iPSCs for Modeling Central Nervous System Disorders, Volume 6
()
About this ebook
iPSCs for Modeling Central Nervous System Disorders, Volume 6 addresses how induced pluripotent stem cells can be used to model various CNS disorders.
Somatic cells can be reprogrammed into Induced pluripotent stem cells by the expression of specific transcription factors. These cells are transforming biomedical research in the last 15 years. The volume teaches readers about current advances in the field. This book describes the use of induced pluripotent stem cells to model several CNS diseases in vitro, enabling us to study the cellular and molecular mechanisms involved in different CNS pathologies. Further insights into these mechanisms will have important implications for our understanding of CNS disease appearance, development, and progression. In recent years, remarkable progress has been made in the obtention of induced pluripotent stem cells and their differentiation into several cell types, tissues and organs using state-of-art techniques. These advantages facilitated identification of key targets and definition of the molecular basis of several CNS disorders. This volume will cover what we know so far about the use of iPSCs to model different CNS disorders, such as: Alzheimer’s disease, Autism, Amyotrophic Lateral Sclerosis, Schizophrenia, Fragile X Syndrome, Spinal Muscular Atrophy, Rett Syndrome, Angelman syndrome, Parkinson`s Disease, Leber Hereditary Optic Neuropathy, Anorexia Nervosa, and more.
The volume is written for researchers and scientists interested in stem cell therapy, cell biology, regenerative medicine, and neuroscience; and is contributed by world-renowned authors in the field.
- Provides overview of the fast-moving field of induced pluripotent stem cell technology and its application in neurobiology
- Covers the following CNS diseases: Alzheimer’s disease, Autism, Amyotrophic Lateral Sclerosis, Schizophrenia, Fragile X Syndrome, Spinal Muscular Atrophy, Rett Syndrome, Angelman syndrome, Parkinson`s Disease, Leber Hereditary Optic Neuropathy, Anorexia Nervosa, and more
- Contains description of cutting-edge research on the development of disease-specific human pluripotent stem cells. These cells allow us to study cellular and molecular processes involved in several CNS human diseases
Related to iPSCs for Modeling Central Nervous System Disorders, Volume 6
Titles in the series (17)
Novel Concepts in iPSC Disease Modeling Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSC Disease Modeling Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSCs for Therapy Rating: 0 out of 5 stars0 ratingsCurrent Topics in iPSCs Technology Rating: 0 out of 5 stars0 ratingsiPSCs from Diverse Species Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSC-Derived Cell Types Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSC Technology Rating: 0 out of 5 stars0 ratingsCell Sources for iPSCs Rating: 0 out of 5 stars0 ratingsCurrent Progress in iPSC-derived Cell Types Rating: 0 out of 5 stars0 ratingsiPSCs for Studying Infectious Diseases Rating: 5 out of 5 stars5/5Methods in iPSC Technology Rating: 0 out of 5 stars0 ratingsiPSCs for Modeling Central Nervous System Disorders, Volume 6 Rating: 0 out of 5 stars0 ratingsiPSCs in Tissue Engineering Rating: 0 out of 5 stars0 ratingsMolecular Players in iPSC Technology Rating: 0 out of 5 stars0 ratingsiPSCs - State of the Science Rating: 0 out of 5 stars0 ratingsCurrent Progress in iPSC Disease Modeling Rating: 0 out of 5 stars0 ratingsiPSC Derived Progenitors Rating: 0 out of 5 stars0 ratings
Related ebooks
iPSCs for Studying Infectious Diseases Rating: 5 out of 5 stars5/5Cell Movement in Health and Disease Rating: 0 out of 5 stars0 ratingsIntracellular Consequences of Amyloid in Alzheimer's Disease Rating: 0 out of 5 stars0 ratingsCurrent Topics in iPSCs Technology Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSC Technology Rating: 0 out of 5 stars0 ratingsMechanisms and Genetics of Neurodevelopmental Cognitive Disorders Rating: 0 out of 5 stars0 ratingsCurrent Progress in iPSC Disease Modeling Rating: 0 out of 5 stars0 ratingsNanotechnology Methods for Neurological Diseases and Brain Tumors: Drug Delivery across the Blood–Brain Barrier Rating: 0 out of 5 stars0 ratingsAnti-Aging Drug Discovery on the Basis of Hallmarks of Aging Rating: 0 out of 5 stars0 ratingsCell Sources for iPSCs Rating: 0 out of 5 stars0 ratingsChromatin Signaling and Neurological Disorders Rating: 0 out of 5 stars0 ratingsThe Molecular Immunology of Neurological Diseases Rating: 0 out of 5 stars0 ratingsEstrogen Effects on Traumatic Brain Injury: Mechanisms of Neuroprotection and Repair Rating: 0 out of 5 stars0 ratingsCellular Senescence in Disease Rating: 0 out of 5 stars0 ratingsCurrent Progress in iPSC-derived Cell Types Rating: 0 out of 5 stars0 ratingsMethods in iPSC Technology Rating: 0 out of 5 stars0 ratingsDiseases of the Nervous System Rating: 0 out of 5 stars0 ratingsMolecular and Cellular Therapies for Motor Neuron Diseases Rating: 5 out of 5 stars5/5TDP-43 and Neurodegeneration: From Bench to Bedside Rating: 0 out of 5 stars0 ratingsiPSCs in Tissue Engineering Rating: 0 out of 5 stars0 ratingsNanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors Rating: 0 out of 5 stars0 ratingsMolecular Players in iPSC Technology Rating: 0 out of 5 stars0 ratingsTranslational Neuroimmunology, Volume 8: Multiple Sclerosis Rating: 0 out of 5 stars0 ratingsTranslational Autoimmunity, Volume 5: Challenges for Autoimmune Diseases Rating: 0 out of 5 stars0 ratingsStem Cell Epigenetics Rating: 0 out of 5 stars0 ratingsCellular and Animal Models in Human Genomics Research Rating: 0 out of 5 stars0 ratingsNeuropsychiatric Disorders and Epigenetics Rating: 0 out of 5 stars0 ratingsAntimicrobial Activity of Nanoparticles: Applications in Wound Healing and Infection Treatment Rating: 0 out of 5 stars0 ratingsA Paradigm Shift to Prevent and Treat Alzheimer's Disease: From Monotargeting Pharmaceuticals to Pleiotropic Plant Polyphenols Rating: 0 out of 5 stars0 ratingsNanotheranostics for Treatment and Diagnosis of Infectious Diseases Rating: 5 out of 5 stars5/5
Biology For You
Gut: The Inside Story of Our Body's Most Underrated Organ (Revised Edition) Rating: 4 out of 5 stars4/5The Soul of an Octopus: A Surprising Exploration into the Wonder of Consciousness Rating: 4 out of 5 stars4/5A Letter to Liberals: Censorship and COVID: An Attack on Science and American Ideals Rating: 3 out of 5 stars3/5The Sixth Extinction: An Unnatural History Rating: 4 out of 5 stars4/5Why We Sleep: Unlocking the Power of Sleep and Dreams Rating: 4 out of 5 stars4/5The Winner Effect: The Neuroscience of Success and Failure Rating: 5 out of 5 stars5/5The Grieving Brain: The Surprising Science of How We Learn from Love and Loss Rating: 4 out of 5 stars4/5Lifespan: Why We Age—and Why We Don't Have To Rating: 4 out of 5 stars4/5Peptide Protocols: Volume One Rating: 4 out of 5 stars4/5Mother of God: An Extraordinary Journey into the Uncharted Tributaries of the Western Amazon Rating: 4 out of 5 stars4/5The Obesity Code: the bestselling guide to unlocking the secrets of weight loss Rating: 4 out of 5 stars4/5Homo Deus: A Brief History of Tomorrow Rating: 4 out of 5 stars4/5Sapiens: A Brief History of Humankind Rating: 4 out of 5 stars4/5All That Remains: A Renowned Forensic Scientist on Death, Mortality, and Solving Crimes Rating: 4 out of 5 stars4/5How Emotions Are Made: The Secret Life of the Brain Rating: 4 out of 5 stars4/5Woman: An Intimate Geography Rating: 4 out of 5 stars4/5"Cause Unknown": The Epidemic of Sudden Deaths in 2021 & 2022 Rating: 5 out of 5 stars5/5The Coming Plague: Newly Emerging Diseases in a World Out of Balance Rating: 4 out of 5 stars4/5Written in Bone: Hidden Stories in What We Leave Behind Rating: 4 out of 5 stars4/5Dopamine Detox: Biohacking Your Way To Better Focus, Greater Happiness, and Peak Performance Rating: 3 out of 5 stars3/5Anatomy 101: From Muscles and Bones to Organs and Systems, Your Guide to How the Human Body Works Rating: 4 out of 5 stars4/5Other Minds: The Octopus, the Sea, and the Deep Origins of Consciousness Rating: 4 out of 5 stars4/5Ultralearning: Master Hard Skills, Outsmart the Competition, and Accelerate Your Career Rating: 4 out of 5 stars4/5The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race Rating: 4 out of 5 stars4/5The Trouble With Testosterone: And Other Essays On The Biology Of The Human Predi Rating: 4 out of 5 stars4/5Fantastic Fungi: How Mushrooms Can Heal, Shift Consciousness, and Save the Planet Rating: 5 out of 5 stars5/5The Great Mortality: An Intimate History of the Black Death, the Most Devastating Plague of All Time Rating: 4 out of 5 stars4/5The Blood of Emmett Till Rating: 4 out of 5 stars4/5Lies My Gov't Told Me: And the Better Future Coming Rating: 4 out of 5 stars4/5Your Brain: A User's Guide: 100 Things You Never Knew Rating: 4 out of 5 stars4/5
Reviews for iPSCs for Modeling Central Nervous System Disorders, Volume 6
0 ratings0 reviews
Book preview
iPSCs for Modeling Central Nervous System Disorders, Volume 6 - Alexander Birbrair
iPSCs for Modeling Central Nervous System Disorders, Volume 6
Editor
Alexander Birbrair
Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil
Columbia University Medical Center, Department of Radiology, New York, NY, United States
Table of Contents
Cover image
Title page
Advances in Stem Cell Biology
Copyright
Dedication
Contributors
About the editor
Preface
Chapter 1. In vitro human stem cell–mediated central nervous system platforms: progress and challenges∗
Introduction: early platform approaches
Human central nervous system and induced pluripotent stem cell platform design aspirations-neuronal modeling
Induced pluripotent stem cell central nervous system platforms-extracellular matrixes
Initial practical decisions—specific and generic platforms
Induced pluripotent stem cells and pharmacogenetics
Induced pluripotent stem cell platform basic building approaches
Induced pluripotent stem cell platform advanced building approaches
Induced pluripotent stem cell platform imaging approaches
Future challenges and developments
Chapter 2. Human induced pluripotent stem cell– based modeling of Alzheimer’s disease, a glial perspective
Introduction
Modeling Alzheimer’s disease using human induced pluripotent stem cell-derived astrocytes
Modeling Alzheimer’s disease using induced pluripotent stem cell-derived microglia
Modeling Alzheimer’s disease using induced pluripotent stem cell-derived brain organoids
Chapter 3. Human induced pluripotent stem cell-based studies; a new route toward modeling autism spectrum disorders
Introduction
Clinical, genetic, and epigenetic bases of autism spectrum disorders
Studies based on induced pluripotent stem cell-derived cells
Brain organoids as a model for neuronal development and activity in autism spectrum disorder
The use of induced pluripotent stem cell-derived cells in the development of therapeutic strategies
Conclusion
Chapter 4. Induced pluripotent stem cells as models for Amyotrophic Lateral Sclerosis
Background to Amyotrophic Lateral Sclerosis disease
Induced pluripotent stem cell-derived cells that are relevant for modeling Amyotrophic Lateral Sclerosis: motor neurons, microglia, astrocytes, cortical cells, and Schwann cells
Cellular and biochemical processes that recapitulate symptoms of the disease: oxidative stress (reactive oxygen species and free radicals), electric activity (microelectrode arrays), protein aggregates, inflammatory role of dendritic cells, spine and dendritic structure
Autophagy and Amyotrophic Lateral Sclerosis
Senescence and Amyotrophic Lateral Sclerosis
Stepping stones to Amyotrophic Lateral Sclerosis drug discovery; potential targets; attempts and prospective
Advantages and future directions of induced pluripotent stem cell models of Amyotrophic Lateral Sclerosis
Summary and prospective—disease in a dish models
Chapter 5. Induced pluripotent stem cells for modeling schizophrenia pathogenesis
Introduction
Methodological considerations in induced pluripotent stem cell-based modeling of schizophrenia
Phenotypes of neural progenies derived from schizophrenia induced pluripotent stem cells
Future directions and considerations
Chapter 6. Human pluripotent stem cells in the research of Fragile X Syndrome
Introduction
Modeling Fragile X Syndrome in animals and in human stem cells
Neuronal differentiation of FXS-hESCs and FXS-hiPSCs
Role of human stem cells in the development of Fragile X Syndrome therapies
Perspective on the research of Fragile X Syndrome using human stem cell
Chapter 7. Induced pluripotent stem cells for modeling of spinal muscular atrophy
Introduction
Introduction to spinal muscular atrophy
Model systems of spinal muscular atrophy
Application of induced pluripotent stem cell technology in spinal muscular atrophy
Induced pluripotent stem cell disease modeling of other spinal muscular atrophy disease relevant cells
Future directions of induced pluripotent stem cell-derived technology in spinal muscular atrophy research
Chapter 8. Induced pluripotent stem cells for modeling of Rett Syndrome
Introduction
Types of Rett syndrome
Pathogenesis of Rett syndrome
Methyl-CpG-binding protein 2 as epigenetic regulator
CDKL5
Pathogenesis of FOXG1
Role of FOXG1 in reelin signaling pathway
Interaction of methyl-CpG-binding protein 2, CDKL5, and FOXG1
Common mutations in Rett syndrome
Modeling Rett syndrome
Organismic model for methyl-CpG-binding protein 2
Organismic model for CDKL5
Organismic model for FOXG1
Induced pluripotent stem cells generation methods
Induced pluripotent stem cells in modeling Rett Syndrome
Induced pluripotent stem cells for methyl-CpG-binding protein 2 mutation
Induced pluripotent stem cells generation with CDKL5 mutation
Induced pluripotent stem cells for FOXG1
Three-dimensional cultures for Rett syndrome
Drugs screening and treatment
Conclusion
Chapter 9. Induced pluripotent stem cells for modeling Angelman syndrome
Introduction
Conclusions and future perspectives
Chapter 10. Induced pluripotent stem cells for modeling of X-linked dystonia-parkinsonism
Introduction
Clinical, imaging, and electrophysiological features
Genetics
Induced pluripotent stem cell-based functional studies
Conclusions
Perspectives
Chapter 11. Studying non–cell-autonomous neurodegeneration in Parkinson’s disease with induced pluripotent stem cells
Introduction
Non–cell-autonomous mechanism in Parkinson’s disease
In vitro induced pluripotent stem cell glial models of Parkinson’s disease
Future perspectives
Chapter 12. Induced pluripotent stem cell–based leber hereditary optic neuropathy model
Leber’s hereditary optic neuropathy
Homoplasmy and incomplete penetrance
Factors of retinal ganglion cell death in Leber’s hereditary optic neuropathy
Mitochondrial biogenesis
Traditional cell models
Leber’s hereditary optic neuropathy induced pluripotent stem cell–based cell model
Mitochondrial dynamics in Leber’s hereditary optic neuropathy induced pluripotent stem cell-based optic nerve
Advances of induced pluripotent stem cell modeling in mitochondrial diseases
Future prospects and challenges
Chapter 13. Investigating the pathophysiology of anorexia nervosa using induced pluripotent stem cells: background, current trends, and perspectives
Introduction
Bain imaging studies in anorexia nervosa
Mouse models in anorexia nervosa
Studies using induced pluripotent stem cell and perspectives
Conclusion
Index
Advances in Stem Cell Biology
Series Editor
Alexander Birbrair
Copyright
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2021 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-323-85764-2
For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals
Publisher: Stacy Masucci
Acquisitions Editor: Elizabeth Brown
Editorial Project Manager: Billie Jean Fernande
Production Project Manager: Omer Mukthar
Cover Designer: Mark Rogers
Typeset by TNQ Technologies
Dedication
This book is dedicated to my mother, Marina Sobolevsky, of blessed memory, who passed away during the creation of this volume. Professor of Mathematics at the State University of Ceará (UECE), she was loved by her colleagues and students, whom she inspired by her unique manner of teaching. All success in my career and personal life I owe to her.
My beloved mom Marina Sobolevsky of blessed memory (July 28, 1959–June 3, 2020).
Contributors
Lenore K. Beitel, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Evguenia P. Bekman
Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Universidade de Lisboa, Lisboa, Portugal
Xianwei Chen, Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United States
Shih-Jen Chen, Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
Shih-Hwa Chiou
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
Genomic Research Center, Academia Sinica, Taipei, Taiwan
Sangmi Chung, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States
Michael D. Coleman, College of Health & Life Sciences, Aston University, Birmingham, United Kingdom
Simão T. da Rocha
Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Dhanjit Kumar Das, Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
Iveta Demirova, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Thomas M. Durcan, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Allison D. Ebert, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
Gundars Goldsteins, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Philip Gorwood
Clinique des Maladies Mentales et de l’Encéphale, Sainte-Anne Hospital, GHU Paris - Psychiatrie & Neurosciences, Paris, France
Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Vulnerability of Psychiatric and Addictive Disorders, Paris, France
Alastair I. Grainger, College of Health & Life Sciences, Aston University, Birmingham, United Kingdom
Eric J. Hill, College of Health & Life Sciences, Aston University, Birmingham, United Kingdom
Christine Klein, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Jari Koistinaho
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Neuroscience Center, University of Helsinki, Helsinki, Finland
Nihay Laham-Karam, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Šárka Lehtonen
A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Neuroscience Center, University of Helsinki, Helsinki, Finland
Zhenqing Liu, Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United States
Carina Maranga
Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Gilles Maussion, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Peiyan Ni, Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Rivka Ofir
Regenerative Medicine & Stem Cell (RMSC) Research Center, Ben Gurion University of the Negev, Beer Sheva, Israel
Desert & Dead Sea Science Center, Central Arava, Israel
H. Rheinallt Parri, College of Health & Life Sciences, Aston University, Birmingham, United Kingdom
Luisa Pimentel, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Lidiia Plotnikova, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Aleksandar Rakovic, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Nicolas Ramoz, Université de Paris, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Vulnerability of Psychiatric and Addictive Disorders, Paris, France
Cecilia Rocha, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
Philip Seibler, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Bipin Raj Shekhar
Genetic Research Centre, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
Yanhong Shi, Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, United States
Tuuli-Maria Sonninen, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Michael Telias, Department of Molecular and Cell Biology, University of California, Berkeley, CA, United States
Adriana A. Vieira
Department of Bioengineering and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
An-Guor Wang, Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan
Anne Weissbach
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
Emily Welby, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
You-Ren Wu, Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
Qingqiu Yang, Department of Veterinary Clinical Science, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
Tien-Chun Yang
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
Aliaksandr A. Yarmishyn, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
About the editor
Alexander Birbrair
Dr. Alexander Birbrair received his bachelor's biomedical degree from Santa Cruz State University in Brazil. He completed his PhD in Neuroscience, in the field of stem cell biology, at the Wake Forest School of Medicine under the mentorship of Osvaldo Delbono. Then, he joined as a postdoc in stem cell biology at Paul Frenette's laboratory at Albert Einstein School of Medicine in New York. In 2016, he was appointed faculty at Federal University of Minas Gerais in Brazil, where he started his own lab. His laboratory is interested in understanding how the cellular components of different tissues function and control disease progression. His group explores the roles of specific cell populations in the tissue microenvironment by using state-of-the-art techniques. His research is funded by the Serrapilheira Institute, CNPq, CAPES, and FAPEMIG. In 2018, Alexander was elected affiliate member of the Brazilian Academy of Sciences (ABC), and, in 2019, he was elected member of the Global Young Academy (GYA). He is the Founding Editor and Editor-in-Chief of Current Tissue Microenvironment Reports, and Associate Editor of Molecular Biotechnology. Alexander also serves in the editorial board of several other international journals: Stem Cell Reviews and Reports, Stem Cell Research, Stem Cells and Development, and Histology and Histopathology.
Preface
This book's initial title was iPSCs: Recent Advances.
Nevertheless, because of the ongoing strong interest in this theme, we were capable to collect more chapters than would fit in one single volume, covering induced pluripotent stem cells (iPSCs) biology from different perspectives. Therefore, the book was subdivided into several volumes.
This volume iPSCs for Modeling Central Nervous System Disorders
offers contributions by known scientists and clinicians in the multidisciplinary areas of biological and medical research. The chapters bring up-to-date comprehensive overviews of current advances in the field. This book describes the use of iPSCs to model several central nervous system diseases in vitro, enabling us to study the cellular and molecular mechanisms involved in different central nervous system pathologies. Further insights into these mechanisms will have important implications for our understanding of central nervous system disease appearance, development, and progression. The authors focus on the modern state-of-art methodologies and the leading-edge concepts in the field of stem cell biology. In recent years, remarkable progress has been made in the obtention of iPSCs and their differentiation into several cell types, tissues, and organs using state-of-art techniques. These advantages facilitated identification of key targets and definition of the molecular basis of several central nervous system disorders. Thus, the present book is an attempt to describe the most recent developments in the area of iPSCs biology which is one of the rising hot topics in the field of molecular and cellular biology today. Here, we present a selected collection of detailed chapters on what we know so far about the use of iPSCs for modeling multiple central nervous system diseases. About 13 chapters written by experts in the field summarize the present knowledge about iPSC disease modeling.
Michael D. Coleman and colleagues from Aston University introduce in vitro human stem cell–mediated central nervous system platforms. Yanhong Shi and colleagues from Beckman Research Institute of City of Hope discuss iPSC-based modeling of Alzheimer's disease from a glial perspective. Thomas M. Durcan and colleagues from McGill University describe iPSC-based studies to model autism spectrum disorders. Rivka Ofir from Ben Gurion University of the Negev compiles our understanding of iPSCs as models for amyotrophic lateral sclerosis. Peiyan Ni and Sangmi Chung from New York Medical College update us with what we know about iPSCs for modeling schizophrenia pathogenesis. Michael Telias from University of California Berkeley summarize current knowledge on iPSCs in the research of Fragile X syndrome. Emily Welby and Allison D. Ebert from Medical College of Wisconsin address the importance of iPSCs for modeling of spinal muscular atrophy. Bipin Raj Shekhar and Dhanjit Kumar Das from National Institute for Research in Reproductive Health talk about iPSCs for modeling of Rett syndrome. Simão Teixeira da Rocha and colleagues from University of Lisboa focus on the contribution of iPSCs for modeling Angelman syndrome. Christine Klein and colleagues from University of Lübeck present iPSCs for modeling of X-linked dystonia-parkinsonism. Šárka Lehtonen and colleagues from University of Helsinki give an overview of iPSCs for studying non–cell-autonomous neurodegeneration in Parkinson's disease. Shih-Hwa Chiou and colleagues from National Yang-Ming University present the iPSC-based Leber Hereditary Optic Neuropathy Model. Finally, Gilles Maussion and colleagues from McGill University update us on the use of iPSCs to investigate the pathophysiology of Anorexia Nervosa.
It is hoped that the articles published in this book will become a source of reference and inspiration for future research ideas. I would like to express my deep gratitude to my wife Veranika Ushakova, and Ms. Billie Jean Fernandez and Ms. Elisabeth Brown from Elsevier, who helped at every step of the execution of this project.
Alexander Birbrair
Editor
Chapter 1: In vitro human stem cell–mediated central nervous system platforms
progress and challenges
∗
Michael D. Coleman, Alastair I. Grainger, H. Rheinallt Parri, and Eric J. Hill College of Health & Life Sciences, Aston University, Birmingham, United Kingdom
Abstract
The need for human cell-based experimental platforms for the study of the brain’s most basic activity and function has never been greater. Initial progress was made through differentiation of the NT2.D1 platform, which facilitated the study of postmitotic but generic neuronal/astrocytic interactions both electrophysiologically and pharmacologically. However, induced pluripotent stem cell (iPSC) platforms can form specific neuronal and astrocytic subpopulations which are identical to those of a functioning area of the brain. Hence, not only functionality can be modeled with iPSC-derived platforms but also specific dysfunctionality in these areas, such as is seen in neurodegenerative disease. Crucially, it has become clear that the contents of the extracellular matrix (ECM) of the living brain have a disproportionate influence not only on cell development and maturity but also continued maintenance of function. For iPSC models to ascend to this level of authenticity requires new methods and technology to include a fully functional ECM in more complete models of specific brain areas. Future approaches in ECM formation, alongside more rapid iPSC-derived tissue formation through lineage reprogramming, will eventually bring human experimental platforms to a more advanced stage of development, which will be combined with the necessary flexibility and practicality for diverse applications ranging from basic research through to drug discovery.
Keywords
Astrocyte; Electrophysiology differentiation; Endothelial; Extracellular matrix; Lineage reprogramming; Neurodegeneration; Neurone; NT2.D1; Pentapartitesynapse; Pharmacogenetics; Tripartite
Introduction: early platform approaches
Human central nervous system and induced pluripotent stem cell platform design aspirations-neuronal modeling
Induced pluripotent stem cell central nervous system platforms-extracellular matrixes
Initial practical decisions—specific and generic platforms
Induced pluripotent stem cells and pharmacogenetics
Induced pluripotent stem cell platform basic building approaches
Induced pluripotent stem cell platform advanced building approaches
Induced pluripotent stem cell platform imaging approaches
Future challenges and developments
References
Introduction: early platform approaches
For some years, it has been clear that many animal models used in drug discovery as well as basic and clinical research have significant limitations. These have been exposed perhaps most markedly through the conspicuous lack of progress in drug discovery for many conditions, particularly in neurodegenerative central nervous system (CNS)-related diseases (Ichida and Kiskinis, 2015; Nestor et al., 2016). Unfortunately, up to the early 2000s, the choice of alternatives to animals in the field of CNS research was very narrow. Modeling the CNS from a practical perspective, such as in neurotoxicity studies, could be accomplished with transformed cell lines, such as the neuroblastomas SK-N-SH and its purer clone, SH-SY5Y (Woehrling et al., 2006, 2007; Coleman et al., 2008). However, even this approach was problematic, as these cell lines originated from malignancies, so they are rapidly dividing and resistant to toxicity, while the CNS is mainly postmitotic.
Some aspects of neural identity could be explored with the SH-SY5Y line, which can undergo limited and quite rapid differentiation to cells that remain useful in research in this area (Guo et al., 2020). However, by the mid-2000s, the authors believed the potential of the NT2.D1 embryocarcinoma cell line would be far greater than that of the neuroblastoma lines for more advanced CNS in vitro model development. This line had been developed in the 1980s (Andrews et al., 1984), and they could be induced to behave as neuronal stem cells capable of forming foetal-like postmitotic human (NT2N) neurones. Indeed, the NT2.D1 cells were developed partly with a view toward replacement of human neural tissue in vivo (Nelson et al., 2002). Importantly, whilst the NT2.D1s originate from malignant tissue like the neuroblastoma lines, the post-mitotic neurones they form did not demonstrate any neoplastic activity in a patient’s brain even 27 months post transplant (Nelson et al., 2002). Since then, the NT2.D1 cell model has undergone considerable development and application (Woehrling et al., 2010, 2013, 2015; Hill et al., 2008, 2012; Lima et al., 2019; Taylor et al., 2019), and its structural and functional resemblance to in vivo postmitotic CNS tissue has yielded valuable insights into neurotoxicity investigations.
Crucially, the NT2.D1 model provided an important preliminary in vitro approach in investigating the burgeoning understanding of the role of glial cells in essentially enabling CNS function at the most fundamental level. In the late 1990s, the relationship at the level of the synapse between the pre-and postsynaptic membrane and associated glia cells was hypothesized as the tripartite synapse
(Araque et al., 1999). This hypothesis recognized the key role of glial cell populations in the synthesis of basic neuronal features that enable memory and processing (synaptic plasticity). However, it required some years of development before NT2.D1-based in vitro models could be brought to the point where a neuronal/astrocytic network could be built with some demonstrable functionality, such as network capacity (Woehrling et al., 2015; Hill et al., 2012) Studies using the NT2.D1 model emphasized that neuronal (NT2N) differentiation and functionality was significantly improved through co-differentiation with glial (NT2A) cell populations (Hill et al., 2012; Kuijlaars et al., 2016; Ishii et al., 2017). Indeed, the study of neuronal populations without their glial support network is of value only in terms of the opportunity afforded to see the marked deficit in functionality displayed because of the incompleteness of the system. Many studies over the past decade have shown beyond doubt the irreplaceable role of astrocytes in the most efficient and complete realization of a functional and responsive CNS cellular platform, ranging from the NT2.D1s (Woehrling et al., 2010, 2015; Hill et al., 2008, 2012) to iPSC models (Kuijlaars et al., 2016; Ishii et al., 2017; Van der Wall et al., 2019).
The NT2.D1 platform provides a high degree of self-assembly
where during retinoic acid-driven differentiation, it arranges itself into a viable basic and effectively generic
(NT2N/NT2A) CNS platform. Indeed, once coupled with calcium imaging systems, it can be interrogated pharmacologically, such as with cholinergic agonists (Woehrling et al., 2015). In addition, it is responsive to electrophysiological, neurotransmitter and mechanical challenge (Woehrling et al., 2015; Hill et al., 2012). This makes the model suitable for ballpark
estimations of structure, function, and performance of the neurone/astrocyte partnership, in response to toxic pressure for example. Indeed, such a generic CNS network retains value in certain advanced triage
contexts, where a next level
screening beyond transformed cells can take place, which will search for toxic impact on network activity. This might save time and resources in narrowing down the search for effective protocols and conditions which would be suitable for the more advanced platforms (Lima et al., 2019; Taylor et al., 2019). However, the self-assembly
aspect of the NT2.D1 platform, which is such an advantage in initial explorations of basic CNS properties, is of course too rigid and limited to explore more advanced CNS activity. Indeed, memory and data processing, for instance, requires extremely complex neuronal and astrocytic structure and functionality, which can only be accessible optimally through the most specialized, authentic, sophisticated, and highly flexible recapitulation of CNS architecture.
Human central nervous system and induced pluripotent stem cell platform design aspirations-neuronal modeling
The required breakthrough to provide such an advanced platform duly arrived when adult human cells were re-routed into induced pluripotent stem cells (iPSCs) (Yu et al., 2007; Takahashi et al., 2007) and this has since tantalized the scientific, medical, and indeed the wider world, with its promise of an apparently omnipotent capacity to create in vitro human cellular research platforms. This opportunity to create potentially any required cell type with the requisite functionality was fortuitous as knowledge gained from existing experimental and clinical models, had already underlined the scale of the variety of the different cellular entities in CNS tissue, not only in terms of neuronal but also in other cell types such as glial, microglial, and oligodendrocytic phenotypes (Tsunemoto et al., 2015). It is also apparent that we have not defined the scale and variation of just neuronal subpopulation types as related to specialized function (Tsunemoto et al., 2015). In addition, it is very clear that specific clinical neurodegenerative conditions often originate not only in anatomically distinct brain areas but also more precisely in terms of those incompletely defined specific neuronal subpopulations. This is highlighted through the pathology of some of the best known CNS neurodegenerative conditions such as Alzheimer’s (AD), Frontotemporal Dementia, Huntington’s, and Parkinson’s diseases. The anatomical loci of these conditions can be narrowed to deficits in particular CNS areas (hippocampus/cortex, orbitofrontal motor cortex, basal ganglia, and the Raphe nuclei, respectively) and further focused to neuronal subtypes (cholinergic, layer V, striatal projection/medium spiny, and dopaminergic, respectively; Ichida and Kiskinis, 2015; Takahashi et al., 2007; Tsunemoto et al., 2015; Reiner et al., 2011). Thus, in many cases, the essential role of a highly distinctive set of neurones, in terms of their structural, morphological, and functional aspects is revealed tragically by the devastating pathological consequences of their degeneration.
The need to recapitulate specific neuronal subpopulations is of course necessary outside of the field of neurodegeneration. For instance, the study of the seizurogenic impact of trauma, either through cerebrovascular, disease, drug, or physical impacts, must be predicated on the availability of models which not only contain the appropriate neuronal subsets but also possess the appropriately sensitive and quantifiable electrophysiological stability (Grainger et al., 2018). In addition, there are of course many other areas of brain activity that rely on highly specific adaptations of specific neuronal populations to accommodate the control of particular sensory functions. An example could be retinal ganglionic neurones that are uniquely adapted to provide rapid response functionality as necessitated by their role in visual processing. Throughout all the functional key roles of the various CNS cell types, the support of various populations of glial cells is now being recognized and being extensively investigated (Van der Wall et al., 2019; Hill et al., 2016).
Crucially for full functionality, as well as the vast array of subpopulations which are dedicated to specific processing tasks, neuronal populations all contain precise proportions of the various divisions of excitatory, (such as glutaminergic) and inhibitory (such as GABA-ergic) components of functional neuronal networks which are necessary to accomplish the full spectrum of processing required for that function (Jurcic et al., 2019). In addition, combinations of specialized inhibitory and excitatory neuronal inputs regulate the neuronal subpopulations themselves.
Currently, if even the most basic aspect of a specific brain function is to be modeled, then the demands on current iPSC technology are extremely extensive. If a particular subset of neurones and astrocytes is to be created, their correct proportions of inhibitory and excitatory neurones must also be present to attain full functionality. While iPSC models have reached considerable sophistication, the full ability to form appropriate inhibitory and excitatory neuronal networks remains a work in progress, although GABA-ergic neuronal iPSC platforms have been investigated in detail in terms of synaptic transmission (Meijer et al., 2019). At this stage, whatever the amount of inbuilt self-assembly
is present in any given iPSC platform will only provide a certain measure of appropriate structure and function. Indeed, very significant advances in the understanding of the sequencing of CNS structure and function creation may well be necessary to recapitulate the required authentic CNS activity in vitro. Without these advances, a chicken and egg
scenario arises, which can arrest progress in model development. In addition, a choice also must be made, regarding whether a healthy or impaired platform is produced. As if all these hurdles were not enough, it is now apparent that the capacity to study a tripartite
CNS activity is not actually sufficient for the most faithful recapitulation of human CNS activity, as more CNS architecture may be required for the most efficient and authentic research platforms to be built.
Induced pluripotent stem cell central nervous system platforms-extracellular matrixes
The additional CNS architecture necessary for the full capitulation process is the CNS tissue matrix and blood supply. This is usually termed the extracellular matrix (ECM), which is about 20% of the volume of the brain (De Luca et al., 2020). This complex matrix includes the endothelial cells that make up the blood brain barrier (BBB), as well as the interstitial matrix, plus other components such as perineural nets and basement membranes (De Luca et al., 2020). To date, the vast bulk of the research involving the ECM has been focused on its BBB role in the regulation of the CNS’s immediate cellular environment. This involves the classic tight junctions
but also the strict mechanisms of selective nutrient transport which essentially define the CNS’s ionic, carbohydrate, and neurotransmitter fluxes. In fact, much of our knowledge on the structure and functionality of the BBB has come from decades of experimental animal (Walker and Coleman, 1995) and more recently, human iPSC models of barrier function in various in vitro concepts (Li et al., 2019).
In terms of iPSC platform development, rather than building a live
ECM, exhaustive efforts have been made to explore different experimental artificial matrixes, which are often termed biomaterials.
These can be manufactured from a wide range of metals, glass, and polymers, as well as various different organic materials such as hydrogels, collagens, and other natural polymers such as hyaluronic acid (George et al., 2018; Balikov et al., 2020). These biomaterials have been aimed at providing a scaffold that might simultaneously encourage neuronal growth and development, while facilitating imaging and electrophysiological technology to observe and interpret cellular activity as it translates to tissue functionality (Crowe, et al., 2020). The combination of dye imaging and/or multielectrode array (MEA) systems is conceptually desirable but can be technically problematic because of difficulties with issues such as cell/MEA contact-induced impact on viability. While these platforms have yielded much information on neuronal and astrocytic interactions with the artificial matrix, they do not shed light on the role of the real CNS supporting matrix and how it simultaneously provides a blood supply and other much more active and necessary developmental and functional support (De Luca et al., 2020).
The issue of a blood supply is defining, in terms of in vitro CNS microtissue or organoid
growth and development. Originating in the field of cancer study, the creation of spheroids or organoids, has focused on providing the culture conditions to promote three-dimensional tissue growth. This is primarily aimed at modeling tissue growth in vivo, which is of course, not two-dimensional, as usually employed using standard laboratory plasticware (Chhibber et al., 2020). Spheroid and organoid size as well as viability is significantly promoted by growth in various dedicated bioreactors that promote tissue gas exchange and nutrient/waste cycling (Balikov et al., 2020; Chhibber et al., 2020; Ransley and Coleman, 2007). However, both size and viability remain limited by the fundamental lack of a practical vasculature.
The developmental and functional support role of the ECM for the CNS is now understood to be crucial, as neurones and astrocytes can produce trophic factors such as brain-derived neurotrophic factor (BDNF), but recent evidence suggests that endothelial cells produce more than 50 fold more BDNF and other factors, compared with cortical neurones (Guo et al., 2008). Such an important source of trophic factors has a potential key role in not only the development of CNS neuronal/astrocytic development but also their maintenance in terms of stem cell activity (Guo et al., 2008; Luczkowski, 2016). It is now clear that the brain is not entirely postmitotic
and is subject to dynamic and comprehensive structural and functional maintenance processes that are essential to support continuity and flexibility in processing and memory. This is achieved through multi-cellular management of existing CNS structure, of which stem cell pools are a vital flexible component. The ECM has a crucial role in the management of stem cell activity. Indeed, it is likely to respond to neuronal, astrocytic, and other CNS cell systems such as microglia in terms of its trophic factor release (Luczkowski, 2016). It has been suggested that insufficiency in the ECM may have a significant role in brain deterioration during AD that has been estimated to proceed at 15–70 times the normal rate, leading to loss of more than 1% of brain structure and function annually (Luczkowski, 2016). It could be speculated that the many other manifestations of AD, such as amyloid, tau, and oxidative stress issues, are merely consequential to the failure in basic trophic maintenance from a variety of CNS sources. Hence, to study such processes, the inclusion of the ECM in future models may well be non-negotiable, as it is an essential and intimate part of the development and functionality of the CNS as well as its protection (Luczkowski, 2016). Indeed, the relationship between the CNS’s tissue organization and its functionality has expanded from tripartite toward the concept of a tetrapartite
neurovascular unit (pre and postsynaptic/neurones/astrocytes/vascularity) and also the immune system in the form of microglia,