Regenerative Medicine

Gustav Steinhoff Editor

Regenerative Medicine

From Protocol to Patient

Second Edition

Editor Gustav Steinhoff Department of Cardiac Surgery and

Reference and Translation Center of Cardiac Stem Cell Therapy (RTC)

Medical Faculty University of Rostock Rostock, Germany

ISBN 978-94-007-5689-2 ISBN 978-94-007-5690-8 (eBook) DOI 10.1007/978-94-007-5690-8 Springer Dordrecht Heidelberg New York London

Library of Congress Control Number: 2013934586

© Springer Science+Business Media Dordrecht 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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v

Foreword

Regenerative Medicine: From Protocol to Patient

Second edition

Regenerative Medicine is a fast emerging interdisciplinary fi eld of research and clinical therapies on the repair, replacement or regeneration of cells, tissues or organs in congenital or acquired disease. This new fi eld of research and clinical development focussing on stem cell science and regenerative biology is just starting to be the most fascinating and controversial medical development at the dawn of the twenty- fi rst century. It can be envisaged that this development will establish com-pletely new molecular and cellular techniques for medical therapy. An early rush of scienti fi c development was set up more than 100 years ago by the physiology of blood regeneration (Hall and Eubanks 1896) and successful vascular surgical tech-niques for organ transplantation (Carrel and Guthrie 1905). However, the clinical realization of allogenic blood transfusion lasted until the discovery of the blood group antigens (Landsteiner and Levine 1928) and successful routine allogenic organ and bone marrow transplantation even until the end of the last century.

Similar to the fi eld of allogenic cell and organ transplantation, it seems that Regenerative Medicine again condenses mankind’s visions, hopes, and fears regard-ing medicine: Hopes of eternal life and effective treatment of uncurable disease as well as fears of misuse of technology and uncontrolled modi fi cations of life are polarizing the scienti fi c fi eld. The development and public acceptance of new ethi-cal and regulatory guidelines is a necessary process to support the further clinical development. Nevertheless, the vision of a new medicine using the regenerative power of biology to treat disease and restructure the organism is setting the aim for scienti fi c, technological and medical development. Viewing the great expectations to restructure and regenerate tissue, organs or organisms the current attempts of scientist and physicians are still in an early phase of development.

The fi eld of Regenerative Medicine has developed rapidly over the last 20 years with the advent of molecular and cellular techniques. This textbook on “Regenerative

vi

Medicine: From Protocol to Patient” is aiming to explain the scienti fi c knowledge and emerging technology as well as the clinical application in different organ systems and diseases. The international leading experts from four continents describe the latest scienti fi c and clinical knowledge of the fi eld of Regenerative Medicine . The process of translating science of laboratory protocols into therapies is explained in sections on regulatory, ethical and industrial issues. Patient needs are advocated by the proposition initiatives on the scienti fi c development of new therapies.

This textbook is organized into fi ve major parts: ( I ) Biology of Tissue Regeneration , ( II ) Stem Cell Science and Technology , ( III ) Tissue Engineering , Biomaterials and Nanotechnology , ( IV ) Regenerative Therapies , and ( V ) Regulation and Ethics .

We start with an overview on the History of Regenerative Medicine . This is fol-lowed by the part of Biology of Tissue Regeneration , which focuses on extracellular matrix, asymmetric stem cell division, stem cell niche regulation and stem cells during embryonic neurogenic development. The part on Stem Cell Science and Technology provides an overview on classi fi cation of stem cells and describes techniques for their derivation and culture. Basic properties of the cells are illus-trated, and some areas of applications for these cells are discussed with emphasis on their possible future use in Regenerative Medicine .

The part of Tissue Engineering , Biomaterials and Nanotechnology focuses the development of technologies, which enable an ef fi cient transfer of therapeutic genes and drugs exclusively to target cells and potential bioactive materials for clinical use. Chimerism, multifunctionalized nanoparticles and nanostructured biomaterials are described with regard to the technological development of new clinical cell technology.

The part on Regenerative Therapies gives a survey on the clinical development in the different organ systems. Disease speci fi c approaches of new therapies, appli-cation technology, clinical achievements and limitations are described. The part on Regulation and Ethics describes the current legislation for clinical translation as the ethical and juridical development in different countries.

The textbook is aiming to give the student, the researcher, the health care profes-sional, the physician, and the patient a complete survey on the current scienti fi c basis, therapeutical protocols, clinical translation and practised therapies in Regenerative Medicine . On behalf of the sincere commitment of the international experts we hope to increase your knowledge, understanding, interest and support by reading the book.

After the successful introduction in 2011, the textbook has been actualized for the second edition. The basic science and clinical part has been extended by fi ve new chapters.

Rostock, August 2012 Gustav Steinhoff (Editor)and Hoang Tu-Rapp (Assistant Editor)

Foreword

vii

Literature

Carrel A, Guthrie CC (1906) Successful transplantation of both kidneys from a dog into a bitch with removal of both normal kidneys from the latter. Science 23(584):394–395 Hall WS, Eubank MD (1896) The regeneration of the blood. J Exp Med 1(4):656–676 Landsteiner K, Levine P (1928) On individual differences in human blood. J Exp Med 47(5):757–775

Prof. Dr. med. Gustav Steinhoff Professor of Cardiac Surgery, Director,

Department of Cardiac Surgeryand

Reference and Translation Center of Cardiac Stem Cell Therapy (RTC)

Medical Faculty, University of Rostock,Schillingallee 35, 18057 Rostock, Germany

Dr. Hoang Tu-RappDepartment of Cardiac Surgery, Medical Faculty,

University of Rostock, Schillingallee 35,18057 Rostock, Germany

Foreword

ix

1 History of Regenerative Medicine ......................................................... 1 Raymund E. Horch , Laurentiu M. Popescu, and Elias Polykandriotis

Part I Biology of Tissue Regeneration

2 Extracellular Matrix and Tissue Regeneration .................................... 21 Yrjö T. Konttinen , Emilia Kaivosoja , Vasily Stegaev , Hanoch Daniel Wagner , Jaakko Levón , Veli-Matti Tiainen, and Zygmunt Mackiewicz

3 Stem Cell Niche ....................................................................................... 79 Chenhui Wang , Pei Wen, Pei Sun, and Rongwen Xi

4 Stem Cells and Asymmetric Cell Division ............................................ 107 Frank Hirth

5 Stem Cells in the Developing and Adult Nervous System ................... 129 Fumitaka Osakada and Masayo Takahashi

Part II Stem Cell Science and Technology

6 Characterization and Classi fi cation of Stem Cells ............................... 155 Ute Bissels, Dominik Eckardt, and Andreas Bosio

7 Human Embryonic Stem Cells............................................................... 177 Mikael C. O. Englund , Peter Sartipy, and Johan Hyllner

8 Induced Pluripotent Stem Cells ............................................................. 197 Keisuke Okita , Kazutoshi Takahashi, and Shinya Yamanaka

9 Spermatogonial Stem Cells .................................................................... 219 Ilya Chuykin, Michael Stauske, and Kaomei Guan

Contents

x Contents

10 Hematopoietic Stem Cells ....................................................................... 251 Mary L. Clarke and Jonathan Frampton

11 Cardiovascular Stem Cells ..................................................................... 279 Christoph Brenner, Robert David, and Wolfgang-Michael Franz

12 Neural Stem Cells .................................................................................... 297 Yoko Arai, Wieland B. Huttner, and Federico Calegari

13 Liver Stem Cells ...................................................................................... 337 Tohru Itoh, Hinako Takase, Minoru Tanaka, and Atsushi Miyajima

14 Gastro Intestinal Stem Cells ................................................................... 365 M. Sasikala, G. V. Rao, Manu Tandan, and D. Nageshwar Reddy

15 Cancer Stem Cells ................................................................................... 387 Murali M. S. Balla, Anjali P. Kusumbe, Geeta K. Vemuganti, and Sharmila A. Bapat

16 Mesenchymal Stem Cells – An Oversimpli fi ed Nomenclature for Extremely Heterogeneous Progenitors ............................................ 413 Patrick Wuchter, Wolfgang Wagner, and Anthony D. Ho

17 Musculoskeletal Stem Cells .................................................................... 433 Gerben M. van Buul and Gerjo J. V. M. van Osch

Part III Tissue Engineering, Biomaterials and Nanotechnology

18 When Stemness Meets Engineering: Towards “Niche” Control of Stem Cell Functions for Enhanced Cardiovascular Regeneration ................................................................ 457 Maurizio Pesce, Giulio Pompilio, Gianluca Polvani, and Maurizio C. Capogrossi

19 Vector Technology and Cell Targeting: Peptide-Tagged Adenoviral Vectors as a Powerful Tool for Cell Speci fi c Targeting ...................................................................... 475 Julia Reetz, Ottmar Herchenröder, Anke Schmidt, and Brigitte M. Pützer

20 Regenerative Chimerism Bioengineered Through Stem Cell Reprogramming ..................................................................... 505 Timothy J. Nelson , Almudena Martinez-Fernandez , Satsuki Yamada, and Andre Terzic

21 Biodegradable Materials ........................................................................ 529 Michael Schroeter, Britt Wildemann, and Andreas Lendlein

xiContents

22 Biomaterials-Enabled Regenerative Medicine in Corneal Applications .......................................................................... 557 Naresh Polisetti, Christopher R. McLaughlin, Geeta K. Vemuganti, and May Grif fi th

23 Functionalized Nanomaterials ............................................................... 581 Jie Zhou, Wenzhong Li, and Changyou Gao

24 Biointerface Technology ......................................................................... 611 Joachim Rychly

Part IV Regenerative Therapies

25 Emerging Concepts in Myocardial Pharmacoregeneration ................ 637 Laura C. Zelarayán, Maria Patapia Za fi riou, and Wolfram-Hubertus Zimmermann

26 Blood ......................................................................................................... 665 Michael Schmitt and Mathias Freund

27 Regenerative Medicine in the Central Nervous System: Stem Cell-Based Cell- and Gene-Therapy ............................................ 695 Seung U. Kim

28 Regenerative Therapy for Central Nervous System Trauma ............. 729 Kewal K. Jain

29 Regenerative Therapies for the Ocular Surface ................................... 755 Geeta K. Vemuganti , Virender S. Sangwan, Indumathi Mariappan, and Dorairajan Balasubramanian

30 Lacrimal Gland Regeneration: Progress and Promise ........................ 775 Shubha Tiwari and Geeta K. Vemuganti

31 The Development of a Stem Cell Therapy for Deafness ...................... 793 Nopporn Jongkamonwiwat and Marcelo N. Rivolta

32 Oral and Maxillo-facial .......................................................................... 823 Kristina Arvidson, Michele Cottler-Fox, Sølve Hellem, and Kamal Mustafa

33 Regenerative Therapies-Trachea ........................................................... 843 Silvia Baiguera and Paolo Macchiarini

34 Lung ......................................................................................................... 861 Lavinia Iuliana Ionescu and Bernard Thébaud

35 Vascular Regeneration: Endothelial Progenitor Cell Therapy for Ischemic Diseases ....................................................... 881 Masaaki Ii, Atsuhiko Kawamoto, and Takayuki Asahara

xii Contents

36 Heart ....................................................................................................... 901 Gustav Steinhoff and Bodo Eckehard Strauer

37 Liver ....................................................................................................... 929 Amar Deep Sharma, Razvan Iacob, Tobias Cantz , Michael P. Manns, and Michael Ott

38 Kidney .................................................................................................... 961 Sajoscha A. Sorrentino and Hermann Haller

39 Gastrointestinal Tract and Endocrine System ................................... 983 Nonsikelelo Mpofu-Mätzig, Michelle Klose , Elmar Jäckel, Michael P. Manns, and Oliver Bachmann

40 Preclinical Animal Models for Segmental Bone Defect Research and Tissue Engineering ........................................................ 1023 Johannes C. Reichert, Arne Berner, Siamak Saifzadeh, and Dietmar W. Hutmacher

41 Constraints to Articular Cartilage Regeneration .............................. 1065 Georg N. Duda, Joshua O. Eniwumide , and Michael Sittinger

42 Muscle and Ligament Regeneration .................................................... 1101 Thomas Mittlmeier and Ioannis Stratos

43 Skin ......................................................................................................... 1117 Hans-Günther Machens, Christina Irene Günter, and Augustinus Bader

Part V Regulation and Ethics

44 Regulatory Frameworks for Cell and Tissue Based Therapies in Europe and the USA ....................................................... 1139 Gudrun Tiedemann and Sebastian C. Sethe

45 Ethics and Law in Regenerative Medicine: A Legal and Ethical Outline on Regenerative Medicine in Research in France, Germany and Poland ..................................... 1173 Gregor Becker and Anna Grabinski

Index ............................................................................................................... 1203

xiii

Contributors

Yoko Arai Ph.D. Alessandra Pierani Group, Genetics and Development of the Cerebral Cortex, Institute Jacques-Monod CNRS UMR 7592 , Université Paris Diderot , Paris Cedex 13 , France

Kristina Arvidson , D.D.S., Ph.D. Department of Clinical Dentistry – Centre for Clinical Dental Research , University of Bergen , Bergen , Norway Solna, Stockholm , Sweden

Takayuki Asahara , M.D., Ph.D. Department of Regenerative Medicine Science , Tokai University School of Medicine , Isehara, Kanagawa , Japan

Group of Vascular Regeneration Research , Institute of Biomedical Research and Innovation (IBRI)/RIKEN Center for Developmental Biology , Chuo-ku, Kobe , Japan

Oliver Bachmann , M.D. Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine , Hannover Medical School (MHH) , Hannover , Germany

Augustinus Bader , M.D. Stem cell biology and cell technology, Medical Faculty , Biotechnological-Biomedical Center (BBZ), Leipzig University , Leipzig , Germany

Silvia Baiguera , Ph.D. BIOAIR (Laboratory of Biomolecular and Bioengineering Airway), Department of General Thoracic and Regenerative Surgery and Intrathoracic Biotransplantation , University Hospital Careggi , Florence , Italy

Dorairajan Balasubramanian , Ph.D. Prof Brien Holden Eye Research Centre , University of Hyderabad, L V Prasad Eye Institute , Banjara Hills, Hyderabad , Andhra Pradesh , India University of Hyderabad , Banjara Hills, Hyderabad , Andhra Pradesh , India

Murali M. S. Balla Champalimaud Translational Centre for Eye Research, Hyderabad Eye Research Foundation , L.V. Prasad Eye Institute , Banjara Hills, Hyderabad , Andhra Pradesh , India

xiv Contributors

Sharmila A. Bapat , Ph.D., FNASc National Centre for Cell Science , Pune , Maharashtra , India

Gregor Becker , Ph.D. Group for Bio-Ethics in Life Sciences (GBLS), Faculty of Biochemistry, Biophysics and Biotechnology , Jagiellonian University , Kraków , Poland

Arne Berner , M.D. Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , QLD , Australia

Ute Bissels , Ph.D. Miltenyi Biotec GmbH , Bergisch Gladbach , Germany

Andreas Bosio , Ph.D. Miltenyi Biotec GmbH , Bergisch Gladbach , Germany

Christoph Brenner , M.D. Department of Internal Medicine I , University of Munich – Campus Grosshadern , Munich , Germany

Federico Calegari , Ph.D. Max Planck Institute of Molecular Cell Biology and Genetics , Dresden , Germany

DFG-Center and Cluster of Excellence for Regenerative Therapies , Dresden University of Technology , Dresden , Germany

Tobias Cantz , M.D. Junior Research Group “Stem Cell Biology”, Cluster of Excellence REBIRTH , Hannover Medical School , Hannover , Germany

Maurizio C. Capogrossi , M.D. Laboratorio di Patologia Vascolare, Istituto Dermo-patico dell’ Immacolata , (IDI)-Istituto di Ricovero e Cura a CarattereScienti fi co (IRCCS) , Rome , Italy

Ilya Chuykin , Ph.D. Department of Cardiology and Pneumology , Georg-August-University Göttingen , Göttingen , Germany

Mary L. Clarke , Ph.D. Institute of Biomedical Research, College of Medical and Dental Sciences , University of Birmingham , Edgbaston, Birmingham , UK

Michele Cottler-Fox , M.D. Department of Clinical Dentistry – Centre for Clinical Dental Research , University of Bergen , Bergen , Norway

Robert David , Ph.D. Department of Internal Medicine I , University of Munich – Campus Grosshadern , Munich , Germany

Georg N. Duda , Ph.D. Julius Wolff Institute and Centre for Musculoskeletal Surgery, Berlin-Brandenburg Centre for Regenerative Therapy , Charité , Berlin , Germany

Dominik Eckardt , Ph.D. Miltenyi Biotec GmbH , Bergisch Gladbach , Germany

Mikael C. O. Englund , Ph.D. Cellectis Stem Cells , Dundee , UK

Joshua O. Eniwumide , Ph.D. Julius Wolff Institute and Centre for Musculoskeletal Surgery, Berlin-Brandenburg Centre for Regenerative Therapy , Charité , Berlin , Germany

xvContributors

Jonathan Frampton , B.A., Ph.D. Institute of Biomedical Research, College of Medical and Dental Sciences , University of Birmingham , Edgbaston, Birmingham , UK

Wolfgang-Michael Franz , M.D. Department of Internal Medicine I , University of Munich – Campus Grosshadern , Munich , Germany

Mathias Freund , M.D., Ph.D. 3rd Medical Department, Hematology, Oncology, Palliative Medicine, Center of Medicine , Rostock University Hospitals , Rostock , Germany

Changyou Gao , Ph.D. Department of Polymer Science and Engineering , Zhejiang University , Hangzhou , Zhejiang Province , People’s Republic of China

Anna Grabinski Paris , France

May Grif fi th , Ph.D., MBA Integrative Regenerative Medicine (IGEN) Centre, Department of Clinical and Experimental Medicine , Linköping University , Linköping , Sweden

Kaomei Guan , Ph.D. Department of Cardiology and Pneumology , Georg-August-University Göttingen , Göttingen , Germany

Christina Irene Günter , M.D. Clinical Trials Research Group, Clinic for Plastic and Hand Surgery , University Hospital Rechts der Isar, Technische Universität München , Munich , Germany

Hermann Haller , M.D. Department of Nephrology and Hypertension , Hannover Medical School , Hannover , Germany

Sølve Hellem , D.D.S., Ph.D. Department of Clinical Dentistry – Centre for Clinical Dental Research , University of Bergen , Bergen , Norway

Ottmar Herchenröder , Ph.D. Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center , University of Rostock Medical School , Rostock , Germany

Frank Hirth , B.Sc., M.Sc., Ph.D., PD Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry , King’s College London , London , UK

Anthony D. Ho , M.D., FRCPC Department of Internal Medicine V , Heidelberg University , Heidelberg , Germany

Raymund E. Horch , M.D. Department of Plastic and Hand Surgery , University of Erlangen , Erlangen , Germany

Dietmar W. Hutmacher , Ph.D., M.B.A., M.Sc. Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , QLD , Australia

Wieland B. Huttner , M.D. Max-Planck-Institute of Molecular Cell Biology and Genetics , Dresden , Germany

xvi Contributors

Johan Hyllner , Ph.D. Cellartis AB , Göteborg , Sweden

Razvan Iacob , M.D. University of Medicine and Pharmacy “Carol Davila” , Bucharest , Romania

Masaaki Ii , M.D., Ph.D. Department of Pharmacology, Group of Translational Stem Cell Research , Osaka Medical College , Takatsuki, Osaka , Japan

Lavinia Iuliana Ionescu , M.D., Ph.D. Department of Physiology, 3032 Katz Group Centre for Pharmacy and Health Research , University of Alberta , Edmonton , AB , Canada

Tohru Itoh , Ph.D. Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences , The University of Tokyo , Tokyo , Japan

Elmar Jäckel , M.D. Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine , Hannover Medical School (MHH) , Hannover , Germany

Kewal K. Jain , M.D., FRACS, FFPM Jain PharmaBiotech , Basel , Switzerland

Nopporn Jongkamonwiwat , Ph.D. Centre for Stem Cell Biology and Department of Biomedical Sciences , University of Shef fi eld , Shef fi eld , UK

Emilia Kaivosoja , M.Sc. Department of Medicine , Institute of Clinical Medicine , Helsinki , Finland

Atsuhiko Kawamoto , M.D., Ph.D. Unit of Regenerative Medicine , Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology , Chuo-ku, Kobe , Japan

Seung U. Kim , M.D., Ph.D. Division of Neurology, Department of Medicine, UBC Hospital , University of British Columbia , Vancouver , BC , Canada

Medical Research Institute , Chung-Ang University College of Medicine , Seoul , South Korea

Michelle Klose (Stange) , M.D. Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine , Hannover Medical School (MHH) , Hannover , Germany

Yrjö T. Konttinen , M.D., Ph.D. Department of Medicine , Institute of Clinical Medicine , Helsinki , Finland

Anjali P. Kusumbe National Centre for Cell Science , Pune , Maharashtra , India

Andreas Lendlein , Prof. Center for Biomaterial Development , Helmholtz-Zentrum Geesthacht , Teltow , Germany

Julius-Wolf Institute and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT) , Charité , Berlin , Germany

Jaakko Levón , B.Sc. Department of Medicine , Institute of Clinical Medicine , Helsinki , Finland

xviiContributors

Wenzhong Li , Dr.-ing (NUS) Center for Biomaterial Development and Berlin Brandenburg Center for Regenerative Therapies , Helmholtz-Zentrum Geesthacht , Teltow , Germany

Paolo Macchiarini , M.D., Ph.D. Department of General Thoracic and Regenera-tive Surgery, and Intrathoracic Biotransplantation , University Hospital Careggi , Florence , Italy

Advanced Center for Translational Regenerative Medicine (ACTREM) , ENT (CLINTEC), Karolinska Institutet , Huddinge, Stockholm , Sweden

University College London , London, UK

Hans-Günther Machens , M.D. Clinic for Plastic and Hand Surgery , University Hospital Rechts der Isar, Technische Universitaet Muenchen , Munich , Germany

Zygmunt Mackiewicz , Ph.D., D.Sc. Department of Histology and Embryology , Medical University of Bialystok , Bialystok , Poland

Michael P. Manns , M.D. Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine , Hannover Medical School (MHH) , Hannover , Germany

Indumathi Mariappan , Ph.D. Sudhakar & Sreekanth Ravi Stem Cell Biology Laboratory, Prof Brien Holden Eye Research Centre , L.V. Prasad Eye Institute , Banjara Hills, Hyderabad , Andhra Pradesh , India

Almudena Martinez-Fernandez , PharmD, Ph.D. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics , Mayo Clinic , Rochester , MN , USA

Christopher R. McLaughlin , Ph.D. Michael G. DeGroote School of Medicine , McMaster University , Hamilton , ON , Canada

Thomas Mittlmeier , M.D. Department of Trauma and Reconstructive Surgery , University of Rostock , Rostock , Germany

Atsushi Miyajima , Ph.D. Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences , The University of Tokyo , Tokyo , Japan

Nonsikelelo Mpofu-Mätzig , Ph.D. Department of Gastroenterology, Hepatology and Endocrinology, Centre for Internal Medicine , Hannover Medical School (MHH) , Hannover , Germany

Kamal Mustafa , D.D.S., Ph.D. Department of Clinical Dentistry – Centre for Clinical Dental Research , University of Bergen , Bergen , Norway

Nageshwar D. Reddy , M.D., D.M., D.Sc, FAMS FRCP Asian Institute of Gastroenterology , Hyderabad , India

Timothy J. Nelson , M.D., Ph.D. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular

xviii Contributors

Pharmacology and Experimental Therapeutics, and Medical Genetics , Mayo Clinic , Rochester , MN , USA

Keisuke Okita , Ph.D. Center for iPS Cell Research and Application(CiRA), Institute for Integrated Cell-Material Sciences , Kyoto University , Kyoto , Japan

Fumitaka Osakada , Ph.D. Systems Neurobiology Laboratory , The Salk Institute for Biological Studies , La Jolla, San Diego , CA , USA

Michael Ott , M.D. Department of Gastroenterology, Hepatology and Endocrinology , Hannover Medical School , Hannover , Germany

TWINCORE, Centre for Experimental and Clinical Infection Research , Hannover , Germany

Maurizio Pesce , Ph.D. Laboratorio di Ingegneria Tissutale Cardiovascolare , Centro Cardiologico Monzino, IRCCS , Milan , Italy

Naresh Polisetti , Ph.D. Department of Ophthalmology, Electron Microscopy and Cell Biology , University of Erlangen-Nuernberg , Erlangen , Germany

Gianluca Polvani , Ph.D. Dipartimento di Chirurgia Cardiovascolare Laboratorio di Biologia, Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Università degli Studi di Milano , Milan , Italy

Elias Polykandriotis , M.D. Department of Plastic and Hand Surgery , University of Erlangen , Erlangen , Germany

Giulio Pompilio , M.D., Ph.D. Dipartimento di Chirurgia Cardiovascolare Laboratorio di Biologia, Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS , Università degli Studi di Milano , Milan , Italy

Laurentiu M. Popescu , M.D., Ph.D. “Victor Babes” National Institute of Pathology , Buchrest , Romania

Department of Cellular and Molecular Medicine , “Carol Davila” University of Medicine and Pharmacy , Bucharest , Romania

Brigitte M. Pützer , M.D., Ph.D. Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center , University of Rostock Medical School , Rostock , Germany

G. V. Rao , M.S., MAMS, FRCS Asian Institute of Gastroenterology , Hyderabad , India

Julia Reetz (Bäder) Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center , University of Rostock Medical School , Rostock , Germany

Johannes C. Reichert , M.D., Ph.D. Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , QLD , Australia

xixContributors

Department of Trauma, Hand, Plastic and Reconstructive Surgery, Julius-Maximilians-University, Würzburg, Germany

Marcelo N. Rivolta , M.D., Ph.D. Centre for Stem Cell Biology and Department of Biomedical Sciences , University of Shef fi eld , Shef fi eld , UK

Joachim Rychly Laboratory of Cell Biology , University of Rostock , Rostock , Germany

Siamak Saifzadeh , DVM., Ph.D. Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , QLD , Australia

Virender S. Sangwan , M.D. Cornea and Anterior Segment, Ocular Immunology & Uveitis Services, Prof Brien Holden Eye Research Centre , L.V. Prasad Eye Institute , Hyderabad , Andhra Pradesh , India

Peter Sartipy , Ph.D. Cellartis AB , Göteborg , Sweden

M. Sasikala , Ph.D., MAMS Institute of Basic Sciences and Translational Research , Asian Healthcare Foundation , Hyderabad , India

Anke Schmidt , Ph.D. Zentrum für Innovationskompetenz (ZIK) plasmatis , INP Greifswald e.V. – VON DER IDEE BIS ZUM PROTOTYP , Greifswald , Germany

Michael Schmitt , M.D., Ph.D., MHBA Cellular Immunotherapy , University Clinic Heidelberg , Heidelberg , Germany

Michael Schroeter , Ph.D. Centre for Biomaterial Development , Institute of Polymer Research, Helmholtz-Zentrum Geesthacht , Teltow , Germany

Sebastian C. Sethe , Ph.D. Lawford Davies Denoon , London , UK

Amar Deep Sharma , Ph.D. Junior Research Group “Stem Cell Biology”, Cluster of Excellence REBIRTH , Hannover Medical School , Hannover , Germany

Michael Sittinger , Ph.D. Department of Rheumatology and Clinical Immunology, Tissue Engineering Laboratory and Berlin-Brandenburg Center for Regenerative Therapies , Charité-Universitätsmedizin Berlin , Berlin , Germany

Sajoscha A. Sorrentino , M.D. Department of Radiology , Hannover Medical School , Hannover , Germany

Michael Stauske , M.Sc. Department of Cardiology and Pneumology , Georg-August-University Göttingen , Göttingen , Germany

Vasily Stegaev , M.D. Department of Medicine , Institute of Clinical Medicine , Helsinki , Finland

Gustav Steinhoff , M.D., Ph.D. Department of Cardiac Surgery and Reference and Translation Center of Cardiac Stem Cell Therapy (RTC), Medical Faculty , University of Rostock , Rostock , Germany

xx Contributors

Ioannis Stratos , M.D. Department of Trauma and Reconstructive Surgery , University of Rostock , Rostock , Germany

Bodo Eckehard Strauer , M.D., FESC, FACC Department of Cardiology, Pneumology and Angiology , Heinrich-Heine-University of Düsseldorf , Düsseldorf , Germany

Pei Sun, Ph.D. Zhongguancun Life Science Park , National Institute of Biological Sciences , Beijing , China

Kazutoshi Takahashi , Ph.D. Center for iPS cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences , Kyoto University , Kyoto , Japan

Masayo Takahashi , M.D., Ph.D. Laboratory for Retinal Regeneration , Center for Developmental Biology, RIKEN , Chuo-ku, Kobe , Japan

Hinako Takase , Ph.D. Department of Developmental Biology, Howard Hughes Medical Institute, School of Medicine , Stanford University , Stanford , CA , USA

Minoru Tanaka , Ph.D. Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences , The University of Tokyo , Tokyo , Japan

Manu Tandan , M.D., D.M. Asian Institute of Gastroenterology , Hyderabad , India

Andre Terzic , M.D., Ph.D. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics , Mayo Clinic , Rochester , MN , USA

Bernard Thébaud , M.D., Ph.D. Department of Pediatrics, Northern Alberta Neonatal Program, Women and Children’s Health Research Institute, Cardio-Vascular Research Center, Pulmonary Research Group , University of Alberta , Edmonton , AB , Canada

Veli-Matti Tiainen , Ph.D. ORTON Orthopaedic Hospital , ORTON Foundation , Helsinki , Finland

Gudrun Tiedemann , Ph.D. Reference and Translation Center for Cardiac Stem Cell Therapy (RTC) , University of Rostock , Rostock , Germany

Shubha Tiwari , M.Pharm. Sudhakar and Sreekant Ravi Stem Cell Biology Laboratory , Prof Brien Holden Research Centre, L.V. Prasad Eye Institute , Hyderabad , India

Gerben M. van Buul , M.D. Departments of Orthopaedics and Radiology , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands

Gerjo J. V. M. van Osch , Ph.D. Departments of Orthopaedics and Radiology , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands

Geeta K. Vemuganti , M.D., DNB, FAMS, FICP School of Medical Sciences , University of Hyderabad , Gachibowli, Hyderabad , Andhra Pradesh, India

xxiContributors

Hanoch Daniel Wagner , Ph.D. Department of Materials and Interfaces , Weizmann Institute of Science , Rehovot , Israel

Wolfgang Wagner , M.D., Ph.D. Institute for Biomedical Engineering , University of Aachen Medical School , Aachen , Germany

Chenhui Wang Zhongguancun Life Science Park , National Institute of Biological Sciences , Beijing , China

Pei Wen Zhongguancun Life Science Park , National Institute of Biological Sciences , Beijing , China

Britt Wildemann , Prof. Julius-Wolf Institute and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT) , Charité , Berlin , Germany

Patrick Wuchter , M.D. Department of Internal Medicine V , Heidelberg University , Heidelberg , Germany

Rongwen Xi, Ph.D. Zhongguancun Life Science Park , National Institute of Biological Sciences , Beijing , China

Satsuki Yamada , M.D., Ph.D. Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics , Mayo Clinic , Rochester , MN , USA

Shinya Yamanaka , M.D., Ph.D. Center for iPS cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences , Kyoto University , Kyoto , Japan

Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Yamanaka iPS Cell Special Project, Japan Science and Technology Agency, Kawaguchi, Japan

Gladstone Institute of Cardiovascular Disease, San Francisco, USA

Maria Patapia Za fi riou, Ph.D. Department of Pharmacology, Heart Research Center Goettingen , University Medical Center Goettingen , Goettingen , Germany

Laura C. Zelarayán, Ph.D. Department of Pharmacology, Heart Research Center Goettingen , University Medical Center Goettingen , Goettingen , Germany

Jie Zhou , Ph.D. R&D Center, Jushi Group Co., Ltd. , Tongxiang City , Zhejiang Province , People’s Republic of China

Wolfram-Hubertus Zimmermann, M.D. Department of Pharmacology, Heart Research Center Goettingen , University Medical Center Goettingen , Goettingen , Germany