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 Tel- 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 Limited 2006

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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, , 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 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 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, Department of Oncology, Biology FESC and Genetics Professor and Chair of Cardiology University of Genova Rabin Medical Center, Petach- Genova, Italy Tikvah Sackler Faculty of Medicine Benjamin Dekel, MD, PhD Tel Aviv University Department of Pediatrics Israel Safra Children’s Hospital Sheba Medical Center Michael Belkin, MA, MD Tel Hashomer, Israel Director Ophthalmic Technologies Shimon Efrat, PhD Laboratory, Eye Research Human Genetics and Molecular Institute Medicine Sackler School of Medicine, Tel Sackler School of Medicine Aviv University Tel Aviv University Sheba Medical Center Tel Aviv, Israel Tel Hashomer, Israel Shmuel Fuchs, MD Tamir Ben-Hur, MD, PhD Head, Catheterization Laboratory Professor Department of Cardiology Rabin Medical Center Hadassah Hebrew University Petch-Tikva, Israel Medical Center Jerusalem, Israel

xv xvi Contributors

Lior Gepstien, MD, PhD Arnon Nagler, MD, MSc Department of Biophysics and Director Hematology Division Physiology Hematology The Bruce Rappaport Faculty of Chaim Sheba Medical Center Medicine Tel Hashomer, Tamat Gan, Technion-Israel Institute of Israel Technology Haifa, Israel Zvi Nevo, PhD ex Department Chairman Yossi Gilgun-Sherki, PhD Clinical Biochemistry Sackler School of Medicine Neurology Tel Aviv University Laboratory of Tel Aviv, Israel Felsenstein Medical Research Center Petah-Tikva, Israel Jon S. Odorico, MD Assistant Professor, Director – Gal Goldstein, MD Islet Cell Transplantation Staff Physician Program Pediatric Hemato-Oncology Transplantation Surgery Edmond & Lili Safra’s children University of Wisconsin – hospital Madison Medical School Tel Hashomer, Israel Madison, WI, USA

Nili Grossman, PhD Daniel Offen, PhD Director Head of Neurology Laboratory Skin Bank and Investigative Felsenstein Medical Research Dermatology Laboratory Center and Department of Microbiology Tel Aviv University and / Health Rabin Medical Center Sciences Petha-Tikva, Israel Soroka University Medical Center and Ben Gurion University of the A. H. Reddi, PhD Negev Center for Tissue Regeneration Beer Sheva, Israel and Repair Department of Orthopaedic Hillel Haim, MD Surgery Physician University of California, Davis Department of Neurology School of Medicine Hadassah University Hospital Sacramento, CA, USA Jerusalem, Israel Thorsten Reffelmann, MD Merav Leiba, MD Medical Clinic I, University Hematology & Bone Marrow Hospital Transplantation Department of Cardiology Chaim Sheba Medical Center RWTH Aachen Tel-Hashomer, Israel Aachen,

Jonathan Leor, MD, FACC, FESC Dror Robinson, MD, PhD Director Chairman Neufeld Cardiac Research Institute Department of Orthopaedics Sackler Faculty of Medicine Rabin Medical Center Tel Aviv University Petah-Tikwa, Israel Sheba Medical Center Tel Hashomer, Israel Contributors xvii

Michal Schwartz, PhD Jeffrey H. Stern, PhD, MD Professor of Retina / Vitreous Surgery Neurobiology Albany, NY, USA The Weizmann Institute of Science Rocky S. Tuan, PhD Rehovot, Israel Branch Chief Cartilage Biology and Avichai Shimoni, MD Orthopaedics Branch Senior Physician National Institute of Arthritis and Division of Hematology and Bone Musculoskeletal and Skin Marrow Transplantation Diseases Chaim Sheba Medical Center Bethesda, MD, USA Tel Hashomer, Israel Kursad Turksen, PhD Adam J. Singer, MD Senior Scientist Vice Chairman for Research Hormones, Growth and Emergency Medicine Development Stony Brook University Ottawa Health Research Institute Stony Brook, NY, USA Ottawa, Ontario, Canada

Christof Stamm, MD Consultant Surgeon Department of Cardiac Surgery University of Rostock Rostock, Germany