patient relapse, as PEDF enhances resistance in breast cancer patient cells' in vitro culture. We have designed a peptide consisting of the C-terminal part of this protein, which acts by blocking endogenous PEDF in cell culture assays. We demonstrate that it is possible to interfere with the self-renewal capacity of cancer stem cells, induce anoikis in vivo, and reduce resistance against docetaxel treatment in cancer patient cells in in vitro culture. We have also demonstrated that this modified PEDF protein produces a significant decrease in the percentage of expressed cancer stem cell markers.
Collapse
Affiliation(s)
- Carmen Gil-Gas
- Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (C.G.-G.); (P.H.-G.)
| | - Marta Sánchez-Díez
- HST Group, Department Biotechnology-BV, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
| | - Paloma Honrubia-Gómez
- Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (C.G.-G.); (P.H.-G.)
| | - Jose Luis Sánchez-Sánchez
- Oncology Unit, Hospital General de Almansa, 02640 Albacete, Spain;
- Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Carmen B. Alvarez-Simón
- Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain; (C.G.-G.); (P.H.-G.)
- Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Sebastia Sabater
- Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Francisco Sánchez-Sánchez
- Laboratory of Medical Genetic, Faculty of Medicine, Instituto de Investigaciones en Discapacidades Neurológicas (IDINE), University of Castilla La-Mancha, 02006 Albacete, Spain
| | - Carmen Ramírez-Castillejo
- HST Group, Department Biotechnology-BV, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28040 Madrid, Spain;
- Oncology Group, Instituto de Investigación Sanitaria San Carlos, 28040 Madrid, Spain
| |
Collapse
|
|
3
|
Paez-Gonzalez P, Lopez-de-San-Sebastian J, Ceron-Funez R, Jimenez AJ, Rodríguez-Perez LM. Therapeutic strategies to recover ependymal barrier after inflammatory damage: relevance for recovering neurogenesis during development. Front Neurosci 2023; 17:1204197. [PMID: 37397456 PMCID: PMC10308384 DOI: 10.3389/fnins.2023.1204197] [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: 04/11/2023] [Accepted: 05/22/2023] [Indexed: 07/04/2023] Open
Abstract
The epithelium covering the surfaces of the cerebral ventricular system is known as the ependyma, and is essential for maintaining the physical and functional integrity of the central nervous system. Additionally, the ependyma plays an essential role in neurogenesis, neuroinflammatory modulation and neurodegenerative diseases. Ependyma barrier is severely affected by perinatal hemorrhages and infections that cross the blood brain barrier. The recovery and regeneration of ependyma after damage are key to stabilizing neuroinflammatory and neurodegenerative processes that are critical during early postnatal ages. Unfortunately, there are no effective therapies to regenerate this tissue in human patients. Here, the roles of the ependymal barrier in the context of neurogenesis and homeostasis are reviewed, and future research lines for development of actual therapeutic strategies are discussed.
Collapse
Affiliation(s)
- Patricia Paez-Gonzalez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Málaga, Spain
| | | | - Raquel Ceron-Funez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, Málaga, Spain
| | - Antonio J. Jimenez
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Málaga, Spain
| | - Luis Manuel Rodríguez-Perez
- Department of Cell Biology, Genetics and Physiology, University of Malaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Málaga, Spain
- Department of Human Physiology, Human Histology, Pathological Anatomy and Sports, University of Malaga, Málaga, Spain
| |
Collapse
|
|
4
|
Genet N, Genet G, Chavkin NW, Paila U, Fang JS, Vasavada HH, Goldberg JS, Acharya BR, Bhatt NS, Baker K, McDonnell SP, Huba M, Sankaranarayanan D, Ma GZM, Eichmann A, Thomas JL, Ffrench-Constant C, Hirschi KK. Connexin 43-mediated neurovascular interactions regulate neurogenesis in the adult brain subventricular zone. Cell Rep 2023; 42:112371. [PMID: 37043357 PMCID: PMC10564973 DOI: 10.1016/j.celrep.2023.112371] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 02/20/2023] [Accepted: 03/22/2023] [Indexed: 04/13/2023] Open
Abstract
The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and in vitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders.
Collapse
Affiliation(s)
- Nafiisha Genet
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
| | - Gael Genet
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Nicholas W Chavkin
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Umadevi Paila
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Jennifer S Fang
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Hema H Vasavada
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Joshua S Goldberg
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Bipul R Acharya
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Neha S Bhatt
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Kasey Baker
- Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Stephanie P McDonnell
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Mahalia Huba
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Danya Sankaranarayanan
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Gerry Z M Ma
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | - Anne Eichmann
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Jean-Leon Thomas
- Departments of Neuroscience and Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Charles Ffrench-Constant
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | - Karen K Hirschi
- Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
| |
Collapse
|
|
5
|
Karakatsani A, Álvarez-Vergara MI, de Almodóvar CR. The vasculature of neurogenic niches: Properties and function. Cells Dev 2023; 174:203841. [PMID: 37060947 DOI: 10.1016/j.cdev.2023.203841] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/31/2023] [Accepted: 04/11/2023] [Indexed: 04/17/2023]
Abstract
In the adult rodent brain, neural stem cells (NSCs) reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. In these areas, NSCs and their progeny integrate intrinsic signals and extrinsic cues provided by their microenvironment that control their behavior. The vasculature in the SVZ and SGZ, and the choroid plexus (ChP) in the SVZ, have emerged as critical compartments of the neurogenic niches as they provide a rich repertoire of cues to regulate NSC quiescence, proliferation, self-renewal and differentiation. Physical contact between NSCs and blood vessels is also a feature within the niches and supports different processes such as quiescence, migration and vesicle transport. In this review, we provide a description of the brain and choroid plexus vasculature in both stem cell niches, highlighting the main properties and role of the vasculature in each niche. We also summarize the current understanding of how blood vessel- and ChP-derived signals influence the behavior of NSCs in physiological adulthood, as well as upon aging.
Collapse
Affiliation(s)
- Andromachi Karakatsani
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute for Neurovascular Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - María I Álvarez-Vergara
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute for Neurovascular Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Carmen Ruiz de Almodóvar
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Institute for Neurovascular Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany; Schlegel Chair for Neurovascular Cell Biology, University of Bonn, Bonn, Germany.
| |
Collapse
|
|
6
|
SERPINF1 Mediates Tumor Progression and Stemness in Glioma. Genes (Basel) 2023; 14:genes14030580. [PMID: 36980858 PMCID: PMC10047918 DOI: 10.3390/genes14030580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
Serpin family F member 1 (SERPINF1) reportedly plays multiple roles in various tumors; however, its clinical significance and molecular functions in glioma have been largely understudied. In the present study, we analyzed the prognostic value of SERPINF1 in three independent glioma datasets. Next, we explored the molecular functions and transcriptional regulation of SERPINF1 at the single-cell level. Moreover, in vitro experiments were conducted to evaluate the roles of SERPINF1 in the proliferation, invasion, migration, and stemness of glioma cells. Our results showed that a higher expression of SERPINF1 correlated with a poor overall survival rate in glioma patients (hazard ratio: 4.061 in TCGA, 2.017 in CGGA, and 1.675 in GSE16011, p < 0.001). Besides, SERPINF1 knockdown could suppress the proliferation, invasion, and migration of glioma cells in vitro. In addition, SERPINF1 expression was significantly upregulated in glioma stem cells (GSCs) compared to parental glioma cells. Knocking down SERPINF1 impaired the sphere formation of GSC-A172 and GSC-LN18. Bioinformatics analysis revealed that Notch signaling activation was closely associated with high SERPINF1 expression at the single-cell level. Furthermore, STAT1, CREM, and NR2F2 may participate in the transcriptional regulation of SERPINF1 in glioma. Overall, our results suggest that SERPINF1 may be a candidate prognostic predictor and potential therapeutic target for glioma.
Collapse
|
|
7
|
Karimy JK, Newville JC, Sadegh C, Morris JA, Monuki ES, Limbrick DD, McAllister Ii JP, Koschnitzky JE, Lehtinen MK, Jantzie LL. Outcomes of the 2019 hydrocephalus association workshop, "Driving common pathways: extending insights from posthemorrhagic hydrocephalus". Fluids Barriers CNS 2023; 20:4. [PMID: 36639792 PMCID: PMC9838022 DOI: 10.1186/s12987-023-00406-7] [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: 10/19/2022] [Accepted: 01/05/2023] [Indexed: 01/15/2023] Open
Abstract
The Hydrocephalus Association (HA) workshop, Driving Common Pathways: Extending Insights from Posthemorrhagic Hydrocephalus, was held on November 4 and 5, 2019 at Washington University in St. Louis. The workshop brought together a diverse group of basic, translational, and clinical scientists conducting research on multiple hydrocephalus etiologies with select outside researchers. The main goals of the workshop were to explore areas of potential overlap between hydrocephalus etiologies and identify drug targets that could positively impact various forms of hydrocephalus. This report details the major themes of the workshop and the research presented on three cell types that are targets for new hydrocephalus interventions: choroid plexus epithelial cells, ventricular ependymal cells, and immune cells (macrophages and microglia).
Collapse
Affiliation(s)
- Jason K Karimy
- Department of Family Medicine, Mountain Area Health Education Center - Boone, North Carolina, 28607, USA
| | - Jessie C Newville
- Department of Pediatrics and Neurosurgery, Johns Hopkins Children's Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
| | - Cameron Sadegh
- Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, MA, Boston, 02114, USA
- Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Jill A Morris
- National Institute of Neurological Disorders and Stroke, Neuroscience Center, National Institutes of Health, 6001 Executive Blvd, NSC Rm 2112, Bethesda, MD, 20892, USA
| | - Edwin S Monuki
- Departments of Pathology & Laboratory Medicine and Developmental & Cell Biology, University of California Irvine, Irvine, CA, 92697, USA
| | - David D Limbrick
- Departments of Neurosurgery and Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - James P McAllister Ii
- Departments of Neurosurgery and Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | | | - Maria K Lehtinen
- Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA.
| | - Lauren L Jantzie
- Department of Pediatrics and Neurosurgery, Johns Hopkins Children's Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
- Kennedy Krieger Institute, Baltimore, MD, 21287, USA.
| |
Collapse
|
|
8
|
Namiki J, Suzuki S, Shibata S, Kubota Y, Kaneko N, Yoshida K, Yamaguchi R, Matsuzaki Y, Masuda T, Ishihama Y, Sawamoto K, Okano H. Chitinase-like protein 3: A novel niche factor for mouse neural stem cells. Stem Cell Reports 2022; 17:2704-2717. [PMID: 36368330 PMCID: PMC9768575 DOI: 10.1016/j.stemcr.2022.10.012] [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: 01/31/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/12/2022] Open
Abstract
The concept of a perivascular niche has been proposed for neural stem cells (NSCs). This study examined endothelial colony-forming cell (ECFC)-secreted proteins as potential niche factors for NSCs. Intraventricle infusion with ECFC-secreted proteins increased the number of NSCs. ECFC-secreted proteins were more effective in promoting NSC self-renewal than marrow stromal cell (MSC)-secreted proteins. Differential proteomics analysis of MSC-secreted and ECFC-secreted proteins was performed, which revealed chitinase-like protein 3 (CHIL3; also called ECF-L or Ym1) as a candidate niche factor for NSCs. Experiments with recombinant CHIL3, small interfering RNA, and neutralizing antibodies demonstrated that CHIL3 stimulated NSC self-renewal with neurogenic propensity. CHIL3 was endogenously expressed in the neurogenic niche of the brain and retina as well as in the injured brain and retina. Transcriptome and phosphoproteome analyses revealed that CHIL3 activated various genes and proteins associated with NSC maintenance or neurogenesis. Thus, CHIL3 is a novel niche factor for NSCs.
Collapse
Affiliation(s)
- Jun Namiki
- Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Corresponding author
| | - Sayuri Suzuki
- Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Shinsuke Shibata
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, 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
| | - Kenji Yoshida
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Sumitomo Pharma Co. Ltd., Osaka, Osaka 541-0045, Japan
| | - Ryo Yamaguchi
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Sumitomo Pharma Co. Ltd., Osaka, Osaka 541-0045, Japan
| | - Yumi Matsuzaki
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
| | - Takeshi Masuda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan
| | - Yasushi Ishihama
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, 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
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan,Corresponding author
| |
Collapse
|
|
9
|
Nelles DG, Hazrati LN. Ependymal cells and neurodegenerative disease: outcomes of compromised ependymal barrier function. Brain Commun 2022; 4:fcac288. [PMID: 36415662 PMCID: PMC9677497 DOI: 10.1093/braincomms/fcac288] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/13/2022] [Accepted: 11/01/2022] [Indexed: 08/08/2023] Open
Abstract
Within the central nervous system, ependymal cells form critical components of the blood-cerebrospinal fluid barrier and the cerebrospinal fluid-brain barrier. These barriers provide biochemical, immunological and physical protection against the entry of molecules and foreign substances into the cerebrospinal fluid while also regulating cerebrospinal fluid dynamics, such as the composition, flow and removal of waste from the cerebrospinal fluid. Previous research has demonstrated that several neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, display irregularities in ependymal cell function, morphology, gene expression and metabolism. Despite playing key roles in maintaining overall brain health, ependymal barriers are largely overlooked and understudied in the context of disease, thus limiting the development of novel diagnostic and treatment options. Therefore, this review explores the anatomical properties, functions and structures that define ependymal cells in the healthy brain, as well as the ways in which ependymal cell dysregulation manifests across several neurodegenerative diseases. Specifically, we will address potential mechanisms, causes and consequences of ependymal cell dysfunction and describe how compromising the integrity of ependymal barriers may initiate, contribute to, or drive widespread neurodegeneration in the brain.
Collapse
Affiliation(s)
- Diana G Nelles
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
- Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Ave, Canada
| | - Lili-Naz Hazrati
- Correspondence to: Dr. Lili-Naz Hazrati 555 University Ave, Toronto ON M5G 1X8, Canada E-mail:
| |
Collapse
|
|
10
|
Baur K, Abdullah Y, Mandl C, Hölzl‐Wenig G, Shi Y, Edelkraut U, Khatri P, Hagenston AM, Irmler M, Beckers J, Ciccolini F. A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis. EMBO Rep 2022; 23:e54078. [PMID: 35861333 PMCID: PMC9442324 DOI: 10.15252/embr.202154078] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 06/20/2022] [Accepted: 07/04/2022] [Indexed: 11/09/2022] Open
Affiliation(s)
- Katja Baur
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Yomn Abdullah
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Claudia Mandl
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Gabriele Hölzl‐Wenig
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Yan Shi
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Udo Edelkraut
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Priti Khatri
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Anna M Hagenston
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| | - Martin Irmler
- Helmholtz Zentrum München GmbH Institute of Experimental Genetics Neuherberg Germany
| | - Johannes Beckers
- Helmholtz Zentrum München GmbH Institute of Experimental Genetics Neuherberg Germany
- Technische Universität München Chair of Experimental Genetics Weihenstephan Germany
- Deutsches Zentrum für Diabetesforschung e.V. (DZD) Neuherberg Germany
| | - Francesca Ciccolini
- Department of Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg University Heidelberg Germany
| |
Collapse
|
|
11
|
Teplyashina EA, Gorina YV, Khilazheva ED, Boytsova EB, Mosyagina AI, Malinovskaya NA, Komleva YK, Morgun AV, Uspenskaya YA, Shuvaev AN, Salmina AB. Cells of Cerebrovascular Endothelium and Perivascular Astroglia in the Regulation of Neurogenesis. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022030097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
12
|
Quaresima S, Istiaq A, Jono H, Cacci E, Ohta K, Lupo G. Assessing the Role of Ependymal and Vascular Cells as Sources of Extracellular Cues Regulating the Mouse Ventricular-Subventricular Zone Neurogenic Niche. Front Cell Dev Biol 2022; 10:845567. [PMID: 35450289 PMCID: PMC9016221 DOI: 10.3389/fcell.2022.845567] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
Neurogenesis persists in selected regions of the adult mouse brain; among them, the ventricular-subventricular zone (V-SVZ) of the lateral ventricles represents a major experimental paradigm due to its conspicuous neurogenic output. Postnatal V-SVZ neurogenesis is maintained by a resident population of neural stem cells (NSCs). Although V-SVZ NSCs are largely quiescent, they can be activated to enter the cell cycle, self-renew and generate progeny that gives rise to olfactory bulb interneurons. These adult-born neurons integrate into existing circuits to modify cognitive functions in response to external stimuli, but cells shed by V-SVZ NSCs can also reach injured brain regions, suggesting a latent regenerative potential. The V-SVZ is endowed with a specialized microenvironment, which is essential to maintain the proliferative and neurogenic potential of NSCs, and to preserve the NSC pool from exhaustion by finely tuning their quiescent and active states. Intercellular communication is paramount to the stem cell niche properties of the V-SVZ, and several extracellular signals acting in the niche milieu have been identified. An important part of these signals comes from non-neural cell types, such as local vascular cells, ependymal and glial cells. Understanding the crosstalk between NSCs and other niche components may aid therapeutic approaches for neuropathological conditions, since neurodevelopmental disorders, age-related cognitive decline and neurodegenerative diseases have been associated with dysfunctional neurogenic niches. Here, we review recent advances in the study of the complex interactions between V-SVZ NSCs and their cellular niche. We focus on the extracellular cues produced by ependymal and vascular cells that regulate NSC behavior in the mouse postnatal V-SVZ, and discuss the potential implication of these molecular signals in pathological conditions.
Collapse
Affiliation(s)
- Sabrina Quaresima
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy
| | - Arif Istiaq
- Department of Stem Cell Biology, Faculty of Arts and Science, Kyushu University, Fukuoka, Japan
- Department of Brain Morphogenesis, Institute of Molecular Embryology and Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirofumi Jono
- Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Emanuele Cacci
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy
| | - Kunimasa Ohta
- Department of Stem Cell Biology, Faculty of Arts and Science, Kyushu University, Fukuoka, Japan
- *Correspondence: Kunimasa Ohta, ; Giuseppe Lupo,
| | - Giuseppe Lupo
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy
- *Correspondence: Kunimasa Ohta, ; Giuseppe Lupo,
| |
Collapse
|
|
13
|
Zhao X, Fisher ES, Wang Y, Zuloaga K, Manley L, Temple S. 4D imaging analysis of the aging mouse neural stem cell niche reveals a dramatic loss of progenitor cell dynamism regulated by the RHO-ROCK pathway. Stem Cell Reports 2022; 17:245-258. [PMID: 35030320 PMCID: PMC8828534 DOI: 10.1016/j.stemcr.2021.12.007] [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: 11/02/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 11/02/2022] Open
Abstract
In the adult ventricular-subventricular zone (V-SVZ), neural stem cells (NSCs) give rise to transit-amplifying progenitor (TAP) cells. These progenitors reside in different subniche locations, implying that cell movement must accompany lineage progression, but the dynamic behaviors of adult NSCs and TAPs remain largely unexplored. Here, we performed live time-lapse imaging with computer-based image analysis of young and aged 3D V-SVZ wholemounts from transgenic mice with fluorescently distinguished NSCs and TAP cells. Young V-SVZ progenitors are highly dynamic, with regular process outgrowth and retraction and cell migration. However, these activities dramatically declined with age. An examination of single-cell RNA sequencing (RNA-seq) data revealed age-associated changes in the Rho-Rock pathway that are important for cell motility. Applying a small molecule to inhibit ROCK transformed young into old V-SVZ progenitor cell dynamic behaviors. Hence RHO-ROCK signaling is critical for normal adult NSC and TAP movement and interactions, which are compromised with age, concomitant with the loss of regenerative ability.
Collapse
Affiliation(s)
- Xiuli Zhao
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | | | - Yue Wang
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | - Kristen Zuloaga
- Department of Neuroscience and Experimental Therapeutics, Albany Medical Center, Albany NY 12208, USA
| | - Luke Manley
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA
| | - Sally Temple
- Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
| |
Collapse
|
|
14
|
Pigment epithelium-derived factor may induce antidepressant phenotypes in mice by the prefrontal cortex. Neurosci Lett 2021; 771:136423. [PMID: 34965441 DOI: 10.1016/j.neulet.2021.136423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 12/07/2021] [Accepted: 12/22/2021] [Indexed: 12/28/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein encoded by SERPINF1 and our previous study reported that PEDF may have antidepressant effects. As a key brain region regulating cognition, memory and emotion, the prefrontal cortex (PFC) has been studied extensively in major depressive disorder (MDD), but there are few reports on the relationship between PEDF and the PFC. In this study, enzyme-linked immunosorbent assay showed that the PEDF level was decreased in the plasma of MDD patients compared with that of healthy controls. Western blotting validated that the PEDF expression in the PFC was downregulated in the mouse chronic social defeat stress and rat chronic unpredictable mild stress models of depression. Correspondingly, normal mice overexpressing PEDF in the PFC showed depression-resistant phenotypes. We detected PFC metabolite levels by liquid chromatography-tandem mass spectrometry and found significant upregulation of 5-hydroxyindoleacetic acid, kynurenine, 5-hydroxytryptamine, ornithine and glutamine, and downregulation of 5-hydroxytryptophan, glutamic acid and aspartic acid in PEDF-overexpressing mice compared with control mice, in which no such changes were detected. Combined with the above findings, this provides an insight into a potential mechanism of the antidepressant effects of PEDF via the PFC, which may help to improve understanding of depression pathophysiology.
Collapse
|
|
15
|
Shin N, Kim Y, Ko J, Choi SW, Hyung S, Lee SE, Park S, Song J, Jeon NL, Kang KS. Vascularization of iNSC spheroid in a 3D spheroid-on-a-chip platform enhances neural maturation. Biotechnol Bioeng 2021; 119:566-574. [PMID: 34716703 PMCID: PMC9298365 DOI: 10.1002/bit.27978] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 11/12/2022]
Abstract
In vitro platforms for studying the human brain have been developed, and brain organoids derived from stem cells have been studied. However, current organoid models lack three-dimensional (3D) vascular networks, limiting organoid proliferation, differentiation, and apoptosis. In this study, we created a 3D model of vascularized spheroid cells using an injection-molded microfluidic chip. We cocultured spheroids derived from induced neural stem cells (iNSCs) with perfusable blood vessels. Gene expression analysis and immunostaining revealed that the vascular network greatly enhanced spheroid differentiation and reduced apoptosis. This platform can be used to further study the functional and structural interactions between blood vessels and neural spheroids, and ultimately to simulate brain development and disease.
Collapse
Affiliation(s)
- Nari Shin
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Youngtaek Kim
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea
| | - Jihoon Ko
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea
| | - Soon Won Choi
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Sujin Hyung
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea
| | - Seung-Eun Lee
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Seunghyuk Park
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea
| | - Jiyoung Song
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea
| | - Noo Li Jeon
- Department of Mechanical Engineering, Seoul National University, Seoul, South Korea.,Institute of Bioengineering, Seoul National University, Seoul, South Korea.,Institute of Advanced Machinery and Design, Seoul National University, Seoul, South Korea
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| |
Collapse
|
|
16
|
Jensen M, Tyryshkina A, Pizzo L, Smolen C, Das M, Huber E, Krishnan A, Girirajan S. Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion. Genome Med 2021; 13:163. [PMID: 34657631 PMCID: PMC8522054 DOI: 10.1186/s13073-021-00982-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. METHODS We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and "second-hit" variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. RESULTS We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations in deletion carriers. CONCLUSIONS Our results suggest a potential mechanism for how "second-hit" variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.
Collapse
Affiliation(s)
- Matthew Jensen
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
- Bioinformatics and Genomics Program, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Anastasia Tyryshkina
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
- Neuroscience Program, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Lucilla Pizzo
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
| | - Corrine Smolen
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
- Bioinformatics and Genomics Program, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA
| | - Maitreya Das
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
| | - Emily Huber
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA
| | - Arjun Krishnan
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, 48824, USA
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA
| | - Santhosh Girirajan
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, PA, 16802, University Park, USA.
- Bioinformatics and Genomics Program, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA.
- Neuroscience Program, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, 16802, USA.
- Department of Anthropology, Pennsylvania State University, University Park, PA, 16802, USA.
| |
Collapse
|
|
17
|
Genet N, Hirschi KK. Understanding neural stem cell regulation in vivo and applying the insights to cell therapy for strokes. Regen Med 2021; 16:861-870. [PMID: 34498495 PMCID: PMC8656322 DOI: 10.2217/rme-2021-0022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The use of neural stem cell (NSC) therapy for the treatment of stroke patients is successfully paving its way into advanced phases of large-scale clinical trials. To understand how to optimize NSC therapeutic approaches, it is fundamental to decipher the crosstalk between NSC and other cells that comprise the NSC microenvironment (niche) and regulate their function, in vivo; namely, the endothelial cells of the microvasculature. In this mini review, we first provide a concise summary of preclinical findings describing the signaling mechanisms between NSC and vascular endothelial cells and vice versa. Second, we describe the progress made in the development of NSC therapy for the treatment of strokes.
Collapse
Affiliation(s)
- Nafiisha Genet
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Karen K Hirschi
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.,Department of Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA
| |
Collapse
|
|
18
|
Sasaki K, Geribaldi-Doldan N, Szele FG, Isoda H. Grape skin extract modulates neuronal stem cell proliferation and improves spatial learning in senescence-accelerated prone 8 mice. Aging (Albany NY) 2021; 13:18131-18149. [PMID: 34319910 PMCID: PMC8351719 DOI: 10.18632/aging.203373] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 07/15/2021] [Indexed: 11/25/2022]
Abstract
In recent years, the number of patients with neurodegenerative illness such as Alzheimer’s disease (AD) has increased with the aging of the population. In this study, we evaluated the effect of Grape skin extract (GSE) on neurotypic SH-SY5Y cells as an in vitro AD model, murine neurospheres as an ex vivo neurogenesis model and SAMP8 mice as an in vivo AD model. Our in vitro result showed that pre-treatment of SH-SY5Y cells with GSE ameliorated Aβ-induced cytotoxicity. Moreover, GSE treatment significantly decreased the number of neurospheres, but increased their size suggesting reduced stem cell self-renewal but increased proliferation. Our in vivo Morris water maze test indicated that GSE improves learning and memory in SAMP8 mice. To detect proliferation and newborn neurons, we measured BrdU+ cells in the dentate gyrus (DG). GSE treatment increased the number of BrdU+ cells in the DG of SAMP8 mice. Finally, we showed that GSE induced a decrease in inflammatory cytokines and an increase in neurotransmitters in the cerebral cortex of SAMP8 mice. These results suggested that GSE increased neurogenic zone proliferation and memory but decreased oxidative stress associated with pro-inflammatory cytokines in aging, thus protecting neurons.
Collapse
Affiliation(s)
- Kazunori Sasaki
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.,Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST) and University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
| | - Noelia Geribaldi-Doldan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.,Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
| | - Francis G Szele
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.,Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST) and University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.,Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan
| |
Collapse
|
|
19
|
Bahram Sangani N, Gomes AR, Curfs LMG, Reutelingsperger CP. The role of Extracellular Vesicles during CNS development. Prog Neurobiol 2021; 205:102124. [PMID: 34314775 DOI: 10.1016/j.pneurobio.2021.102124] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 04/16/2021] [Accepted: 07/20/2021] [Indexed: 12/21/2022]
Abstract
With a diverse set of neuronal and glial cell populations, Central Nervous System (CNS) has one of the most complex structures in the body. Intercellular communication is therefore highly important to coordinate cell-to-cell interactions. Besides electrical and chemical messengers, CNS cells also benefit from another communication route, what is known as extracellular vesicles, to harmonize their interactions. Extracellular Vesicles (EVs) and their subtype exosomes are membranous particles secreted by cells and contain information packaged in the form of biomolecules such as small fragments of DNA, lipids, miRNAs, mRNAs, and proteins. They are able to efficiently drive changes upon their arrival to recipient cells. EVs actively participate in all stages of CNS development by stimulating neural cell proliferation, differentiation, synaptic formation, and mediating reciprocal interactions between neurons and oligodendrocyte for myelination process. The aim of the present review is to enlighten the presence and contribution of EVs at each CNS developmental milestone.
Collapse
Affiliation(s)
- Nasim Bahram Sangani
- Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; GKC-Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Ana Rita Gomes
- Department of Bioengineering and IBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisboa, Portugal; Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal.
| | - Leopold M G Curfs
- GKC-Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, the Netherlands.
| | - Chris P Reutelingsperger
- Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; GKC-Rett Expertise Centre, Maastricht University Medical Centre, Maastricht, the Netherlands.
| |
Collapse
|
|
20
|
Chung KPS, Leung RWH, Lee TKW. Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells. Cancers (Basel) 2021; 13:3191. [PMID: 34202411 PMCID: PMC8268361 DOI: 10.3390/cancers13133191] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 06/21/2021] [Indexed: 12/27/2022] Open
Abstract
Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.
Collapse
Affiliation(s)
- Katherine Po Sin Chung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
| | - Rainbow Wing Hei Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; (K.P.S.C.); (R.W.H.L.)
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China
| |
Collapse
|
|
21
|
Taberner L, Bañón A, Alsina B. Sensory Neuroblast Quiescence Depends on Vascular Cytoneme Contacts and Sensory Neuronal Differentiation Requires Initiation of Blood Flow. Cell Rep 2021; 32:107903. [PMID: 32668260 DOI: 10.1016/j.celrep.2020.107903] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 04/02/2020] [Accepted: 06/23/2020] [Indexed: 02/08/2023] Open
Abstract
In many organs, stem cell function depends on communication with their niche partners. Cranial sensory neurons develop in close proximity to blood vessels; however, whether vasculature is an integral component of their niches is yet unknown. Here, two separate roles for vasculature in cranial sensory neurogenesis in zebrafish are uncovered. The first involves precise spatiotemporal endothelial-neuroblast cytoneme contacts and Dll4-Notch signaling to restrain neuroblast proliferation. The second, instead, requires blood flow to trigger a transcriptional response that modifies neuroblast metabolic status and induces sensory neuron differentiation. In contrast, no role of sensory neurogenesis in vascular development is found, suggesting unidirectional signaling from vasculature to sensory neuroblasts. Altogether, we demonstrate that the cranial vasculature constitutes a niche component of the sensory ganglia that regulates the pace of their growth and differentiation dynamics.
Collapse
Affiliation(s)
- Laura Taberner
- Developmental Biology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra-Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain
| | - Aitor Bañón
- Developmental Biology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra-Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain
| | - Berta Alsina
- Developmental Biology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra-Parc de Recerca Biomèdica de Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.
| |
Collapse
|
|
22
|
Rojas-Vázquez S, Blasco-Chamarro L, López-Fabuel I, Martínez-Máñez R, Fariñas I. Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline. Front Neurosci 2021; 15:666881. [PMID: 33958987 PMCID: PMC8093510 DOI: 10.3389/fnins.2021.666881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/25/2021] [Indexed: 01/25/2023] Open
Abstract
The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.
Collapse
Affiliation(s)
- Sara Rojas-Vázquez
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València-Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Valencia, Spain.,Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain
| | - Laura Blasco-Chamarro
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Irene López-Fabuel
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Ramón Martínez-Máñez
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València-Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Valencia, Spain.,Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia, Spain.,Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe, Valencia, Spain
| | - Isabel Fariñas
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universitat de València, Valencia, Spain.,Instituto de Biotecnología y Biomedicina (BioTecMed), Universitat de València, Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| |
Collapse
|
|
23
|
Winkelman MA, Koppes AN, Koppes RA, Dai G. Bioengineering the neurovascular niche to study the interaction of neural stem cells and endothelial cells. APL Bioeng 2021; 5:011507. [PMID: 33688617 PMCID: PMC7932757 DOI: 10.1063/5.0027211] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 02/15/2021] [Indexed: 12/13/2022] Open
Abstract
The ability of mammalian neural stem cells (NSCs) to self-renew and differentiate throughout adulthood has made them ideal to study neurogenesis and attractive candidates for neurodegenerative disease therapies. In the adult mammalian brain, NSCs are maintained in the neurovascular niche (NVN) where they are found near the specialized blood vessels, suggesting that brain endothelial cells (BECs) are prominent orchestrators of NSC fate. However, most of the current knowledge of the mammalian NVN has been deduced from nonhuman studies. To circumvent the challenges of in vivo studies, in vitro models have been developed to better understand the reciprocal cellular mechanisms of human NSCs and BECs. This review will cover the current understanding of mammalian NVN biology, the effects of endothelial cell-derived signals on NSC fate, and the in vitro models developed to study the interactions between NSCs and BECs.
Collapse
Affiliation(s)
- Max A Winkelman
- Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, USA
| | | | - Ryan A Koppes
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, USA
| | - Guohao Dai
- Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, USA
| |
Collapse
|
|
24
|
Bertrand L, Velichkovska M, Toborek M. Cerebral Vascular Toxicity of Antiretroviral Therapy. J Neuroimmune Pharmacol 2021; 16:74-89. [PMID: 31209776 PMCID: PMC7952282 DOI: 10.1007/s11481-019-09858-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 05/27/2019] [Indexed: 01/14/2023]
Abstract
HIV infection is associated with comorbidities that are likely to be driven not only by HIV itself, but also by the toxicity of long-term use of antiretroviral therapy (ART). Indeed, increasing evidence demonstrates that the antiretroviral drugs used for HIV treatment have toxic effects resulting in various cellular and tissue pathologies. The blood-brain barrier (BBB) is a modulated anatomophysiological interface which separates and controls substance exchange between the blood and the brain parenchyma; therefore, it is particularly exposed to ART-induced toxicity. Balancing the health risks and gains of ART has to be considered in order to maximize the positive effects of therapy. The current review discusses the cerebrovascular toxicity of ART, with the focus on mitochondrial dysfunction. Graphical Abstract Graphical representation of the interactions between HIV, antiretroviral therapy (ART), and the blood-brain barrier (BBB).
Collapse
Affiliation(s)
- Luc Bertrand
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Room 528, 1011 NW 15th Street, Miami, FL, 33136, USA
| | - Martina Velichkovska
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Room 528, 1011 NW 15th Street, Miami, FL, 33136, USA
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Gautier Bldg., Room 528, 1011 NW 15th Street, Miami, FL, 33136, USA.
| |
Collapse
|
|
25
|
Yeh SI, Yu SH, Chu HS, Huang CT, Tsao YP, Cheng CM, Chen WL. Pigment Epithelium-Derived Factor Peptide Promotes Corneal Nerve Regeneration: An In Vivo and In Vitro Study. Invest Ophthalmol Vis Sci 2021; 62:23. [PMID: 33481984 PMCID: PMC7838554 DOI: 10.1167/iovs.62.1.23] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 12/28/2020] [Indexed: 12/17/2022] Open
Abstract
Purpose To investigate the potential of a pigment epithelium-derived factor (PEDF) peptide 44-mer to promote nerve regeneration in a rabbit corneal nerve injury model to demonstrate its neurotrophic ability in cultivated mouse trigeminal neuron cells. Methods Subconjunctival or intrastromal injection of 44-mer on the cornea was performed in a rabbit model of corneal nerve injury created by corneal epithelial debridement. Immunocytochemical analysis (44-mer, anti-tubulin III, SMI312, CD11b, and α-SMA) and in vivo confocal microscopy were performed. Corneal sensation was estimated using a Cochet-Bonnet corneal esthesiometer. Primary cultivated mouse trigeminal neurons were used to examine the in vitro neurotrophic ability of 44-mer. The cellular morphology and the immunocytochemical staining with anti-tubulin III and SMI312 in different concentrations of 44-mer were compared, and a quantitative assessment of neurite outgrowth was performed. Results Immunohistochemical staining showed the retention of 44-mer in the corneal stroma for at least 7 days after a single dose of corneal intrastromal injection and promoted corneal nerve regeneration revealed by in vivo confocal microscopy. Corneal esthesiometer demonstrated gradual recovery of the corneal sensation in 44-mer-treated eyes with a lower corneal touch threshold than wounded vehicles and closer to baseline at 3 weeks after corneal injury (P < 0.001). In vitro studies showed a dose-dependent neurotrophic effect of 44-mer in cultivated trigeminal neuron cells. Conclusions The 44-mer showed in vivo and in vitro corneal neurotrophic abilities. Our results suggest that intrastromal injection of 44-mer into the corneal stroma may have a potential role in treating diseases related to corneal nerve damage.
Collapse
Affiliation(s)
- Shu-I Yeh
- Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Sung-Hsun Yu
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Advanced Ocular Surface and Corneal Nerve Research Center, National Taiwan University, Taipei, Taiwan
| | - Hsiao-Sang Chu
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Advanced Ocular Surface and Corneal Nerve Research Center, National Taiwan University, Taipei, Taiwan
| | - Chin-Te Huang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Advanced Ocular Surface and Corneal Nerve Research Center, National Taiwan University, Taipei, Taiwan
- Department of Ophthalmology, Chung Shan Medical University Hospital, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yeou-Ping Tsao
- Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
- Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
| | - Chao-Min Cheng
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Wei-Li Chen
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Advanced Ocular Surface and Corneal Nerve Research Center, National Taiwan University, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University; Taipei, Taiwan
| |
Collapse
|
|
26
|
Abstract
Neural stem cells (NSCs) persist into adulthood in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and in the ventricular-subventricular zone (V-SVZ) of the lateral ventricles, where they generate new neurons and glia cells that contribute to neural plasticity. A better understanding of the developmental process that enables NSCs to persist beyond development will provide insight into factors that determine the size and properties of the adult NSC pool and thus the capacity for life-long neurogenesis in the adult mammalian brain. We review current knowledge regarding the developmental origins of adult NSCs and the developmental process by which embryonic NSCs transition into their adult form. We also discuss potential mechanisms that might regulate proper establishment of the adult NSC pool, and propose future directions of research that will be key to unraveling how NSCs transform to establish the adult NSC pool in the mammalian brain.
Collapse
Affiliation(s)
- Allison M Bond
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, United States; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
| |
Collapse
|
|
27
|
Horowitz A, Saugier-Veber P, Gilard V. Inference of Diagnostic Markers and Therapeutic Targets From CSF Proteomics for the Treatment of Hydrocephalus. Front Cell Neurosci 2020; 14:576028. [PMID: 33192320 PMCID: PMC7609871 DOI: 10.3389/fncel.2020.576028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/08/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Arie Horowitz
- Normandy University, UNIROUEN, INSERM U1245, Rouen, France
| | - Pascale Saugier-Veber
- Department of Genetics and Reference Center for Developmental Disorders, Normandie University, UNIROUEN, INSERM U1245 and Rouen University Hospital, Rouen, France
| | - Vianney Gilard
- Department of Neurosurgery, Normandy University, UNIROUEN, INSERM U1245 and Rouen University Hospital, Rouen, France
| |
Collapse
|
|
28
|
Ngo MT, Harley BAC. Angiogenic biomaterials to promote therapeutic regeneration and investigate disease progression. Biomaterials 2020; 255:120207. [PMID: 32569868 PMCID: PMC7396313 DOI: 10.1016/j.biomaterials.2020.120207] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023]
Abstract
The vasculature is a key component of the tissue microenvironment. Traditionally known for its role in providing nutrients and oxygen to surrounding cells, the vasculature is now also acknowledged to provide signaling cues that influence biological outcomes in regeneration and disease. These cues come from the cells that comprise vasculature, as well as the dynamic biophysical and biochemical properties of the surrounding extracellular matrix that accompany vascular development and remodeling. In this review, we illustrate the larger role of the vasculature in the context of regenerative biology and cancer progression. We describe cellular, biophysical, biochemical, and metabolic components of vascularized microenvironments. Moreover, we provide an overview of multidimensional angiogenic biomaterials that have been developed to promote therapeutic vascularization and regeneration, as well as to mimic elements of vascularized microenvironments as a means to uncover mechanisms by which vasculature influences cancer progression and therapy.
Collapse
Affiliation(s)
- Mai T Ngo
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Brendan A C Harley
- Dept. Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
| |
Collapse
|
|
29
|
Jurkowski MP, Bettio L, K. Woo E, Patten A, Yau SY, Gil-Mohapel J. Beyond the Hippocampus and the SVZ: Adult Neurogenesis Throughout the Brain. Front Cell Neurosci 2020; 14:576444. [PMID: 33132848 PMCID: PMC7550688 DOI: 10.3389/fncel.2020.576444] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/19/2020] [Indexed: 12/31/2022] Open
Abstract
Convincing evidence has repeatedly shown that new neurons are produced in the mammalian brain into adulthood. Adult neurogenesis has been best described in the hippocampus and the subventricular zone (SVZ), in which a series of distinct stages of neuronal development has been well characterized. However, more recently, new neurons have also been found in other brain regions of the adult mammalian brain, including the hypothalamus, striatum, substantia nigra, cortex, and amygdala. While some studies have suggested that these new neurons originate from endogenous stem cell pools located within these brain regions, others have shown the migration of neurons from the SVZ to these regions. Notably, it has been shown that the generation of new neurons in these brain regions is impacted by neurologic processes such as stroke/ischemia and neurodegenerative disorders. Furthermore, numerous factors such as neurotrophic support, pharmacologic interventions, environmental exposures, and stem cell therapy can modulate this endogenous process. While the presence and significance of adult neurogenesis in the human brain (and particularly outside of the classical neurogenic regions) is still an area of debate, this intrinsic neurogenic potential and its possible regulation through therapeutic measures present an exciting alternative for the treatment of several neurologic conditions. This review summarizes evidence in support of the classic and novel neurogenic zones present within the mammalian brain and discusses the functional significance of these new neurons as well as the factors that regulate their production. Finally, it also discusses the potential clinical applications of promoting neurogenesis outside of the classical neurogenic niches, particularly in the hypothalamus, cortex, striatum, substantia nigra, and amygdala.
Collapse
Affiliation(s)
- Michal P. Jurkowski
- Island Medical Program, University of British Columbia, Vancouver, BC, Canada
| | - Luis Bettio
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Emma K. Woo
- Island Medical Program, University of British Columbia, Vancouver, BC, Canada
| | - Anna Patten
- Centre for Interprofessional Clinical Simulation Learning (CICSL), Royal Jubilee Hospital, Victoria, BC, Canada
| | - Suk-Yu Yau
- Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hung Hom, Hong Kong
| | - Joana Gil-Mohapel
- Island Medical Program, University of British Columbia, Vancouver, BC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| |
Collapse
|
|
30
|
Ju W, Lu W, Ding L, Bao Y, Hong F, Chen Y, Gao H, Xu X, Wang G, Wang W, Zhang X, Fu C, Qi K, Li Z, Xu K, Qiao J, Zeng L. PEDF promotes the repair of bone marrow endothelial cell injury and accelerates hematopoietic reconstruction after bone marrow transplantation. J Biomed Sci 2020; 27:91. [PMID: 32873283 PMCID: PMC7466818 DOI: 10.1186/s12929-020-00685-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 08/26/2020] [Indexed: 12/27/2022] Open
Abstract
Background Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Pigment epithelium-derived factor (PEDF) regulates vascular permeability. However, PEDF’s role in the repair of damaged endothelial cells during preconditioning remains unclear. The purpose of our study is to investigate PEDF’s effect on preconditioning-induced damage of endothelial cells and hematopoietic reconstitution. Methods Damaged endothelial cells induced by irradiation was co-cultured with hematopoietic stem cells (HSC) in the absence or presence of PEDF followed by analysis of HSC number, cell cycle, colony formation and differentiation. In addition, PEDF was injected into mice model of bone marrow transplantation followed by analysis of bone marrow injury, HSC number and peripheral hematopoietic reconstitution as well as the secretion of cytokines (SCF, TGF-β, IL-6 and TNF-α). Comparisons between two groups were performed by student t-test and multiple groups by one-way or two-way ANOVA. Results Damaged endothelial cells reduced HSC expansion and colony formation, induced HSC cell cycle arrest and apoptosis and promoted HSC differentiation as well as decreased PEDF expression. Addition of PEDF increased CD144 expression in damaged endothelial cells and inhibited the increase of endothelial permeability, which were abolished after addition of PEDF receptor inhibitor Atglistatin. Additionally, PEDF ameliorated the inhibitory effect of damaged endothelial cells on HSC expansion in vitro. Finally, PEDF accelerated hematopoietic reconstitution after bone marrow transplantation in mice and promoted the secretion of SCF, TGF-β and IL-6. Conclusions PEDF inhibits the increased endothelial permeability induced by irradiation and reverse the inhibitory effect of injured endothelial cells on hematopoietic stem cells and promote hematopoietic reconstruction.
Collapse
Affiliation(s)
- Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wenyi Lu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Lan Ding
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yurong Bao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Fei Hong
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yuting Chen
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hui Gao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiaoqi Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Guozhang Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Weiwei Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chunling Fu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kunming Qi
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Zhenyu Li
- Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kailin Xu
- Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China. .,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Jianlin Qiao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China. .,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China. .,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China. .,Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China. .,Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| |
Collapse
|
|
31
|
Labusch M, Mancini L, Morizet D, Bally-Cuif L. Conserved and Divergent Features of Adult Neurogenesis in Zebrafish. Front Cell Dev Biol 2020; 8:525. [PMID: 32695781 PMCID: PMC7338623 DOI: 10.3389/fcell.2020.00525] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/03/2020] [Indexed: 12/14/2022] Open
Abstract
Adult neurogenesis, i.e., the generation of neurons from neural stem cells (NSCs) in the adult brain, contributes to brain plasticity in all vertebrates. It varies, however, greatly in extent, location and physiological characteristics between species. During the last decade, the teleost zebrafish (D. rerio) was increasingly used to study the molecular and cellular properties of adult NSCs, in particular as a prominent NSC population was discovered at the ventricular surface of the dorsal telencephalon (pallium), in territories homologous to the adult neurogenic niches of rodents. This model, for its specific features (large NSC population, amenability to intravital imaging, high regenerative capacity) allowed rapid progress in the characterization of basic adult NSC features. We review here these findings, with specific comparisons with the situation in rodents. We specifically discuss the cellular nature of NSCs (astroglial or neuroepithelial cells), their heterogeneities and their neurogenic lineages, and the mechanisms controlling NSC quiescence and fate choices, which all impact the neurogenic output. We further discuss the regulation of NSC activity in response to physiological triggers and non-physiological conditions such as regenerative contexts.
Collapse
Affiliation(s)
- Miriam Labusch
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - Laure Mancini
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - David Morizet
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France.,Sorbonne Université, Collège Doctoral, Paris, France
| | - Laure Bally-Cuif
- Zebrafish Neurogenetics Unit, Institut Pasteur, UMR 3738, CNRS, Team Supported by the Ligue Nationale Contre le Cancer, Paris, France
| |
Collapse
|
|
32
|
Wilton DK, Stevens B. The contribution of glial cells to Huntington's disease pathogenesis. Neurobiol Dis 2020; 143:104963. [PMID: 32593752 DOI: 10.1016/j.nbd.2020.104963] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 05/07/2020] [Accepted: 06/10/2020] [Indexed: 12/20/2022] Open
Abstract
Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease-related impairments in motor and cognitive performance, suggesting that these cells may drive the development of certain aspects of Huntington's disease pathogenesis. In support of this imaging studies in pre-symptomatic HD patients and work on mouse models have suggested that glial cell dysfunction occurs at a very early stage of the disease, prior to the onset of motor and cognitive deficits. Furthermore, selectively ablating mHTT from specific glial cells or correcting for HD-induced changes in their transcriptional profile rescues some HD-related phenotypes, demonstrating the potential of targeting these cells for therapeutic intervention. Here we review emerging research focused on understanding the involvement of different glial cell types in specific aspects of HD pathogenesis. This work is providing new insight into how HD impacts biological functions of glial cells in the healthy brain as well as how HD induced dysfunction in these cells might change the way they integrate into biological circuits.
Collapse
Affiliation(s)
- Daniel K Wilton
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Beth Stevens
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Stanley Center, Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|
|
33
|
Zhou S, Gao B, Sun C, Bai Y, Cheng D, Zhang Y, Li X, Zhao J, Xu D. Vascular Endothelial Cell-derived Exosomes Protect Neural Stem Cells Against Ischemia/reperfusion Injury. Neuroscience 2020; 441:184-196. [PMID: 32502570 DOI: 10.1016/j.neuroscience.2020.05.046] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 12/30/2022]
Abstract
Vascular endothelial cells were activated during acute ischemic brain injury, which could induce neural progenitor cell proliferation and migration. However, the mechanism was still unknown. In the current study, we explored whether vascular endothelial cells promoted neural progenitor cell proliferation and whether migration occurs via exosome communication. The acute middle cerebral artery occlusion (MCAO) model was prepared, and exosomes were isolated from bEnd.3 cells by ultracentrifugation. In the exosome injection (Exos) group and PBS injection (control) group, exosomes or PBS were injected intraventricularly into rats' brains 2 h after MCAO surgery, respectively. Sham group rats received the same surgical but did not cause middle cerebral artery occlusion. The infarct volume was reduced on day 21 after ischemic brain injury by MRI, and neurobehavioral outcomes were improved on day 7, 14, and 21 by exosome injection compared with the control (p < 0.05). On the 21st day after MCAO, the animals were euthanized, and the number of BrdU/nestin-positive cells was measured by immunofluorescence. BrdU/nestin-positive cells in Exos group rats were significantly increased (p < 0.05) in the peri infarct area, the ipsilateral DG zone of the hippocampus, and the ventral sub-regions of SVZ when compared with the rats in the control group. Further, in vitro study demonstrated that neural progenitor cell proliferation and migration were activated after exosomes treatment, and cell apoptosis was attenuated compared to the control (p < 0.05). Our study suggested that exosomes should be essential for the reconstruction of neuronal vascular units and brain protection in an acute ischemic injured brain.
Collapse
Affiliation(s)
- Shaoting Zhou
- Department of Neurology, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China
| | - Beiyao Gao
- Department of Rehabilitation, Huashan Hospital Affiliated to Fudan University, Shanghai 200041, China
| | - Chengcheng Sun
- Rehabilitation Center, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China
| | - Yulong Bai
- Department of Rehabilitation, Huashan Hospital Affiliated to Fudan University, Shanghai 200041, China
| | - Dandan Cheng
- Department of Rehabilitation, Huashan Hospital Affiliated to Fudan University, Shanghai 200041, China
| | - Ye Zhang
- Rehabilitation Center, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China
| | - Xutong Li
- Department of Neurology, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China
| | - Jing Zhao
- Department of Neurology, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China.
| | - Dongsheng Xu
- Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Institute of Rehabilitation Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| |
Collapse
|
|
34
|
de Diego-Otero Y, Giráldez-Pérez RM, Lima-Cabello E, Heredia-Farfan R, Calvo Medina R, Sanchez-Salido L, Pérez Costillas L. Pigment epithelium-derived factor (PEDF) and PEDF-receptor in the adult mouse brain: Differential spatial/temporal localization pattern. J Comp Neurol 2020; 529:141-158. [PMID: 32427349 DOI: 10.1002/cne.24940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/20/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western-blotting, and also by enzyme-linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age-dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas.
Collapse
Affiliation(s)
- Yolanda de Diego-Otero
- Research Laboratory, Hospital Civil, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain.,Mental Health Clinic Unit, .Regional University Hospital, Hospital Civil, Málaga, Spain.,Research Unit, International Institute of Innovation and Attention to Neurodevelopment and Language, Málaga, Spain
| | - Rosa María Giráldez-Pérez
- Cellular Biology, Physiology and Immunology Department, University of Cordoba, Edificio Charles Darwin, Córdoba, Spain
| | - Elena Lima-Cabello
- Research Laboratory, Hospital Civil, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain
| | - Raúl Heredia-Farfan
- Research Laboratory, Hospital Civil, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain
| | - Rocío Calvo Medina
- Pediatric Clinic Unit. Regional University Hospital, Hospital Materno-Infantil Avd, Arroyo de los Angeles, Málaga, Spain
| | - Lourdes Sanchez-Salido
- Research Laboratory, Hospital Civil, Institute of Biomedical Research in Malaga (IBIMA), Málaga, Spain
| | - Lucía Pérez Costillas
- Mental Health Clinic Unit, .Regional University Hospital, Hospital Civil, Málaga, Spain.,Psychiatry and Physiotherapy Department, University of Malaga. Medical School, Málaga, Spain
| |
Collapse
|
|
35
|
Waking up quiescent neural stem cells: Molecular mechanisms and implications in neurodevelopmental disorders. PLoS Genet 2020; 16:e1008653. [PMID: 32324743 PMCID: PMC7179833 DOI: 10.1371/journal.pgen.1008653] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Neural stem cells (NSCs) are crucial for development, regeneration, and repair of the nervous system. Most NSCs in mammalian adult brains are quiescent, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to give rise to new neurons. The delicate balance between NSC quiescence and activation is important for adult neurogenesis and NSC maintenance. However, how NSCs transit between quiescence and activation remains largely elusive. Here, we discuss our current understanding of the molecular mechanisms underlying the reactivation of quiescent NSCs. We review recent advances on signaling pathways originated from the NSC niche and their crosstalk in regulating NSC reactivation. We also highlight new intrinsic paradigms that control NSC reactivation in Drosophila and mammalian systems. We also discuss emerging evidence on modeling human neurodevelopmental disorders using NSCs.
Collapse
|
|
36
|
Brook N, Brook E, Dharmarajan A, Chan A, Dass CR. Pigment epithelium-derived factor regulation of neuronal and stem cell fate. Exp Cell Res 2020; 389:111891. [DOI: 10.1016/j.yexcr.2020.111891] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 02/02/2020] [Accepted: 02/04/2020] [Indexed: 01/25/2023]
|
|
37
|
Shin K, Shin H, Cho HJ, Kang H, Lee JK, Seo YJ, Shin YJ, Kim D, Koo H, Kong DS, Seol HJ, Lee JI, Lee HW, Nam DH. Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening. Cancers (Basel) 2020; 12:cancers12030549. [PMID: 32120790 PMCID: PMC7139415 DOI: 10.3390/cancers12030549] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 02/21/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called ‘GFSCAN’, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.
Collapse
Affiliation(s)
- Kayoung Shin
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06531, Korea; (K.S.); (H.K.)
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
| | - Hyemi Shin
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
- Precision Medicine Research Institute, Samsung Medical Center, Seoul 06351, Korea
| | - Hee Jin Cho
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
- Precision Medicine Research Institute, Samsung Medical Center, Seoul 06351, Korea
| | - Hyunju Kang
- Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Korea; (H.K.); (J.-K.L.)
| | - Jin-Ku Lee
- Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Korea; (H.K.); (J.-K.L.)
| | - Yun Jee Seo
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
| | - Yong Jae Shin
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
| | - Donggeon Kim
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
| | - Harim Koo
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06531, Korea; (K.S.); (H.K.)
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
| | - Doo-Sik Kong
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea; (D.-S.K.); (H.J.S.); (J.-I.L.)
| | - Ho Jun Seol
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea; (D.-S.K.); (H.J.S.); (J.-I.L.)
| | - Jung-Il Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea; (D.-S.K.); (H.J.S.); (J.-I.L.)
| | - Hye Won Lee
- Department of Hospital Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: (H.W.L.); (D.-H.N.); Tel.: +82-31-5189-8531 (H.W.L.); +82-2-2148-3497 (D.-H.N.); Fax: +82-2-2148-9829 (H.W.L.); +82-2-2149-9829 (D.-H.N.)
| | - Do-Hyun Nam
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 06531, Korea; (K.S.); (H.K.)
- Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea; (H.S.); (H.J.C.); (Y.J.S.); (Y.J.S.); (D.K.)
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea; (D.-S.K.); (H.J.S.); (J.-I.L.)
- Correspondence: (H.W.L.); (D.-H.N.); Tel.: +82-31-5189-8531 (H.W.L.); +82-2-2148-3497 (D.-H.N.); Fax: +82-2-2148-9829 (H.W.L.); +82-2-2149-9829 (D.-H.N.)
| |
Collapse
|
|
38
|
Pasquier J, Ghiabi P, Chouchane L, Razzouk K, Rafii S, Rafii A. Angiocrine endothelium: from physiology to cancer. J Transl Med 2020; 18:52. [PMID: 32014047 PMCID: PMC6998193 DOI: 10.1186/s12967-020-02244-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/28/2020] [Indexed: 02/08/2023] Open
Abstract
The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
Collapse
Affiliation(s)
- Jennifer Pasquier
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France.
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar.
| | - Pegah Ghiabi
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Lotfi Chouchane
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Kais Razzouk
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
| | - Shahin Rafii
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Arash Rafii
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| |
Collapse
|
|
39
|
Wu J, Tian WJ, Liu Y, Wang HJ, Zheng J, Wang X, Pan H, Li J, Luo J, Yang X, Lau LF, Ghashghaei HT, Shen Q. Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone. EMBO J 2020; 39:e101679. [PMID: 32009252 DOI: 10.15252/embj.2019101679] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 11/19/2019] [Accepted: 12/12/2019] [Indexed: 12/17/2022] Open
Abstract
Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
Collapse
Affiliation(s)
- Jun Wu
- School of Medicine, Tsinghua University, Beijing, China.,IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Wen-Jia Tian
- IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yang Liu
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China.,MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Huanhuan J Wang
- IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jiangli Zheng
- School of Medicine, Tsinghua University, Beijing, China.,IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xin Wang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Han Pan
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Ji Li
- School of Medicine, Tsinghua University, Beijing, China
| | - Junyu Luo
- Peking University-Tsinghua University-National Institute of Biological Sciences (PTN) Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xuerui Yang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Lester F Lau
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
| | - H Troy Ghashghaei
- WM Keck Center for Behavioral Biology, Program in Genetics, Program in Comparative Biomedical Sciences, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Qin Shen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China.,Tongji University Brain and Spinal Cord Clinical Research Center, Shanghai, China
| |
Collapse
|
|
40
|
Abstract
The transition between proliferating and quiescent states must be carefully regulated to ensure that cells divide to create the cells an organism needs only at the appropriate time and place. Cyclin-dependent kinases (CDKs) are critical for both transitioning cells from one cell cycle state to the next, and for regulating whether cells are proliferating or quiescent. CDKs are regulated by association with cognate cyclins, activating and inhibitory phosphorylation events, and proteins that bind to them and inhibit their activity. The substrates of these kinases, including the retinoblastoma protein, enforce the changes in cell cycle status. Single cell analysis has clarified that competition among factors that activate and inhibit CDK activity leads to the cell's decision to enter the cell cycle, a decision the cell makes before S phase. Signaling pathways that control the activity of CDKs regulate the transition between quiescence and proliferation in stem cells, including stem cells that generate muscle and neurons. © 2020 American Physiological Society. Compr Physiol 10:317-344, 2020.
Collapse
Affiliation(s)
- Hilary A Coller
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA.,Department of Biological Chemistry, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, California, USA.,Molecular Biology Institute, University of California, Los Angeles, California, USA
| |
Collapse
|
|
41
|
Wang J, Cui Y, Yu Z, Wang W, Cheng X, Ji W, Guo S, Zhou Q, Wu N, Chen Y, Chen Y, Song X, Jiang H, Wang Y, Lan Y, Zhou B, Mao L, Li J, Yang H, Guo W, Yang X. Brain Endothelial Cells Maintain Lactate Homeostasis and Control Adult Hippocampal Neurogenesis. Cell Stem Cell 2019; 25:754-767.e9. [DOI: 10.1016/j.stem.2019.09.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 02/24/2019] [Accepted: 09/26/2019] [Indexed: 12/29/2022]
|
|
42
|
Wei WJ, Shi B, Guan X, Ma JY, Wang YC, Liu J. Mapping theme trends and knowledge structures for human neural stem cells: a quantitative and co-word biclustering analysis for the 2013-2018 period. Neural Regen Res 2019; 14:1823-1832. [PMID: 31169201 PMCID: PMC6585554 DOI: 10.4103/1673-5374.257535] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 03/06/2019] [Indexed: 01/27/2023] Open
Abstract
Neural stem cells, which are capable of multi-potential differentiation and self-renewal, have recently been shown to have clinical potential for repairing central nervous system tissue damage. However, the theme trends and knowledge structures for human neural stem cells have not yet been studied bibliometrically. In this study, we retrieved 2742 articles from the PubMed database from 2013 to 2018 using "Neural Stem Cells" as the retrieval word. Co-word analysis was conducted to statistically quantify the characteristics and popular themes of human neural stem cell-related studies. Bibliographic data matrices were generated with the Bibliographic Item Co-Occurrence Matrix Builder. We identified 78 high-frequency Medical Subject Heading (MeSH) terms. A visual matrix was built with the repeated bisection method in gCLUTO software. A social network analysis network was generated with Ucinet 6.0 software and GraphPad Prism 5 software. The analyses demonstrated that in the 6-year period, hot topics were clustered into five categories. As suggested by the constructed strategic diagram, studies related to cytology and physiology were well-developed, whereas those related to neural stem cell applications, tissue engineering, metabolism and cell signaling, and neural stem cell pathology and virology remained immature. Neural stem cell therapy for stroke and Parkinson's disease, the genetics of microRNAs and brain neoplasms, as well as neuroprotective agents, Zika virus, Notch receptor, neural crest and embryonic stem cells were identified as emerging hot spots. These undeveloped themes and popular topics are potential points of focus for new studies on human neural stem cells.
Collapse
Affiliation(s)
- Wen-Juan Wei
- Stem Cell Clinical Research Center, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- National Joint Engineering Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Bei Shi
- Department of Physiology, China Medical University, Shenyang, Liaoning Province, China
| | - Xin Guan
- Stem Cell Clinical Research Center, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- National Joint Engineering Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Jing-Yun Ma
- Stem Cell Clinical Research Center, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- National Joint Engineering Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Ya-Chen Wang
- Stem Cell Clinical Research Center, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- National Joint Engineering Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| | - Jing Liu
- Stem Cell Clinical Research Center, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
- National Joint Engineering Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China
| |
Collapse
|
|
43
|
Lepko T, Pusch M, Müller T, Schulte D, Ehses J, Kiebler M, Hasler J, Huttner HB, Vandenbroucke RE, Vandendriessche C, Modic M, Martin‐Villalba A, Zhao S, LLorens‐Bobadilla E, Schneider A, Fischer A, Breunig CT, Stricker SH, Götz M, Ninkovic J. Choroid plexus-derived miR-204 regulates the number of quiescent neural stem cells in the adult brain. EMBO J 2019; 38:e100481. [PMID: 31304985 PMCID: PMC6717894 DOI: 10.15252/embj.2018100481] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 06/07/2019] [Accepted: 06/13/2019] [Indexed: 12/12/2022] Open
Abstract
Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post-transcriptional control mechanism, centered around the microRNA 204 (miR-204), to control the maintenance of quiescent (q)NSCs. miR-204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR-204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre-mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche-specific miRNA repressing activation and differentiation of stem cells.
Collapse
Affiliation(s)
- Tjasa Lepko
- Institute of Stem Cell ResearchHelmholtz Center MunichNeuherbergGermany
- Graduate School of Systemic NeurosciencesLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Physiological GenomicsBiomedical CenterMedical FacultyLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
| | - Melanie Pusch
- Institute of Stem Cell ResearchHelmholtz Center MunichNeuherbergGermany
| | - Tamara Müller
- Institute of Neurology (Edinger Institute)University HospitalGoethe University FrankfurtFrankfurtGermany
| | - Dorothea Schulte
- Institute of Neurology (Edinger Institute)University HospitalGoethe University FrankfurtFrankfurtGermany
| | - Janina Ehses
- Department for Cell Biology and AnatomyBiomedical CenterLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
| | - Michael Kiebler
- Department for Cell Biology and AnatomyBiomedical CenterLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
| | - Julia Hasler
- Institute of Stem Cell ResearchHelmholtz Center MunichNeuherbergGermany
| | - Hagen B Huttner
- Department of NeurologyUniversity Hospital ErlangenFriedrich‐Alexander‐University Erlangen‐NürnbergErlangenGermany
| | - Roosmarijn E Vandenbroucke
- VIB Center for Inflammation Research, VIBGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
- Ghent Gut Inflammation Group (GGIG)Ghent UniversityGhentBelgium
| | - Charysse Vandendriessche
- VIB Center for Inflammation Research, VIBGhentBelgium
- Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
- Ghent Gut Inflammation Group (GGIG)Ghent UniversityGhentBelgium
| | - Miha Modic
- The Francis Crick InstituteLondonUK
- Department for Neuromuscular DiseasesUCL Queen Square Institute of NeurologyLondonUK
| | | | - Sheng Zhao
- Molecular NeurobiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | | | - Anja Schneider
- Translational Dementia Research GroupGerman Center for Neurodegenerative Diseases (DZNE) BonnBonnGermany
- Department of Neurodegenerative Diseases and Geriatric PsychiatryUniversity Clinic BonnBonnGermany
| | - Andre Fischer
- Department for Epigenetics and Systems MedicineGerman Center for Neurodegenerative Diseases (DZNE) GöttingenGöttingenGermany
| | - Christopher T Breunig
- MCN Junior Research GroupMunich Center for NeurosciencesBioMedical CenterLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Epigenetic EngineeringHelmholtz Zentrum MünchenNeuherbergGermany
| | - Stefan H Stricker
- MCN Junior Research GroupMunich Center for NeurosciencesBioMedical CenterLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Epigenetic EngineeringHelmholtz Zentrum MünchenNeuherbergGermany
| | - Magdalena Götz
- Institute of Stem Cell ResearchHelmholtz Center MunichNeuherbergGermany
- Physiological GenomicsBiomedical CenterMedical FacultyLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Munich Cluster for Systems Neurology (SyNergy)MunichGermany
| | - Jovica Ninkovic
- Institute of Stem Cell ResearchHelmholtz Center MunichNeuherbergGermany
- Physiological GenomicsBiomedical CenterMedical FacultyLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Department for Cell Biology and AnatomyBiomedical CenterLudwig‐Maximilians UniversitaetPlanegg‐MartinsriedGermany
- Munich Cluster for Systems Neurology (SyNergy)MunichGermany
| |
Collapse
|
|
44
|
Adult Neurogenesis in the Subventricular Zone and Its Regulation After Ischemic Stroke: Implications for Therapeutic Approaches. Transl Stroke Res 2019; 11:60-79. [DOI: 10.1007/s12975-019-00717-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/13/2019] [Accepted: 06/27/2019] [Indexed: 12/21/2022]
|
|
45
|
Wei Y, Elahy M, Friedhuber AM, Wong JY, Hughes JD, Doschak MR, Dass CR. Triple-threat activity of PEDF in bone tumors: Tumor inhibition, tissue preservation and cardioprotection against doxorubicin. Bone 2019; 124:103-117. [PMID: 31028961 DOI: 10.1016/j.bone.2019.04.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/20/2019] [Accepted: 04/23/2019] [Indexed: 12/31/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is known for its osteogenic properties, but its effects against primary and secondary bone tumors have not comprehensively been demonstrated. We show the ubiquitous expression of PEDF in murine embryonic tissue. Continuous administration of PEDF in pregnant mice for five days did not adversely affect foetal health, despite PEDF's known potent antiangiogenic properties. In the case of the devastating childhood bone cancer osteosarcoma, PEDF has direct anticancer activity per se, and protects against the toxicity of doxorubicin in the heart, small intestine and testes. PEDF demonstrated anti-proliferative and pro-apoptotic effects against human prostate and breast cancer cells, tumors which are known to metastasize to bone as the preferred secondary site. Caspase-2 was activated in both tumor cell types by PEDF. In models of prostate and breast cancer in bone, PEDF significantly reduced tumor volumes. When combined with zoledronic acid, continuously-administered PEDF significantly reduced breast tumor volume at the bone, and was able to preserve the quality of bone better than the combination therapy. These multiple positive findings make PEDF an ideal endogenous and safe biological for possible future clinical testing.
Collapse
Affiliation(s)
- Yongzhong Wei
- Department of Orthopaedics, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Mina Elahy
- School of Medical Sciences, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
| | - Anna M Friedhuber
- Department of Pathology, University of Melbourne, Parkville, Melbourne, VIC 3050, Australia
| | - Jia Y Wong
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Jeffery D Hughes
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Michael R Doschak
- Department of Biomedical Engineering, University of Alberta, Alberta T6G 2E1, Canada; Department of Dentistry, University of Alberta, Alberta T6G 2E1, Canada
| | - Crispin R Dass
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Perth, WA 6102, Australia; Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA 6102, Australia; College of Health and Biomedicine, Victoria University, St Albans, Melbourne, VIC 3021, Australia.
| |
Collapse
|
|
46
|
Obernier K, Cebrian-Silla A, Thomson M, Parraguez JI, Anderson R, Guinto C, Rodas Rodriguez J, Garcia-Verdugo JM, Alvarez-Buylla A. Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation. Cell Stem Cell 2019; 22:221-234.e8. [PMID: 29395056 DOI: 10.1016/j.stem.2018.01.003] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 10/16/2017] [Accepted: 01/02/2018] [Indexed: 12/21/2022]
Abstract
Somatic stem cells have been identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]). The mechanism of B1 cell retention into adulthood for lifelong neurogenesis is unknown. Using multiple clonal labeling techniques, we show that the vast majority of B1 cells divide symmetrically. Whereas 20%-30% symmetrically self-renew and can remain in the niche for several months before generating neurons, 70%-80% undergo consuming divisions generating progeny, resulting in the depletion of B1 cells over time. This cellular mechanism decouples self-renewal from the generation of progeny. Limited rounds of symmetric self-renewal and consuming symmetric differentiation divisions can explain the levels of neurogenesis observed throughout life.
Collapse
Affiliation(s)
- Kirsten Obernier
- 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
| | - Arantxa Cebrian-Silla
- Laboratory of Comparative Neurobiology, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia 46980, Spain
| | - Matthew Thomson
- Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - José Ignacio Parraguez
- 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
| | - Rio Anderson
- 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
| | - Cristina Guinto
- 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
| | - José Rodas 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
| | - José-Manuel Garcia-Verdugo
- Laboratory of Comparative Neurobiology, Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia 46980, 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.
| |
Collapse
|
|
47
|
Honrubia-Gómez P, López-Garrido MP, Gil-Gas C, Sánchez-Sánchez J, Alvarez-Simon C, Cuenca-Escalona J, Perez AF, Arias E, Moreno R, Sánchez-Sánchez F, Ramirez-Castillejo C. Pedf derived peptides affect colorectal cancer cell lines resistance and tumour re-growth capacity. Oncotarget 2019; 10:2973-2986. [PMID: 31105879 PMCID: PMC6508205 DOI: 10.18632/oncotarget.26085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022] Open
Abstract
Relapse after chemotherapy treatment depends on the cancer initiating cells (CICs). PEDF (Pigmented Epithelium Derived Factor) is an anti-angiogenic, neurotrophic and self-renewal regulator molecule, also involved in CICs biology. Acute and chronic exposition of colon cancer cell lines to CT/CTE PEDF-derived peptides decreased drug-resistance to conventional colorectal cancer treatments, such as oxaliplatin or irinotecan. We confirmed a reduction in the irinotecan and oxaliplatin IC50 doses for all tested tumour cell lines. After xenograft transplantation, CT/CTE treatments also produced a reduction in resistance to conventional chemotherapy treatments as in culture-assays. Metastatic capacity of these treated cell lines was also depleted. The PEDF signaling pathway could be a future therapeutic tool for use as an adjuvant therapy that decreases IC50 dosis, adverse effects and treatment costs. This pathway could also be involved in an increase of the time relapse in patients, decreased tumourigenicity, and decreased capacity to produce metastasis.
Collapse
Affiliation(s)
| | - María-Pilar López-Garrido
- Genética Médica, Departamento de Ciencia y Tecnología Agroforestal y Genética, IDINE, UCLM, Albacete, Spain
| | - Carmen Gil-Gas
- Stem Cell Laboratory, Departamento Ciencias Médicas, CRIB, UCLM, Albacete, Spain
| | | | - Carmen Alvarez-Simon
- Stem Cell Laboratory, Departamento Ciencias Médicas, CRIB, UCLM, Albacete, Spain
| | - Jorge Cuenca-Escalona
- Cancer Stem Cell Laboratory, HST Group, Biotechnology and V Biology Department, ETSIAAB, UPM, Madrid, Spain
| | - Ana Ferrer Perez
- Current address: Oncology Division, Hospital Obispo Polanco, Teruel, Spain
| | - Enrique Arias
- Departamento de Sistemas Informáticos, UCLM, Albacete, Spain
| | | | - Francisco Sánchez-Sánchez
- Genética Médica, Departamento de Ciencia y Tecnología Agroforestal y Genética, IDINE, UCLM, Albacete, Spain
| | - Carmen Ramirez-Castillejo
- Stem Cell Laboratory, Departamento Ciencias Médicas, CRIB, UCLM, Albacete, Spain.,Cancer Stem Cell Laboratory, HST Group, Biotechnology and V Biology Department, ETSIAAB, UPM, Madrid, Spain
| |
Collapse
|
|
48
|
Karakatsani A, Shah B, Ruiz de Almodovar C. Blood Vessels as Regulators of Neural Stem Cell Properties. Front Mol Neurosci 2019; 12:85. [PMID: 31031591 PMCID: PMC6473036 DOI: 10.3389/fnmol.2019.00085] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/20/2019] [Indexed: 01/07/2023] Open
Abstract
In the central nervous system (CNS), a precise communication between the vascular and neural compartments is essential for proper development and function. Recent studies demonstrate that certain neuronal populations secrete various molecular cues to regulate blood vessel growth and patterning in the spinal cord and brain during development. Interestingly, the vasculature is now emerging as a critical component that regulates stem cell niches during neocortical development, as well as during adulthood. In this review article, we will first provide an overview of blood vessel development and maintenance in embryonic and adult neurogenic niches. We will also summarize the current understanding of how blood vessel-derived signals influence the behavior of neural stem cells (NSCs) during early development as well as in adulthood, with a focus on their metabolism.
Collapse
Affiliation(s)
- Andromachi Karakatsani
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bhavin Shah
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Carmen Ruiz de Almodovar
- European Center for Angioscience, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Institute for Transfusion Medicine and Immunology, Medicine Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
49
|
Sirerol-Piquer MS, Belenguer G, Morante-Redolat JM, Duart-Abadia P, Perez-Villalba A, Fariñas I. Physiological Interactions between Microglia and Neural Stem Cells in the Adult Subependymal Niche. Neuroscience 2019; 405:77-91. [PMID: 30677487 DOI: 10.1016/j.neuroscience.2019.01.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/07/2019] [Accepted: 01/10/2019] [Indexed: 12/31/2022]
Abstract
Microglia are the prototypical innate immune cells of the central nervous system. They constitute a unique type of tissue-resident mononuclear phagocytes which act as glial cells. Elegant experiments in the last few years have revealed the origin, extraordinary molecular diversity, and phenotypic plasticity of these cells and how their potential relates to both immune and non-immune actions in the normal and diseased brain. Microglial cells originate in the yolk sac and colonize the brain during embryogenesis, playing a role in neural development and later in adult brain function. Neurogenesis continues after birth in discrete areas of the mammalian brain sustained by the postnatal persistence of neural stem cells in specific neurogenic niches. Recent data indicate that microglial cells are distinct cellular elements of these neurogenic niches where they regulate different aspects of stem cell biology. Interestingly, microglial and neural stem cells are specified very early in fetal development and persist as self-renewing populations throughout life, suggesting potential life-long interactions between them. We aim at reviewing these interactions in one neurogenic niche, the subependymal zone.
Collapse
Affiliation(s)
- Mª Salomé Sirerol-Piquer
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain
| | - Germán Belenguer
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain
| | - José Manuel Morante-Redolat
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain
| | - Pere Duart-Abadia
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain
| | - Ana Perez-Villalba
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain
| | - Isabel Fariñas
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Departamento de Biología Celular, Biología Funcional y Antropología Física and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universidad de Valencia, 46100 Burjassot, Spain.
| |
Collapse
|
|
50
|
Cenpj Regulates Cilia Disassembly and Neurogenesis in the Developing Mouse Cortex. J Neurosci 2019; 39:1994-2010. [PMID: 30626697 DOI: 10.1523/jneurosci.1849-18.2018] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 12/19/2018] [Accepted: 12/24/2018] [Indexed: 11/21/2022] Open
Abstract
Primary cilia are microtubule-based protuberances that project from the eukaryotic cell body to sense the extracellular environment. Ciliogenesis is closely correlated to the cell cycle and defects of cilia are related to human systemic diseases such as primary ciliary dyskinesia. However, the role of ciliogenesis in cortical development remains unclear. Here, we demonstrate that Cenpj, a protein that is required for centriole biogenesis, plays a role in regulating cilium disassembly in vivo Depletion of Cenpj in neural progenitor cells results in long cilia and abnormal cilia disassembly. Radial glial cells Cenpj depletion exhibit uncompleted cell division, reduced cell proliferation, and increased cell apoptosis in the developing mouse cerebrum cortex, leading to microcephaly. In addition, Cenpj depletion causes long and thin primary cilia and motile cilia in adult neural stem cells and reduced cell proliferation in the subventricular zone. Furthermore, we show that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, a plus-end-directed motor protein. These data collected from mice of both sexes provide insights into how ciliogenesis plays roles in cortical development and how primary microcephaly is induced by Cenpj mutations in humans.SIGNIFICANCE STATEMENT Autosomal recessive primary microcephaly is a neurodevelopmental disorder with the major symptoms of reduction of circumference of the head, brain volume, and cortex thickness with normal brain architecture in birth. We used conditional Cenpj deletion mice and found that neural progenitor cells (NPCs) exhibited long primary cilia and abnormal cilium appendages. The defective cilium disassembly caused by Cenpj depletion might correlate to reduced cell proliferation, uncompleted cell division, cell apoptosis, and microcephaly in mice. Cenpj also regulates the cilium structure of adult neural stem cells and adult neurogenesis in mice. Additionally, our results illustrate that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, indicating that primary cilia dynamics play a crucial role in NPC mitosis and adult neurogenesis.
Collapse
|