Stem Cell Biology and Regenerative Medicine

Series EditorKursad Turksen, Ph.D.kturksen@ohri.ca

For further volumes: http://www.springer.com/series/7896

Peiman Hematti ● Armand Keating Editors

Mesenchymal Stromal Cells

Biology and Clinical Applications

Editors Peiman Hematti Division of Hematology/OncologyDepartment of MedicineUniversity of Wisconsin-MadisonSchool of Medicine and Public Health Madison , WI, USA

Armand Keating Cell Therapy ProgramPrincess Margaret Hospital University of Toronto Toronto , ON, Canada

ISBN 978-1-4614-5710-7 ISBN 978-1-4614-5711-4 (eBook) DOI 10.1007/978-1-4614-5711-4 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012953270

© Springer Science+Business Media New York 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.

Printed on acid-free paper

Humana Press is a brand of SpringerSpringer is part of Springer Science+Business Media (www.springer.com)

To my wife Shirin, and my daughters Neeloufar and Faranak, for their love and support.

Peiman Hematti

To all my students and collaborators who have labored in this challenging and exciting area of research.

Armand Keating

vii

Foreword

Every tissue has some degree of mesenchymal cell contribution whether it be rare as with perivascular cells in the brain or abundant as in bone. In mesenchymal tis-sues like bone, there is a great deal known about lineage relationships and function, but the same cannot be said to be true for most organs where the epithelial compo-nents have largely been the focus of research. The ubiquity of mesenchymal cells in all organs may be one reason why they have generally been understudied as they are regarded as simply a part of supportive stroma.

However, the role of mesenchymal cells in organ formation is well recognized as central to development, providing an interplay with other cell types in guiding pat-terning and morphology. In adult tissues, they have been most evident as functional participants in wounding but are highly likely to play important roles in the mainte-nance of the tissue as well. The setting where this is increasingly appreciated is the bone marrow. A number of studies have now indicated a primary role for mesenchy-mal cells in regulating the hematopoietic stem and progenitor cells. These studies have further indicated that mesenchymal cells are highly diverse even within a given tissue. For example, in the bone marrow, it is evident that cells expressing different marker genes like nestin, leptin receptor, or osterix are not entirely overlapping and express different levels of other proteins implicated in stem cell function. Further, at least some of the cells appear to turn over rapidly and be replenished by a resident stem cell pool. And the function of the mesenchymal cells seems to be important in the integrity of the tissue. Several models of altered mesenchymal cell function have resulted in changes in hematologic function indicating the clear dependence on intact interplay between mesenchymal and parenchymal cell types for the tissue to function normally. Collectively, these kinds of studies are raising awareness of the complexity, dynamism, and centrality of endogenous mesenchymal cells for tissue health. They have to some extent trailed the many studies of mesenchymal cells cultured ex vivo and used therapeutically, and yet, they support and deepen the rationale for such studies.

The behavior of endogenous mesenchymal cells in tissues includes a highly unusual ability to fundamentally change cell state. In development, certain mesen-chymal cells such as those of the developing kidney are known to transition to

viii Foreword

acquire epithelial features. Mesenchymal to epithelial transition is well accepted in the normal course of tissue formation, particularly in forming the nephron. Similarly, mesenchymal cell characteristics are known to be acquired by some epithelial cells in development such as in gastrulation but are best characterized in pathologic con-ditions, speci fi cally in cancer. The epithelial to mesenchymal transition (EMT) is regarded as a signature pathologic process of malignancy that is now being associ-ated with cells acquiring more stem cell-like features and to be driven by particular genes like Twist, Snail, and Slug. This process is thought to re fl ect a potentially more metastasis-prone cell phenotype. It is striking that cells can acquire mesenchy-mal features with very little evidence that alternative cell states can be achieved. Transition to other somatic cell types is simply not seen. This does raise the issue of whether the mesenchymal cell state is not rigidly constrained and that cells can achieve it perhaps with less epigenetic precision than required for other cell types.

The ability of cells to acquire mesenchymal-like features may be part of the rea-son why virtually every organ appears to have so-called mesenchymal stem cells. These cells are generally de fi ned by their functions in vitro, the ability to form three lineages, bone, cartilage, and adipose cell types. The cells from different tissues are likely to be distinctive, yet once cultured they have a highly similar phenotype. It is not clear if this is re fl ective of a uniform phenotype in vivo or even of a uniform gene expression signature after in vitro culture. However, whether such distinctions exist may be of interest but may not have signi fi cant functional consequences. The cultured cell populations may very well share critical features selected for by the process of cell culture.

The cultured mesenchymal cells with a shared tri-lineage differentiation poten-tial also appear to have unexpected immunologic features. They are capable of alter-ing the immunologic reactivity of the host upon adoptive transfer and may have immune-modulating properties in residence. While there is skepticism regarding this issue, it should be remembered that tissue resident immunologic functions of dendritic cells and endothelial cells were also regarded skeptically when fi rst pro-posed and it may well be that mesenchymal cells represent the next generation of such cell populations discovered to play central roles. The putative immunologic effects of transferred mesenchymal cells are not a global immune suppression. There is no evidence of a predisposition to infection as occurs with most immuno-suppressive drugs. The immunologic alteration may be more subtle and perhaps more of a reset of a hyperreactive immunologic state as is present in most of the conditions where the cells have been tested. The mechanistic basis by which the cells can induce an effect that apparently lasts longer than the persistence of the infused mesenchymal cells has many hypotheses. Most of these are related to elabo-ration of proteins exerting a paracrine effect. Some of these effects may also alter activities like hematopoietic stem cell engraftment.

The volume expertly edited here by Drs. Peiman Hematti and Armand Keating represents an assembly of reviews and perspectives from leading investigators in the fi eld. It addresses controversies of the fi eld head-on and covers topics from underly-ing biology to clinical testing in multiple settings to the all important regulatory considerations in preparing such cells for use in patients. It is an extremely impor-

ixForeword

tant, timely, and thoughtful addition to a rapidly changing fi eld and will be a resource for those entering or active in the study of these intriguing cells. This cell type is likely to become a mainstay in the medical armamentarium. We are still in the early days of de fi ning where and how they can be optimally active. A guiding resource such as this volume will help move the process forward.

David T. Scadden, M.D. Gerald and Darlene Jordan Professor of Medicine, Harvard University

Director, Center for Regenerative Medicine, Massachusetts General Hospital Co-Director, Harvard Stem Cell Institute, Harvard University

Co-Chair, Department of Stem Cell and Regenerative Biology, Harvard University

Chief, Hematologic Malignancies, Massachusetts General Hospital Cancer Center

xi

Preface

Alexander Friedenstein is rightfully credited with discovery of what we now know as mesenchymal stromal cells (MSCs) more than four decades ago. Friedenstein’s seminal work showed that bone marrow, in addition to hematopoietic stem cells, contained a population of cells capable of generating hematopoietic supportive stroma, bone, fat, and cartilage. In the last decade, work in the fi eld of MSCs has exploded, and now these cells have become the most commonly used in regenera-tive medicine only after hematopoietic stem/progenitor cells. The rapidly increasing number of clinical trials in a broad range of applications attests to considerable clinical potential. Applications span from their use as supportive cells for the ex vivo expansion of cord blood cells to treatment of localized defects, wounds and pathologies, and for systemic diseases with different pathophysiology. MSCs have been investigated in small- and large-scale clinical trials for acute and chronic graft-versus-host disease, myocardial infarction, diabetes, chronic obstructive pulmonary disease, systemic lupus erythematosus, systemic sclerosis, lower limb ischemia, stroke, multiple sclerosis, amyotrophic lateral sclerosis, kidney transplantation, nonhealing cutaneous wounds, bone and cartilage defects, and inborn errors of metabolism. Despite the rapid advances into the clinic, an assessment of the thera-peutic ef fi cacy of MSCs remains a challenge. It is therefore incumbent on us to carefully evaluate and reappraise the fi eld. This book attempts to address these issues and consists of 38 chapters that comprise a range of topics from basic biology of MSCs to their clinical application. It also addresses the controversies surround-ing their mechanisms of action.

The fi rst part of this book discusses the latest advances in our understanding of the biological properties of MSCs in vitro and in vivo. This part covers the basic science involved in immunophenotypic and functional characterization of MSCs, technological innovations of their in vivo investigation, and a new understanding of potential mechanisms of action. Also, views and controversies are discussed in the context of a more recent understanding of cellular and molecular mechanisms of action of MSCs. The second part of the book is a comprehensive resource to readers interested in the translational and regulatory aspects of MSCs as cell therapy. Our goal here is to fi ll the gaps between “bench” and “bedside” and help connect our

xii Preface

understanding of MSC biology with the requirements of clinical investigation. These chapters provide a guide on how to bring MSCs from basic research labora-tories to the clinic. The third part of the book offers an extensive coverage of the clinical use of MSCs involving almost all human tissues and organs that have served as targets for this treatment. These chapters explore the rationale, design, safety, and ef fi cacy of published and ongoing clinical trials.

The authors represent an international group of basic, translational, and clinical investigators from almost all sub-subspecialties of medicine as well as experts in the regulatory aspects of cellular therapy. Moreover, all the contributors have been directly involved in the various aspects of MSC research. We hope that this book will provide a benchmark for the most exciting developments in the investigation and clinical use of mesenchymal stromal cells.

xiii

Contents

Part I Basic Biology

1 Mesenchymal Stromal Cells in Regenerative Medicine: A Perspective ......................................................................... 3Peiman Hematti and Armand Keating

2 MSCs: Changing Hypotheses, Paradigms, and Controversies on Mechanisms of Action in Repairing Tissues ................................... 17Darwin J. Prockop and Roxanne L. Reger

3 MSCs: The Need to Rethink .................................................................. 43Paolo Bianco and Pamela G. Robey

4 Characterization of MSCs: From Early Studies to the Present ......... 59Mark F. Pittenger

5 MSCs as Therapeutics ............................................................................ 79Arnold I. Caplan

6 MSC Niche for Hematopoiesis ............................................................... 91Daniel Lucas, Sandra Pinho, and Paul S. Frenette

7 Immunomodulatory Properties of MSCs ............................................. 107Maria Ester Bernardo, Lynne M. Ball, Franco Locatelli, and Willem E. Fibbe

8 MSCs and Innate Immune Responses: A Balancing Act .................... 135Krisztián Németh and Éva Mezey

9 MSCs: Paracrine Effects ........................................................................ 145Siddiraju V. Boregowda and Donald G. Phinney

10 Cross-Talk Between MSCs and Their Environments .......................... 169Thomas P. Lozito and Rocky S. Tuan

xiv Contents

11 Human MSCs from Bone Marrow, Umbilical Cord Blood, and Adipose Tissue: All the Same? ........................................... 193Patrick Wuchter and Anthony D. Ho

12 MSCs in Solid Tumors and Hematological Malignancies: From Basic Biology to Therapeutic Applications ................................ 209Rodrigo Jacamo, Erika Spaeth, Venkata Battula, Frank Marini, and Michael Andreeff

13 MSC Studies in Large-Animal Models ................................................. 237Bruce A. Bunnell, Christine Gagliardi, and Maria Isabel Ribeiro Dias

14 Defining the Potential of MSCs with a Prenatal Large Animal Model ............................................................................... 259Graça Almeida-Porada, Christopher D. Porada, and Esmail D. Zanjani

Part II From Bench to Bedside

15 Bench-to-Bedside Development of MSC Therapies: A Multidisciplinary Approach ............................................................... 279Sowmya Viswanathan and Elizabeth J. Read

16 cGMP Production of MSCs .................................................................... 317Derek J. Hei and David H. McKenna Jr

17 MSCs: The US Regulatory Perspective ................................................ 343Adrian P. Gee

18 MSCs: Clinical Applications and European Regulatory Aspects ................................................................................. 355Jens Reinhardt, Egbert Flory, Isabel Büttel, Christa Schröder, Stefan Fricke, Vladan Vucinic, Michael Cross, and Dietger Niederwieser

19 Stem Cell Treatments Around the World: Boon or Bane? ......................................................................................... 365Alok Srivastava

20 Safety Issues in MSC Therapy ............................................................... 377Minoo Battiwalla and A. John Barrett

21 In Vivo Imaging of MSCs ....................................................................... 389Jeff W.M. Bulte

22 National Heart, Lung, and Blood Institute Support of Cellular Therapies Regenerative Medicine ...................................... 403Traci Heath Mondoro and John Thomas

xvContents

Part III Clinical Applications

23 MSC Therapy of Inborn Errors ............................................................ 427Edwin M. Horwitz

24 MSCs for Enhancement of Hematopoietic Progenitor Cell Engraftment and Poor Graft Function ......................................... 443Paolo F. Caimi and Hillard M. Lazarus

25 MSCs for Graft-Versus-Host Disease .................................................... 455Jakub Tolar, Katarina Le Blanc, and Bruce R. Blazar

26 MSCs in Pediatric Hematopoietic Stem Cell Transplantation ....................................................................................... 467Lynne M. Ball, Maria Ester Bernardo, Franco Locatelli, and R. Maarten Egeler

27 MSC for Ex Vivo Expansion of Umbilical CordBlood Cells ............................................................................................... 485Ian K. McNiece, Simon N. Robinson, and Elizabeth J. Shpall

28 MSCs for Autoimmune Diseases ............................................................ 503Alan Tyndall and Chiara Bocelli

29 MSCs for Induction of Solid Organ Allograft Acceptance ................. 519Marc Dahlke, Philipp Renner, and Elke Eggenhofer

30 MSCs for Gastrointestinal Disorders .................................................... 529Maria Ester Bernardo, Angela Maria Cometa, and Franco Locatelli

31 MSCs for Cardiac Repair....................................................................... 541Amish N. Raval and Timothy A. Hacker

32 MSCs for Treatment of Acute Lung Injury .......................................... 561Vladimir B. Serikov, Anna Krasnodembskaya, Jae Woo Lee, Marlowe W. Eldridge, and Michael A. Matthay

33 MSCs for Diabetes .................................................................................. 571Luca Inverardi, Giacomo Lanzoni, Juan Dominguez-Bendala, and Camillo Ricordi

34 MSCs for Renal Repair .......................................................................... 599Anna M. Gooch and Christof Westenfelder

35 MSCs for the Treatment of Stroke, Spinal Cord Injury, and Traumatic Brain Injury: From Bench Work to Clinical Trials .......................................................................................... 617Bing Yang, Ramy El Khoury, and Sean I. Savitz

xvi Contents

36 MSCs in Reconstructive Surgery ........................................................... 639Summer E. Hanson and Michael L. Bentz

37 MSCs in Orthopedic Surgery ................................................................ 655Summer E. Hanson and Nicholas H. Maassen

38 Adipose Tissue-Derived MSCs: Moving to the Clinic ......................... 663Pedro P. Carvalho, Manuela E. Gomes, Rui L. Reis, and Jeffrey M. Gimble

About the Editors ............................................................................................ 683

Index ................................................................................................................. 685

Contributors

Graça Almeida-Porada M.D., Ph.D. Department of Regenerative Medicine, Wake Forest Institute for Regenerative Medicine , Winston-Salem , NC , USA

Michael Andreeff , M.D., Ph.D. Section of Molecular Hematology and Therapy, Department of Leukemia , and Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Lynne M. Ball Department of Paediatric Immunology, Hematology, Oncology, and Stem Cell Transplantation , Leiden University Medical Center , Leiden , The Netherlands

Minoo Battiwalla , M.D. Stem Cell Allogeneic Transplant Section, Hematology Branch , National Heart, Lung and Blood Institute, National Institute of Health , Bethesda , MD , USA

A. John Barrett , M.D. Stem Cell Allogeneic Transplant Section, Hematology Branch , National Heart, Lung and Blood Institute, National Institute of Health , Bethesda , MD , USA

Venkata Battula Section of Molecular Hematology and Therapy, Department of Leukemia , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Michael L. Bentz , M.D., FACS, FAAP Division of Plastic and Reconstructive Surgery , University of Wisconsin School of Medicine and Public Health , Madison , WI , USA

Maria Ester Bernardo, M.D., Ph.D. Dipartimento di Ematologia ed Oncologia Pediatrica , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy

Paolo Bianco , M.D. Department of Molecular Medicine , Sapienza University of Rome , Rome , Italy

xviii Contributors

Bruce R. Blazar , M.D. Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics , University of Minnesota , Minneapolis , MN , USA

Chiara Bocelli Department of Rheumatology , University of Basel, Felix Platter Spital , Basel , Switzerland

Siddiraju V. Boregowda , DVM Department of Molecular Therapeutics and Kellogg School of Science and Technology , The Scripps Research Institute , Jupiter , FL , USA

Jeff W. M. Bulte , Ph.D. Division of MR Research, and Cellular Imaging Section, Russell H. Morgan Department of Radiology and Radiological Science , Institute for Cell Engineering, The Johns Hopkins University School of Medicine , Baltimore , MD , USA

Bruce A. Bunnell , Ph.D. Division of Regenerative Medicine , Tulane National Primate Research Center, Tulane University School of Medicine , New Orleans , LA , USA

Division of Regenerative Medicine, Tulane National Primate Research Center, New Orleans, LA, USA

Department of Pharmacology , Tulane University School of Medicine , New Orleans , LA , USA

Isabel Büttel Paul Ehrlich Institute , Medical Biotechnology , Langen , Germany

Paolo F. Caimi , M.D. Department of Medicine , University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland , OH , USA

Arnold I. Caplan , Ph.D. Department of Biology , Skeletal Research Center, Case Western Reserve University , Cleveland , OH , USA

Pedro P. Carvalho , DVM 3B’s Research Group, Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering , University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Guimarães , Portugal

Angela Maria Cometa Dipartimento di Ematologia ed Oncologia Pediatrica , IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy

Michael Cross Department of Hematology and Clinical Oncology , University of Leipzig , Leipzig , Germany

Marc Dahlke , M.D., Ph.D. Department of Surgery , University Medical Center Regensburg , Regensburg , Germany

Maria Isabel Ribeiro Dias Department of Veterinary Sciences, School of Agrarian and Veterinary Sciences , University of Trás-os-Montes e Alto Douro , Vila Real , Portugal

xixContributors

Juan Dominguez-Bendala Diabetes Research Institute, University of Miami Miller School of Medicine , Miami , FL , USA

R. Maarten Egeler , M.D., Ph.D. Department of Paediatric Immunology, Hematology, Oncology, and Stem Cell Transplantation , Leiden University Medical Center , Leiden , The Netherlands

Currently Section Stem Cell Transplantation, Division of Haematology/Oncology , The Hospital for Sick Children , University of Toronto, Toronto , Canada

Elke Eggenhofer , Ph.D. Department of Surgery , University Medical Center Regensburg , Regensburg , Germany

Ramy El Khoury , M.D. Department of Neurology , University of Texas Medical School at Houston, UT-Health , Houston , TX , USA

Marlowe W. Eldridge, M.D. Departments of Pediatrics and Biomedical Engineering , University of Wisconsin, School of Medicine and Public Health , Madison , WI , USA

Willem E. Fibbe Department of Immunohematology and Blood Transfusion , Center for Stem Cell Therapy, Leiden University Medical Center , Leiden , The Netherlands

Egbert Flory Paul Ehrlich Institute , Medical Biotechnology , Langen , Germany

Paul S. Frenette Department of Medicine, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine , Bronx , NY , USA

Stefan Fricke Department of Hematology and Clinical Oncology , University of Leipzig , Leipzig , Germany

Christine Gagliardi Division of Regenerative Medicine , Tulane National Primate Research Center , New Orleans , LA , USA

Department of Pharmacology , Tulane University School of Medicine , New Orleans , LA , USA

Adrian P. Gee Departments of Medicine and Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine , Houston , TX , USA

Jeffrey M. Gimble , M.D., Ph.D. Stem Cell Biology Laboratory , Pennington Biomedical Research Center, Louisiana State University System , Baton Rouge , LA , USA

Manuela E. Gomes , Ph.D. 3B’s Research Group, Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering , University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Guimarães , Portugal

Anna M. Gooch Department of Nephrology, University of Utah and VA Medical Centers , Salt Lake City , UT , USA

xx Contributors

Timothy A. Hacker , Ph.D. Division of Cardiovascular Medicine, Department of Medicine and Physiology , School of Medicine and Public Health, University of Wisconsin , Madison , WI , USA

Summer E. Hanson , M.D., Ph.D. Division of Plastic and Reconstructive Surgery , University of Wisconsin, School of Medicine and Public Health , Madison , WI , USA

Derek J. Hei , Ph.D Waisman Biomanufacturing , Waisman Center, University of Wisconsin , Madison , WI , USA

Peiman Hematti , M.D. Division of Hematology/Oncology, Department of Medicine , University of Wisconsin-Madison, School of Medicine and Public Health , Madison , WI , USA

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

Edwin M. Horwitz , M.D., Ph.D. Division of Oncology/Blood and Marrow Transplantation , The Children’s Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine , Philadelphia , PA , USA

Luca Inverardi Diabetes Research Institute, University of Miami Miller School of Medicine , Miami , FL , USA

Rodrigo Jacamo Section of Molecular Hematology and Therapy, Department of Leukemia , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Armand Keating , M.D. Cell Therapy Program , Princess Margaret Hospital, University of Toronto , Toronto , ON , Canada

Anna Krasnodembskaya , Ph.D. Cardiovascular Research Institute, University of California , San Francisco , CA , USA

Giacomo Lanzoni Diabetes Research Institute, University of Miami Miller School of Medicine , Miami , FL , USA

Hillard M. Lazarus , M.D., FACP Department of Medicine , University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve University , Cleveland , OH , USA

Katarina Le Blanc , M.D., Ph.D. Division of Clinical Immunology and Transfusion Medicine , Karolinska Institutet , Stockholm , Sweden

Jae Woo Lee , M.D. Department of Anesthesia and Perioperative Care , and Cardiovascular Research Institute, University of California , San Francisco, CA , USA

Franco Locatelli , M.D., Ph.D. Department of Pediatric Hematology/Oncology , IRCCS Bambino Gesù Children’s Hospita , Rome , Italy

University of Pavia , Pavia , Italy

xxiContributors

Thomas P. Lozito Department of Orthopaedic Surgery , Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine , Pittsburgh , PA , USA

Daniel Lucas Department of Medicine, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine , Bronx , NY , USA

Nicholas H. Maassen , M.D. Department of Orthopedic Surgery , University of Wisconsin, School of Medicine and Public Health , Madison , WI , USA

Frank Marini Section of Molecular Hematology and Therapy, Department of Leukemia , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Michael A. Matthay , M.D. Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California , San Francisco , CA , USA

Cardiovascular Research Institute, San Francisco, CA, USA

David H. McKenna Jr., M.D. Molecular and Cellular Therapeutics , University of Minnesota Medical Center , Minneapolis , MN , USA

Ian K. McNiece , Ph.D. Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Éva Mezey , M.D., Ph.D. Adult Stem Cell Unit , National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda , MD , USA

Traci Heath Mondoro , Ph.D. Transfusion Medicine and Cellular Therapeutics Branch, Division of Blood Diseases and Resources , The National Heart, Lung, and Blood Institutes, National Institutes of Health , Bethesda , MD , USA

Krisztián Németh, M.D., Ph.D. Adult Stem Cell Unit , National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda , MD , USA

Dietger Niederwieser , M.D. Department of Hematology and Clinical Oncology , University of Leipzig , Leipzig , Germany

Donald G. Phinney , Ph.D. Department of Molecular Therapeutics , The Scripps Research Institute , Jupiter , FL , USA

Sandra Pinho Department of Cell Biology, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine , Bronx , NY , USA

Mark F. Pittenger , Ph.D. Department of Surgery/Cardiac , University of Maryland School of Medicine , Baltimore , MD , USA

Christopher D. Porada , Ph.D. Department of Regenerative Medicine, Wake Forest Institute for Regenerative Medicine , NC , USA

xxii Contributors

Darwin J. Prockop , M.D., Ph.D. Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott&White , Temple , TX , USA

Amish N. Raval , M.D. Division of Cardiovascular Medicine, Department of Medicine and Biomedical Engineering , School of Medicine and Public Health, University of Wisconsin , Madison , WI , USA

Elizabeth J. Read , M.D. Department of Laboratory Medicine , University of California, San Francisco , San Francisco , CA , USA

Roxanne L. Reger , M.S. Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott&White , Temple , TX , USA

Jens Reinhardt Paul Ehrlich Institute , Medical Biotechnology , Langen , Germany

Rui L. Reis , CEng, M.Sc., Ph.D., D.Sc., M.D. (Doctor h.c) 3B’s Research Group, Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering , University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine , Guimarães , Portugal

Philipp Renner , M.D. Department of Surgery , University Medical Center Regensburg , Regensburg , Germany

Camillo Ricordi Diabetes Research Institute, University of Miami Miller School of Medicine , Miami , FL , USA

Pamela G. Robey , Ph.D. Craniofacial and Skeletal Diseases Branch , National Institute of Dental and Craniofacial Research, National Institutes of Health , Department of Health and Human Services, Bethesda , MD , USA

Simon N. Robinson Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Sean I. Savitz , M.D. Department of Neurology , University of Texas Medical School at Houston, UT-Health , Houston , TX , USA

Christa Schröder Fakultät Life Sciences , Hochschule Albstadt-Sigmaringen , Sigmaringen , Germany

Vladimir B. Serikov, Ph.D. Children’s Hospital Oakland Research Institute , Oakland , CA , USA

Elizabeth J. Shpall Department of Stem Cell Transplantation and Cellular Therapy , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

Erika Spaeth Section of Molecular Hematology and Therapy, Department of Leukemia , The University of Texas M.D. Anderson Cancer Center , Houston , TX , USA

xxiiiContributors

Alok Srivastava , M.D., FRACP, FRCPA, FRCP Department of Haematology , Center for Stem Cell Research, Christian Medical College , Vellore , Tamil Nadu , India

John Thomas Division of Blood Diseases and Resources , National Heart, Lung, and Blood Institutes, National Institutes of Health , Bethesda , MD , USA

Jakub Tolar , M.D., Ph.D. Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics , University of Minnesota , Minneapolis , MN , USA

Rocky S. Tuan Department of Orthopaedic Surgery , Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine , Pittsburgh , PA , USA

Alan Tyndall Department of Rheumatology , University of Basel, Felix Platter Spital , Basel , Switzerland

Sowmya Viswanathan , Ph.D. Cell Therapy Program , University Health Network , Toronto , ON , Canada

Vladan Vucinic Department of Hematology and Clinical Oncology , University of Leipzig , Leipzig , Germany

Christof Westenfelder , M.D. Section of Nephrology , University of Utah and VA Medical Centers , Salt Lake City , UT , USA

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

Bing Yang , M.D. Department of Neurology , University of Texas Medical School at Houston, UT-Health , Houston , TX , USA

Esmail D. Zanjani , Ph.D. Department of Animal Biotechnology and Department of Medicine , University of Nevada , Reno , NV , USA

xxv

List of Commonly Used Abbreviations

AT Adipose tissue ALS Amyotrophic lateral sclerosis ANG1 Angiopoietin 1 ASCs Adipose-derived stromal/stem cells BAL Bronchoalveolar lavage BDNF Brain-derived neurotropic factor BLI Bioluminescence imaging BM Bone marrow CD Cluster of differentiation CFU Colony-forming units cGMP Current good manufacturing practice CMC Chemistry, manufacturing, and controls CNS Central nervous system CXCR4 C-X-C chemokine receptor type 4 CXCL12 Chemokine, CXC motif, ligand 12 DC Dendritic cells EGF Epidermal growth factor FBS Fetal bovine serum FCS Fetal calf serum FGF Fibroblast growth factor G-CSF Granulocyte colony-stimulating factor GDNF Glial cell-derived neurotropic factor GM-CSF Granulocyte macrophage colony-stimulating factor GMP Good manufacturing practice HGF Hepatocyte growth factor HLA Human leukocyte antigen HSCs Hematopoietic stem cells IA Intraarterial IC Intracerebral IFN- g Interferon-gamma IGF Insulin-like growth factor

xxvi List of Commonly Used Abbreviations

IL Interleukin IND Investigational new drug IP Intraperitoneal IT Intrathecal IV Intravenous LPS Lipopolysaccharides M-CSF Macrophage colony-stimulating factor MCP1 Macrophage chemotactic protein 1 MLR Mixed lymphocyte reactions MCP1 Monocyte chemotactic protein 1 MI Myocardial infarction MIF Macrophage inhibitory factor MRI Magnetic resonance imaging MS Multiple sclerosis MSCs Mesenchymal stromal/stem cells NGF Nerve growth factor NK cells Natural killer cells OI Osteogenesis imperfecta PDGF Platelet-derived growth factor PGE2 Prostaglandin E2 PHA Phytohemagglutinin PI3K Phosphatidylinositol 3-kinase SAGE Serial analysis of gene expression SMA Smooth muscle actin SOD1 Superoxide dismutase 1 SVF Stromal-vascular fraction TGF- b Transforming Growth Factor- b Th1 Type 1 T helper cells Th2 Type 2 helper cells TLR Toll-like receptors TNF a Tumor necrosis factor-alpha T-regs Regulatory T cells UCB Umbilical cord blood VEGF Vascular endothelial growth factor