Stem Cell and Gene-Based Therapy Alexander Battler and Jonathan Leor Stem Cell and Gene-Based Therapy Frontiers in Regenerative Medicine With 62 Figures including 27 Color Plates Alexander Battler, MD, FACC, FESC Jonathan Leor, MD, FACC, FESC Department of Cardiology Neufeld Cardiac Research Institute Rabin Medical Center, Petach-Tikwa Sackler Faculty of Medicine Sackler Faculty of Medicine Tel Aviv University Tel Aviv University Sheba Medical Center Israel Tel-Hashomer Israel British Library Cataloguing in Publication Data Stem cell and gene-based therapy: frontiers in regenerative medicine 1. Stem cells – Research 2. Gene therapy – Research 3. Regeneration (Biology) – Research I. Battler, Alexander II. Leor, Jonathan 616′.02774 ISBN-10: 1852339799 Library of Congress Control Number: 2005925974 ISBN-10: 1-85233-979-9 e-ISBN 1-84628-142-3 Printed on acid-free paper ISBN-13: 978-1-85233-979-1 © Springer-Verlag London Limited 2006 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or trans- mitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a spe- cific statement, that such names are exempt from the relevant laws and regulations and therefore free for gen- eral use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by con- sulting other pharmaceutical literature. Printed in the United States of America (SPI/SB) 987654321 Springer Science+Business Media springeronline.com Foreword Regenerative medicine promises to be one of the great future frontiers. Critical to the success of this area is stem cell research, and cell- and gene-based therapy. In this book, a variety of outstanding authors discuss important aspects of these research areas. Important topics include new types of cell therapies and stem cell-based therapy for angiogenesis and cardiac repair. They also include cell-therapy approaches in neuro- logic areas such as Parkinson’s disease, multiple sclerosis, and stroke. A third area that is explored involves the development of cell-based systems for cartilage and bone repair, bladder repair, and kidney regeneration. A fourth area involves important work in the eye, specifically, optic nerve regeneration, retinal repair, and ocular surface regenera- tion. The potential of using insulin-producing cells or islets is also examined in this book, as are strategies for cord blood transplantation for various hematologic disorders. Finally, important areas of research involving skin regeneration and wound healing are discussed. This book should provide an excellent overview of the important areas in regenerative medicine with respect to cell and gene therapy and hopefully will be a use- ful guide for scientists doing research in these areas. Robert Langer Massachusetts Institute of Technology Cambridge, MA, USA v Preface The human body has limited potential to rejuvenate injured organs and tissues. An old dream of scientists and physicians is to be able to rebuild “spare parts” to replace injured or diseased tissues—a notion that was once referred to as the field of science fic- tion. The new discipline of regenerative medicine aims to help the body heal itself with cells, genes, and bioactive molecules and materials. In the last decade, the notion that stem cells can give rise to mature tissues has made stem cells the focus of intense research designed to explore their promise for the treatment of a variety of diseases. The aim of our book is to cover key aspects of the promise and existing problems in the emerging field of regenerative medicine. With the contribution of leading figures and pioneers in various disciplines of regenerative medicine and science, the book brings together major approaches of stem cell and gene-based therapy in one text. The appearance of this book has been made by the willing and corporation of many individuals. We thank our contributors, and section editors Belkin, Dekel, Efrat, Grossman, Melamed, Nagler, Offen, Nevo, and Reisner for generously sharing their expertise and scientific skills on which this book is based. We hope that the book will provide a realistic image of the huge potential, promise and challenges facing the fan- tastic field of regenerative medicine in its quest to cure disease and prolong life. Alexander Battler Jonathan Leor vii Acknowledgment We thank the section editors and coauthors for generously sharing their expertise and skills on which this book is based. We thank Mrs. Elaine Finkelstein from Neufeld Cardiac Research Institute, Tel-Hashomer, Israel, for her unfailing skills that were very helpful in editing and preparing this book. Alexander Battler, MD, FACC, FESC Jonathan Leor, MD, FACC, FESC ix Contents Foreword Robert Langer . v Preface Alexander Battler and Jonathan Leor . vii Acknowledgment . ix List of Contributors . xv Section 1 Heart Introduction Alexander Battler and Jonathan Leor . 2 1 Renovation of the Injured Heart with Myocardial Tissue Engineering Jonathan Leor, Natali Landa, and Smadar Cohen . 3 2 Adult Stem Cells for Myocardial Tissue Repair Dirk Strunk and Christof Stamm . 17 3 Regeneration of the Functional Myocardium Using Human Embryonic Stem Cells Oren Caspi and Lior Gepstien . 33 4 Therapeutic Angiogenesis Shmuel Fuchs and Alexander Battler . 45 5 Cell Therapy for Heart Failure Thorsten Reffelmann and Robert A. Kloner . 59 Section 2 Neuro Introduction Daniel Offen and Eldad Melamed . 72 6 Cell Transplantation for Diseases of Myelin Tamir Ben-Hur and Ofira Einstein . 75 xi xii Contents 7 Stem Cells as a Source for Cell Replacement in Parkinson’s Disease Daniel Offen, Yossef S. Levy, and Eldad Melamed . 97 8 Cell Replacement Therapy in Acute Stroke: Current State Yossi Gilgun-Sherki and Jonathan Y. Streifler . 123 9 Gene Therapy to the Nervous System Hillel Haim and Israel Steiner . 133 Section 3 Musculoskeletal Introduction Zvi Nevo and Mark M. Levy . 156 10 Mesenchymal Stem Cells: Where Can You Find Them? How Can You Use Them? Anna Derubeis, Giuseppina Pennesi, and Ranieri Cancedda . 159 11 Basic to Clinical Cartilage Engineering: Past, Present, and Future Discussions Mats Brittberg, Tommi Tallheden, and Anders H. Lindahl . 169 12 Cartilage Rocky S. Tuan and Faye H. Chen . 179 13 Bone Regeneration A.H. Reddi . 195 14 Osteoarthritis and Mesenchymal Cells – The Prospects for Repair of the Disease by Cell Transplantation and Tissue Engineering Dror Robinson . 203 Section 4 Kidney Introduction Benjamin Dekel and Yair Reisner . 208 15 Progenitor Cell Therapy for Kidney Regeneration Benjamin Dekel and Yair Reisner . 209 16 Tissue Engineering – The Bladder Anthony Atala . 225 Section 5 Eye Introduction Michael Belkin . 234 17 Neuroprotection in Ophthalmology: A Review Yaniv Barkana and Michael Belkin . 237 Contents xiii 18 Autoimmunity for Central Nervous System Maintenance, Regeneration, and Renewal: Development of a T Cell-Based Vaccination Against Neurodegeneration Michal Schwartz and Jonathan Kipnis . 251 19 Retinal Repair by Stem Cell Transplantation Jeffrey H. Stern, Sally Temple, and Soma De . 259 20 Induction of Ocular Surface Regeneration Irina S. Barequet . 281 Section 6 Pancreas Introduction Shimon Efrat . 298 21 Insulin-Producing Cells Generated from Nonpancreatic Tissues Shimon Efrat . 301 22 Generation of Islets from Pancreatic Progenitor Cells Susan Bonner-Weir, Tandy Aye, Akari Inada, Elena Toschi, and Arun Sharma . 309 23 Embryonic Stem Cells as a Source of Pancreatic Precursors and Islet Cells In Vitro Victoria L. Browning, Brenda W. Kahan, and Jon S. Odorico . 321 Section 7 Hematology Introduction Arnon Nagler . 332 24 Human Umbilical Cord Blood Transplantation: A Viable Option for Stem Cell Graft Gal Goldstein, Amos Toren, and Arnon Nagler . 333 25 Nonmyeloablative Stem Cell Transplantation in the Treatment of Hematologic Malignancies Avichai Shimoni and Arnon Nagler . 351 26 Hematopoietic Stem Cell Transplantation from Human Leukocyte Antigen Haploidentical Donor Merav Leiba and Arnon Nagler . 361 Section 8 Skin Introduction Nili Grossman . 372 27 Wound Healing and Skin Substitutes Adam J. Singer and Marcia Simon . 375 xiv Contents 28 Skin Regeneration from Multipotent Adult and Embryonic Stem Cells Kursad Turksen and Tammy-Claire Troy . 395 Index . 407 Color Insert . following page 206 Contributors Anthony Atala, MD Susan Bonner-Weir, PhD The William Boyce Professor and Senior Investigator, Joslin Diabetes Chair, Department of Urology Center Director, Wake Forest Institute for Associate Professor of Medicine, Regenerative Medicine Harvard Medical School Wake Forest University School of Boston, MA, USA Medicine Winston-Salem, NC, USA Mats Brittberg, MD, PhD Cartilage Research Unit Irina S. Barequet, MD Göteborg University The Goldschleger Eye Institute Department of Orthopaedics Sheba Medical Center Sackler Kungsbacka Hospital Faculty of Medicine Kungsbacka, Sweden Tel Aviv University, Tel Aviv, Israel Ranieri Cancedda, MD Professor Alexander Battler, MD, FACC,