Printed Edition of the Special Issue Published in Journal of Clinical Medicine iPS Cells for Modelling and Treatment of Human Diseases Edited by Michael J. Edel www.mdpi.com/journal/jcm Michael J. Edel (Ed.) iPS Cells for Modelling and Treatment of Human Diseases This book is a reprint of the special issue that appeared in the online open access journal Journal of Clinical Medicine (ISSN 2077-0383) in 2014 and 2015 (available at: http://www.mdpi.com/journal/jcm/special_issues/iPS). Guest Editor Michael J. Edel Departament de Ciències Fisiològiques I Facultat de Medicina Universitat de Barcelona Spain The University of Western Australia Centre for Cell Therapy and Regenerative Medicine (CCTRM) Editorial Office MDPI AG Klybeckstrasse 64 Basel, Switzerland Publisher Dr. Shu-Kun Lin Managing Editor Maple Lv 1. Edition 2015 MDPI • Basel • Beijing • Wuhan ISBN 978-3-03842-121-4 (PDF) ISBN 978-3-03842-122-1 (Hbk) © 2015 by the authors; licensee MDPI, Basel, Switzerland. All articles in this volume are Open Access distributed under the Creative Commons Attribution 4.0 license (http://creativecommons.org/licenses/by/4.0/), which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. However, the dissemination and distribution of copies of this book as a whole is restricted to MDPI, Basel, Switzerland. III Table of Contents List of Contributors ............................................................................................................ VII About the Guest Editor ....................................................................................................... XII Preface .............................................................................................................................. XIII Chapter 1: Neuronal Roger Torrent, Francesca de Angelis Rigotti , Patrizia Dell’Era, Maurizio Memo, Angel Raya and Antonella Consiglio Using iPS Cells toward the Understanding of Parkinson’s Disease Reprinted from: J. Clin. Med. 2015 , 4 (4), 548-566 http://www.mdpi.com/2077-0383/4/4/548 .............................................................................. 1 Dmitry A. Ovchinnikov and Ernst J. Wolvetang Opportunities and Limitations of Modelling Alzheimer’s Disease with Induced Pluripotent Stem Cells Reprinted from: J. Clin. Med. 2014 , 3 (4), 1357-1372 http://www.mdpi.com/2077-0383/3/4/1357 .......................................................................... 21 Kristine Freude, Carlota Pires, Poul Hyttel and Vanessa Jane Hall Induced Pluripotent Stem Cells Derived from Alzheimer’s Disease Patients: The Promise, t he Hope and the Path Ahead Reprinted from: J. Clin. Med. 2014 , 3 (4), 1402-1436 http://www.mdpi.com/2077-0383/3/4/1402 ..........................................................................36 Irene Faravelli, Emanuele Frattini, Agnese Ramirez, Giulia Stuppia, Monica Nizzardo and Stefania Corti iPSC-based Models to Unravel Key Pathogenetic Processes underlying Motor Neuron Diseases Development Reprinted from: J. Clin. Med. 2014 , 3 (4), 1124-1145 http://www.mdpi.com/2077-0383/3/4/1124 .......................................................................... 68 IV Chapter 2: Cardiac Alexis Bosman, Michael J. Edel, Gillian Blue, Rodney J. Dilley, Richard P. Harvey and David S. Winlaw Bioengineering and Stem Cell Technology in the Treatment of Congenital Heart Disease Reprinted from: J. Clin. Med. 2015 , 4 (4), 768-781 http://www.mdpi.com/2077-0383/4/4/768 ............................................................................89 Stephanie Friedrichs, Daniela Malan, Yvonne Voss and Philipp Sasse Scalable Electrophysiological Investigation of iPS Cell Derived Cardiomyocytes Obtained by a Lentiviral Purification Strategy Reprinted from: J. Clin. Med. 2015 , 4 (1), 102-123 http://www.mdpi.com/2077-0383/4/1/102 ..........................................................................103 Kwong-Man Ng, Cheuk-Yiu Law and Hung-Fat Tse Clinical Potentials of Cardiomyocytes Derived from Patient-Specific Induced Pluripotent Stem Cells Reprinted from: J. Clin. Med. 2014 , 3 (4), 1105-1123 http://www.mdpi.com/2077-0383/3/4/1105 ........................................................................124 Chapter 3: Eye Fred Kuanfu Chen, Samuel McLenachan, Michael Edel, Lyndon Da Cruz, Peter Coffey and David A. Mackey iPS Cells for Modelling and Treatment of Retinal Diseases Reprinted from: J. Clin. Med. 2014 , 3 (4), 1511-1541 http://www.mdpi.com/2077-0383/3/4/1511 ........................................................................ 145 Huy V. Nguyen, Yao Li and Stephen H. Tsang Patient-Specific iPSC-Derived RPE for Modeling of Retinal Diseases Reprinted from: J. Clin. Med. 2015 , 4 (4), 567-578 http://www.mdpi.com/2077-0383/4/4/567 ..........................................................................174 Ricardo P. Casaroli-Marano, Núria Nieto-Nicolau, Eva M. Martínez-Conesa, Michael Edel and Ana B. Álvarez-Palomo Potential role of Induced Pluripotent Stem Cells (IPSCs) for Cell-Based Therapy of the Ocular Surface Reprinted from: J. Clin. Med. 2015 , 4 (2), 318-342 http://www.mdpi.com/2077-0383/4/2/318 .......................................................................... 186 V Chapter 4: Spinal Cord Injury Mohamad Khazaei, Ahad M. Siddiqui and Michael G. Fehlings The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges Reprinted from: J. Clin. Med. 2015 , 4 (1), 37-65 http://www.mdpi.com/2077-0383/4/1/37 ............................................................................ 213 Stuart I. Hodgetts, Michael J. Edel and Alan R. Harvey The State of Play with iPSCs and Spinal Cord Injury Models Reprinted from: J. Clin. Med. 2015 , 4 (1), 193-203 http://www.mdpi.com/2077-0383/4/1/193 ..........................................................................243 Chapter 5: Liver Yue Yu, Xuehao Wang and Scott Nyberg Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment Reprinted from: J. Clin. Med. 2014 , 3 (3), 997-1017 http://www.mdpi.com/2077-0383/3/3/997 .......................................................................... 257 Chapter 6: Muscle Isart Roca, Jordi Requena, Michael J. Edel and Ana Belén Alvarez-Palomo Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy Reprinted from: J. Clin. Med. 2015 , 4 (2), 243-259 http://www.mdpi.com/2077-0383/4/2/243 ..........................................................................281 Chapter 7: Bone I-Ping Chen The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders Reprinted from: J. Clin. Med. 2014 , 3 (4), 1490-1510 http://www.mdpi.com/2077-0383/3/4/1490 ........................................................................ 299 VI Chapter 8: Germ Cells Tetsuya Ishii Human iPS Cell-derived Germ Cells: Current Status and Clinical Potential Reprinted from: J. Clin. Med. 2014 , 3 (4), 1064-1083 http://www.mdpi.com/2077-0383/3/4/1064 ........................................................................321 Chapter 9: Genetic Disorders Tomer Halevy and Achia Urbach Comparing ESC and iPSC — Based Models for Human Genetic Disorders Reprinted from: J. Clin. Med. 2014 , 3 (4), 1146-1162 http://www.mdpi.com/2077-0383/3/4/1146 ........................................................................ 343 Shin Kawamata, Hoshimi Kanemura, Noriko Sakai, Masayo Takahashi and Masahiro J. Go Design of a Tumorigenicity Test for Induced Pluripotent Stem Cell (iPSC)-Derived Cell Products Reprinted from: J. Clin. Med. 2015 , 4 (1), 159-171 http://www.mdpi.com/2077-0383/4/1/159 ..........................................................................359 Youssef Hibaoui and Anis Feki Concise Review: Methods and Cell Types Used to Generate Down Syndrome Induced Pluripotent Stem Cells Reprinted from: J. Clin. Med. 2015 , 4 (4), 696-714 http://www.mdpi.com/2077-0383/4/4/696 ..........................................................................371 Chapter 10: Immune Response Meilyn Hew, Kevin O'Connor, Michael J. Edel, Michaela Lucas The Possible Future Roles for iPSC-Derived Therapy for Autoimmune Diseases Reprinted from: J. Clin. Med. 2015 , 4 (6), 1193-1206 http://www.mdpi.com/2077-0383/4/6/1193 ........................................................................ 393 VII List of Contributors Ana Belén Alvarez-Palomo: Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, 08036, Barcelona, Spain Gillian Blue: Heart Centre for Children, The Children's Hospital at Westmead, Westmead NSW 2145, Australia; Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia Alexis Bosman: Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St., Darlinghurst NSW 2010, Australia; St. Vincent's Clinical School and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington NSW 2052, Australia Ricardo P. Casaroli-Marano: Department of Surgery, School of Medicine and Hospital Clínic de Barcelona (IDIBAPS), University of Barcelona, Calle Sabino de Arana 1 (2nd floor), E-08028 Barcelona, Spain; CellTec-UB and the Clinic Foundation for Biomedical Research (FCRB), University of Barcelona, Avda. Diagonal 643, E-08028 Barcelona, Spain; Tissue Bank of BST (GenCat), Calle Dr Antoni Pujadas 42, SSMM Sant Joan de Déu, Edifici Pujadas, E-08830 Sant Boi de Llobregat, Spain Fred Kuanfu Chen: Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, Perth WA 6009, Australia; Ophthalmology Department, Royal Perth Hospital, Perth WA 6009, Australia I-Ping Chen: Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA Peter Coffey: Division of Cellular Therapy, Institute of Ophthalmology, University College of London, London EC1V 9EL, UK Antonella Consiglio: Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain; Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy Stefania Corti: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Lyndon Da Cruz: Department of Vitreoretinal Surgery, Moorfields Eye Hospital, London EC1V 2PD, UK; Division of Cellular Therapy, Institute of Ophthalmology, University College of London, London EC1V 9EL, UK Francesca de Angelis Rigotti: Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain Patrizia Dell’Era: Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy VIII Rodney J. Dilley: Ear Science Institute Australia, Centre for Cell Therapy and Regenerative Medicine and School of Surgery, University of Western Australia, Nedlands WA 6009, Australia Michael J. Edel: Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, Barcelona 08036, Spain; Developmental and Stem Cell Biology, Victor Chang Cardiac Research Institute, Sydney NSW 2145, Australia; Faculty of Medicine, Westmead Children's Hospital, Division of Paediatrics and Child Health, University of Sydney Medical School, Sydney NSW 2145, Australia; School of Anatomy, Physiology and Human Biology, and the Harry Perkins Institute for Medical Research (CCTRM), The University of Western Australia, Western Australia 6009 Irene Faravelli: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Michael G. Fehlings: Department of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, M5T 2S8, ON, Canada; Department of Surgery, University of Toronto, Toronto, M5T 1P5, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, M5S 1A8, ON, Canada Anis Feki: Department of Obstetrics and Gynecology, Cantonal Hospital of Fribourg, Chemin des Pensionnats 2-6, 1708 Fribourg, Switzerland Emanuele Frattini: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Kristine Freude: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gronnegaardsvej 7, Frederiksberg C DK- 1870, Denmark Stephanie Friedrichs: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn 53127, Germany Masahiro J. Go: Research and Development Center for Cell Therapy, Foundation for Biomedical Research and Innovation, TRI#308 1-5-4, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan Tomer Halevy: Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel Vanessa Jane Hall: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gronnegaardsvej 7, Frederiksberg C DK-1870, Denmark Alan R. Harvey: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia Richard P. Harvey: Victor Chang Cardiac Research Institute, Lowy Packer Building, 405 Liverpool St., Darlinghurst NSW 2010, Australia; St. Vincent's Clinical School and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington NSW 2052, Australia IX Meilyn Hew: Department of Clinical Immunology, Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth 6009, Western Australia, Australia Youssef Hibaoui: Department of Genetic Medicine and Development, University of Geneva Medical School and Geneva University Hospitals, 1 Rue Michel-Servet, CH-1211 Geneva, Switzerland Stuart I. Hodgetts: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, Western Australia 6009, Australia Poul Hyttel: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gronnegaardsvej 7, Frederiksberg C DK-1870, Denmark Tetsuya Ishii: Office of Health and Safety, Hokkaido University, Sapporo 060-0808, Japan Hoshimi Kanemura: Research and Development Center for Cell Therapy, Foundation for Biomedical Research and Innovation, TRI#308 1-5-4, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan; Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, 2-2-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan Shin Kawamata: Research and Development Center for Cell Therapy, Foundation for Biomedical Research and Innovation, TRI#308 1-5-4, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan Mohamad Khazaei: Department of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, M5T 2S8, ON, Canada Cheuk-Yiu Law: Cardiology Division, Department of Medicine, Rm. 1928, Block K, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China Yao Li: Department of Ophthalmology, Columbia University, 635 W 165th St, New York, NY 10032, USA Michaela Lucas: Department of Clinical Immunology, Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth 6009, Western Australia, Australia; School of Medicine and Pharmacology and School of Pathology and Laboratory Medicine, The University of Western Australia, Harry Perkins Institute of Medical Research, Perth, 6009, Western Australia, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Perth, 6150, Western Australia David A. Mackey: Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, Perth WA 6009, Australia Daniela Malan: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn 53127, Germany Eva M. Martínez-Conesa: Tissue Bank of BST (GenCat), Calle Dr Antoni Pujadas 42, SSMM Sant Joan de Déu, Edifici Pujadas, E-08830 Sant Boi de Llobregat, Spain Samuel McLenachan: Centre for Ophthalmology and Visual Science (Incorporating Lions Eye Institute), The University of Western Australia, Perth WA 6009, Australia Maurizio Memo: Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy X Kwong-Man Ng: Cardiology Division, Department of Medicine, Rm. 1928, Block K, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China Huy V. Nguyen: College of Physicians and Surgeons, Columbia University, 100 Haven Ave, Apt 14B, New York, NY 10032, USA Núria Nieto-Nicolau: CellTec-UB and the Clinic Foundation for Biomedical Research (FCRB), University of Barcelona, Avda. Diagonal 643, E-08028 Barcelona, Spain Monica Nizzardo: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Scott Nyberg: Division of Experimental Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA Kevin O'Connor: Department of Clinical Immunology, Royal Perth Hospital, Perth 6000, Western Australia, Australia Dmitry A. Ovchinnikov: Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia 4072, Australia Carlota Pires: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gronnegaardsvej 7, Frederiksberg C DK- 1870, Denmark Agnese Ramirez: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Angel Raya: Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain; Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid 28029, Spain; Center of Regenerative Medicine in Barcelona, Dr. Aiguader 88, Barcelona 08003, Spain Jordi Requena: Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, 08036, Barcelona, Spain Isart Roca: Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, 08036, Barcelona, Spain Noriko Sakai: Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, 2-2-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan Philipp Sasse: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn 53127, Germany Ahad M. Siddiqui: Department of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, M5T 2S8, ON, Canada XI Giulia Stuppia: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy Masayo Takahashi: Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, 2-2-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan Roger Torrent: Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain Stephen H. Tsang: Department of Ophthalmology, Columbia University, 635 W 165th St, New York, NY 10032, USA Hung-Fat Tse: Cardiology Division, Department of Medicine, Rm. 1928, Block K, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China; Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, the University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China; Shenzhen Institutes of Research and Innovation, the University of Hong Kong, Hong Kong SAR, China Achia Urbach: Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel Yvonne Voss: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn 53127, Germany; Physical Chemistry I, University of Siegen, Siegen 57076, Germany Xuehao Wang: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province 210029, China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China David S. Winlaw: Heart Centre for Children, The Children's Hospital at Westmead, Westmead NSW 2145, Australia; Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia Ernst J. Wolvetang: Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia 4072, Australia Yue Yu: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province 210029, China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China XII About the Guest Editor Dr. Michael Edel has specialised his university studies in the basic and fundamental principles of Anatomy, Embryology and Human Physiology, completing his PhD in Pathology in 2000 at the University of Western Australia, Perth, Australia. He moved to Barcelona in 2004, and works with his wife, Dr. Ana Belen Alvarez Palomo, to develop new clinical grade cell reprogramming technology to make stem cells to study and treat human disease. He is currently a Group Leader/Ramon y Cajal Investigator and accredited Associate Professor, based at the University of Barcelona, Faculty of Medicine. He is a senior researcher in the field of IPSCs, hESC, gene regulation, epigenetics, cell cycle, direct cell reprogramming to neurons, lung or cardiac muscle cells for the use of such cells as a cell replacement therapy. He has 46 publications to date, a book on the state of the art of iPSC technology (Journal of Clinical Medicine, 2015), he is an Editorial Board Member for the Journal of Clinical Medicine , ten years post-doctoral experience and five years as a group leader. He is affiliated as a Senior Research Fellow at the University of Western Australia, Centre for Cell Therapy and Regenerative Medicine (CCTRM), School of Medicine and Pharmacology, as well as at the University of Sydney, Faculty of Medicine, and Visiting International Research Fellow at the Victor Chang Cardiac Research Institute, Sydney, Australia. Dr. Edel has a number of current research project grants as chief investigator to develop new clinical grade stem cell technology, including a University of Western Australia near miss grant to develop a project on bioengineering cardiac muscle from iPSC to treat heart disease. He has been invited as a guest speaker as part of the distinguished faculty or co-chair for over 20 congresses the past ten years. For more information see his Lab Web Page: http://pluripotencylaboratory.wordpress.com/ XIII Preface Dear Colleagues, The field of reprogramming somatic cells into induced pluripotent stem cells (iPSC) has moved very quickly, from bench to bedside in just eight years since its first discovery in humans. The best example of this is the RIKEN clinical trial this year in Japan, which will use iPSC-derived retinal pigmented epithelial (RPE) cells to treat macular degeneration (MD). This is the first human disease to be tested for regeneration and repair by iPSC-derived cells and others will follow in the near future. Currently, there is an intense worldwide research effort to bring stem cell technology to the clinic for application to treat human diseases and pathologies. Human tissue diseases, including those of the lung, heart, brain, spinal cord, and muscle, drive organ bioengineering to the forefront of technology concerning cell replacement therapy. Given the critical mass of research and translational work being performed, iPSCs may very well be the cell type of choice for regenerative medicine in the future. Basic science questions, such as efficient differentiation protocols to the correct cell type for regenerating human tissues, the immune response of iPSC replacement therapy, gene editing for disease modeling and genetic stability of iPSC-derived cells, are currently being investigated for future clinical applications. New methodologies to change cell fate are being developed. The field of direct cell reprogramming is also gaining momentum with over five different cell types generated to date including central nervous system cells, spinal motor neurons, RPE cells, pericytes, monocytes and hepatocytes. As this field develops, new applications not previously thought possible before will open up to take advantage to treat human diseases and conditions. Please join us in presenting this Special Issue on the state of the art research currently being performed worldwide to bring iPSC to the clinic so as to help understand and treat various human diseases. It is my pleasure to thank the authors and reviewers for contributing to this special issue and am sure it will become an excellent reference text for iPSC research covering ten different human disease/conditions. Dr. Michael J. Edel Guest Editor Editorial Board Member University of Barcelona: michaeledel@ub.edu University of Western Australia: Michael.edel@uwa.edu.au Centre for Cell Therapy and Regenerative Medicine (CCTRM) Chapter 1: Neuronal 3 Using iPS Cells toward the Understanding of Parkinson’s Disease Roger Torrent, Francesca De Angelis Rigotti, Patrizia Dell’Era, Maurizio Memo, Angel Raya and Antonella Consiglio Abstract: Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC) represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell types, including neurons, carrying the genetic background of the donor and enabling de novo generation of human models of genetically complex disorders. Parkinson’s disease (PD) is the second most common age-related progressive neurodegenerative disease, which is mainly characterized by nigrostriatal dopaminergic (DA) neuron degeneration and synaptic dysfunction. Recently, the generation of disease-specific iPSC from patients suffering from PD has unveiled a recapitulation of disease-related cell phenotypes, such as abnormal Į -synuclein accumulation and alterations in autophagy machinery. The use of patient-specific iPSC has a remarkable potential to uncover novel insights of the disease pathogenesis, which in turn will open new avenues for clinical intervention. This review explores the current Parkinson’s disease iPSC-based models highlighting their role in the discovery of new drugs, as well as discussing the most challenging limitations iPSC-models face today. Reprinted from J. Clin. Med. Cite as: Torrent, R.; De Angelis Rigotti, F.; Dell’Era, P.; Memo, M.; Raya, A.; Consiglio, A. Using iPS Cells toward the Understanding of Parkinson’s Disease. J. Clin. Med. 2015 , 4 , 548–566. 1. Parkinson’s Disease Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer’s disease (AD), affecting 2% of the population over the age of 60. The mean duration of the disease from the time of diagnosis to death is approximately 15 years, with a mortality ratio of 2 to 1 in the affected subjects [1]. PD is characterized by debilitating motor deficits, such as tremor, limb rigidity and slowness of movements (bradykinesia) although non-motor features, such as hyposmia, cognitive decline, depression, and disturbed sleep are also present in later stages of the disease [1–3]. Neuropathologically, these motor deficits are caused by the progressive preferential loss of striatal-projecting neurons of the substantia nigra pars compacta; more specifically a subtype of dopaminergic neurons (DAn) patterned for the ventral midbrain (vmDAn). Neuronal loss is typically accompanied by the presence of intra-cytoplasmic ubiquitin-positive inclusions in surviving neurons. These structures are known as Lewy bodies and Lewy neurites and they are mainly composed of the neuronal protein Į -synuclein ( Į -syn). These protein inclusions are not only found throughout the brain but also outside of the CNS. Moreover, microglial activation and an increase in astroglia and lymphocyte infiltration also occur in PD [4]. 4 Approximately 90%–95% of all PD cases are sporadic with no family history. Although disease onset and age are highly correlated, PD occurs when complex mechanisms such as mitochondrial activity, autophagy or degradation via proteasome are dysregulated by environmental influence or PD-specific mutation susceptibility [5]. Studies of rare large families showing classical Mendelian inherited PD have allowed for the identification of 11 genes out of 16 identified disease loci . They include dominant mutations in Leucine-rich repeat kinase 2 ( LRRK2 ), recessive mutations in Parkin (coded by PARK2 ) and PTEN-induced putative kinase ( PINK1 ) [6], as well as both rare dominant mutations and multiplications in the gene encoding Į -synuclein ( SNCA ). Current treatment for PD is limited to targeting only the symptoms of the disease and does not cure or delay disease progression. Therefore, the identification of new and more effective drugs to slow down, stop and even reverse PD is critical. This limited symptomatic treatment is due to the lack of clear understanding of the underlying mechanisms affected during PD. Using patient-specific iPSC-based models to recapitulate the disease from start to finish delivers a more detailed picture of the mechanisms involved in the progression of Parkinson’s disease and will aid in the discovery of disease-targeted therapies in the future. 2. Models of Parkinson’s Disease Despite advances in the identification of genes and proteins involved in PD, there are still gaps in our understanding of the underlying mechanisms involved [7,8]. The lack of PD models fully representing the complex mechanisms involved in disease progression, as well as the near impossible task of extracting live neurons from patients has proven the investigation of PD difficult [8]. In general, genetic mouse models do not represent the pathophysiological neurodegeneration and protein aggregation pattern observed in PD patients [9,10], and are thus limited [11,12]. On the other hand, PD animal models of administration of neurotoxins systemically or locally have successfully replicated DAn neurodegeneration, however they fail to recapitulate the degeneration in a slow and progressive manner, nor the formation of Lewy body-like inclusions which occur in PD human pathology [13]. Although the cellular models of PD, mostly based on human neuronal tumor cell lines, have provided helpful insights into alterations in specific subcellular components (such as proteasome, lysosome and mitochondrion), the relevance of these findings for PD pathogenesis is not always immediate. These models do not, however, investigate the defective mechanisms within the predominantly affected cell in PD, the DAn [14]. In addition, all studies involving human tissue have been performed with post-mortem samples, which can only allow for a limited analysis. The recent discovery of cellular reprogramming to generate induced pluripotent stem cells (iPSC) from patient somatic cells offers a remarkable opportunity to generate disease-specific iPSC [15], and to reproduce at a cellular and molecular level the mechanisms involved in disease progression. The use of iPSC offers not only the possibility of addressing important questions such as the functional relevance of the molecular findings, the contribution of individual genetic variations, patient-specific response to specific interventions, but also helps to recapitulate the prolonged time-course of the disease (Figure 1). 5 Figure 1. Generation and use of iPSC modelling in PD. Somatic cells from a diseased patient are isolated and then reprogrammed to a pluripotent state (iPSCs). iPSCs can be maintained in culture or induced to differentiate along tissue- and cell-type specific pathways. Differentiated cells can be used to elucidate disease mechanism pathways, as well as for the development of novel therapies. 3. Generation of PD-Specific iPSCs In recent years, neurodegenerative disease research has quickly advanced with the help of stem cell technology reprogramming somatic cells, such as fibroblasts, into induced pluripotent stem cells (iPSC) [15]. Human iPSC share many characteristics with human embryonic stem cells (hESC), including similarities in their morphologies, gene expression profiles, self-renewal ability, and capacity to differentiate into cell types of the three embryonic germ layers in vitro and in vivo [16]. An important advantage of induced cell reprogramming is represented by the possibility of generating iPSC from patients showing sporadic or familial forms of the disease. These in vitro models are composed of cells that carry the patients’ genetic variants, some known and others not, that are key to the contribution of disease onset and progression. Moreover, given that iPSC can be further differentiated into neurons, this technology potentially provides, for the first time, an unlimited source of native phenotypes of cells specifically involved in the process related to neuronal death in neurodegeneration in vitro. One issue found in modeling PD with the use of iPSC is to correctly reproduce its late-onset characteristics, since aging is a crucial risk factor. Indeed, at first it was unclear whether disease-specific features of neurodegenerative disorders that usually progressively appear over several years were reproducible in vitro over a period of only a few days to a few months. As a consequence, iPSC were initially used to model neurodevelopmental phenotypes and a variety of monogenic early-onset diseases [17–24]. However, studies using iPSC derived from patients with monogenic and sporadic forms of PD have illustrated these key features of PD pathophysiology, as a late-onset neurodegenerative disorder, after differentiating these iPSC into dopaminergic neurons. Moreover, several inducible factors that cause cell stress, such as mitochondrial toxins [25], growth factor deficiency, or even modulated aging with induced expression of progerin (a protein causing