Essentials of Stem Cell Biology, Third Edition

Essentials of Stem Cell Biology

Essentials of Stem Cell

Biology

Third Edition

Edited by

Robert Lanza

Anthony Atala

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xix

Foreword

It is with great pleasure that I pen this foreword to the third edition of the

Essentials of Stem Cell Biology. The field of stem cell biology is moving

extremely rapidly as the concept and potential practical applications have

entered the mainstream. Despite this worldwide intensity and diversity of

endeavor, there remain a smaller number of definable leaders in the field,

and this volume brings most of them together.

Although the concept of stem and progenitor cells has been known for a long

time, it was the progress towards embryonic stem cells which lit the field.

Mouse embryonic stem (ES) cells originally came from work aimed at under￾standing the control and progress of embryonic differentiation, but their

in vitro differentiation, despite being magnificent, was overshadowed experi￾mentally by their use as a vector to the germline, and hence as a vehicle for

experimental mammalian genetics. This now has led to studies of targeted

mutation in up to one third of gene loci, and an ongoing international pro￾gram to provide mutation in every locus of the mouse. These studies greatly

illuminate our understanding of human genetics.

Jamie Thomson, reporting the advent of the equivalent human embryonic

stem cells, very clearly signaled that their utility would be neither in genetic

studies (impractical and unethical in man), nor in fundamental studies

of embryonic development (already catered for by mouse ES cells), but, by

providing a universal source of a diversity of tissue-specific precursors, as a

resource for tissue repair and regenerative medicine.

Progress towards the understanding of pluripotentiality and the control of

cellular differentiation, that is basic fundamental developmental biology at

the cell and molecular level, now stands as a gateway to major future clini￾cal applications. This volume provides a timely, up-to-date state-of-the-art

reference.

The ideas behind regenerative medicine, powered by the products of embry￾onic stem cells, reinvigorated study of committed stem and precursor cells

within the adult body. The use of such stem cells in regenerative medicine

xx Foreword

already has a long history, for example in bone marrow transplantation and

skin grafting. In both of these examples not only gross tissue transplanta￾tion, but also purified or cultured stem cells may be used. They have been

extensively applied in clinical treatment, and have most clearly demonstrated

the problems which arise with histoincompatibility. Ideally, in most cases, a

patient is better treated with his own – autologous – cells than with partially

matching allogeneic cells. An ideal future would be isolation, manipulation,

or generation of suitable committed stem or precursor cell populations from

the patient for the patient. The amazing advances of induced pluripotential

stem cells point to the possibilities of patient-specific ad hominem treatment.

This personalized medicine would be an ideal scenario, but as yet the costs

of the technologies may not allow it to be a commercial way forward. The

timelines are, however, likely to be long before the full promise of these tech￾nologies is realized, and there is every possibility that such hurdles will be

circumvented. Quite properly, much of this book concentrates on the fun￾damental developmental and cell biology from which the solid applications

will arise.

This is a knowledge-based field in which we have come a long way, but are

still relatively ignorant. We know many of the major principles of cell differ￾entiation, but as yet need to understand more in detail, more about devel￾opmental niches, more about the details of cell–cell and cell growth-factor

interaction, and more about the epigenetic programming which maintains

the stability of the differentiated state.

Professor Sir Martin Evans

Sir Martin Evans, PhD, FRS

Nobel Prize for Medicine 2007

Sir Martin is credited with discovering embryonic stem cells, and is con￾sidered one of the chief architects of the field of stem cell research. His

ground-breaking discoveries have enabled gene targeting in mice, a technol￾ogy that has revolutionized genetics and developmental biology, and have

been applied in virtually all areas of biomedicine – from basic research to

the development of new medical therapies. Among other things, his research

inspired the effort of Ian Wilmut and his team to create Dolly the cloned

sheep, and Jamie Thomson’s efforts to isolate embryonic stem cells from

human embryos, another of the great medical milestones in the field of stem

cell research. Professor Evans was knighted in 2004 by Queen Elizabeth for

his services to medical science. He studied at Cambridge University and

University College London before leaving to become director of bioscience at

Cardiff University.

xxi

Preface

Much has happened since the first edition of Essentials of Stem Cell Biology

was published. Sir Martin Evans, who is credited with discovering embryonic

stem cells, received the Nobel Prize for Physiology or Medicine in 2007; and

Shinya Yamanaka, who discovered how to reprogram differentiated cells into

induced pluripotent stem (iPS) cells, won the Nobel Prize in 2012 for the

achievement. The third edition of Essentials includes chapters by both of these

groundbreaking pioneers, as well as by dozens of other scientists whose pio￾neering work has defined our understanding of stem cell biology. The volume

covers the latest advances in stem cell research, with updated chapters on

pluripotent, adult, and fetal stem cells. While it offers a comprehensive – and

much needed – update of the rapid progress that has been achieved in the

field in the last several years, we have retained those facts and subject matter

which, while not new, is pertinent to the understanding of this exciting area

of biology.

As in previous editions, the third edition of Essentials is presented in an acces￾sible format suitable for students and general readers interested in following

the latest advances in stem cells. The organization of the book remains largely

unchanged, combining the prerequisites for a general understanding of pluri￾potent and adult stem cells; the tools and methods needed to study and char￾acterize stem cells and progenitor populations; as well as a presentation by

the world’s leading scientists of what is currently known about each specific

organ system. Sections include basic biology/mechanisms, tissue and organ

development (ectoderm, mesoderm, and endoderm), methods (such as

detailed descriptions of how to generate both iPS and embryonic stem cells),

application of stem cells to specific human diseases, regulation and ethics,

and a patient perspective by Mary Tyler Moore. For the third edition, Anthony

Atala joins me as a new Editor to the book. The result is a comprehensive ref￾erence that we believe will be useful to students and experts alike.

Robert Lanza M.D.

Boston, Massachusetts

xxiii

List of Contributors

Russell C. Addis Johns Hopkins University, School of Medicine, Baltimore,

MD, USA

Piero Anversa Cardiovascular Research Institute, New York Medical College,

Valhalla, NY, USA

Judith Arcidiacono Center for Biologics Evaluation and Research, Food and

Drug Administration, Rockville, MD, USA

Anthony Atala Wake Forest Institute for Regenerative Medicine, Winston

Salem, NC, USA

Joyce Axelman Johns Hopkins University, School of Medicine, Baltimore,

MD, USA

Ashok Batra US Biotechnology & Pharma Consulting Group, Potomac,

MD, USA

Helen M. Blau Baxter Laboratory for Stem Cell Biology, Stanford University

School of Medicine, Stanford, CA, USA

Susan Bonner-Weir Diabetes Center, Harvard University, Boston, MA, USA

Mairi Brittan Histopathology Unit, Cancer Research UK, London, UK

Hal E. Broxmeyer Department of Microbiology and Immunology, Indiana

University School of Medicine, Indianapolis, IN, USA

Mara Cananzi Surgery Unit, UCL Institute of Child Health, Great Ormond

Street Hospital, London, UK, and Department of Pediatrics, University of

Padua, Padua, Italy

Constance Cepko Department of Genetics, Howard Hughes Medical

Institute, Harvard Medical School, Boston, MA, USA

Tao Cheng University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Susana M. Chuva de Sousa Lopes Department of Anatomy and

Embryology, Leiden University Medical Center, Leiden, The Netherlands

Gregory O. Clark Division of Endocrinology, Johns Hopkins University,

School of Medicine, Baltimore, MD, USA

Maegen Colehour Center for Devices and Radiological Health, FDA, Silver

Spring, MD, USA

Paolo de Coppi Surgery Unit, UCL Institute of Child Health, Great

Ormond Street Hospital, London, UK, Department of Pediatrics, University

xxiv List of Contributors

of Padua, Padua, Italy, and Wake Forest Institute for Regenerative Medicine,

Winston Salem, NC, USA

Giulio Cossu Department of Cell and Developmental Biology, Center for

Stem Cells and Regenerative Medicine, University College London, London,

UK, and Division of Regenerative Medicine, Stem Cells and Gene Therapy,

San Raffaele Scientific Institute, Milan, Italy

George Q. Daley Division of Hematology/Oncology, Children's Hospital,

Boston, MA, USA

Jiyoung M. Dang Center for Devices and Radiological Health, FDA, Silver

Spring, MD, USA

Natalie Direkze Histopathology Unit, Cancer Research UK, London, UK

Yuval Dor Department of Developmental Biology and Cancer Research,

The Institute for Medical Research Israel-Canada, The Hebrew University￾Hadassah Medical School, Jerusalem 91120, Israel.

Gregory R. Dressler Department of Pathology, University of Michigan, Ann

Arbor, MI, USA

Charles N. Durfor Center for Devices and Radiological Health, FDA, Silver

Spring, MD, USA

Ewa C.S. Ellis Department of Clinical Science, Intervention and

Technology, Division of Transplantation, Liver Cell Laboratory, Karolinska

Institute, Stockholm, Sweden

Martin Evans Cardiff School of Biosciences, Cardiff University, Cardiff, UK

Donna M. Fekete Department of Neurobiology, Harvard Medical School,

Boston, MA, USA

Donald Fink Center for Biologics Evaluation and Research, FDA, Rockville,

MD, USA

Elaine Fuchs The Rockefeller University, New York, NY, USA

Margaret T. Fuller Departments of Developmental Biology and Genetics,

Stanford University School of Medicine, Stanford, CA, USA

Richard L. Gardner Department of Molecular and Cellular Biology and

Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA

Zulma Gazit Skeletal Biotechnology Laboratory, Hebrew University –

Hadassah Faculty of Dental Medicine, Jerusalem, Israel and Department

of Surgery and Cedars-Sinai Regenerative Medicine Institute, Cedars-Sinai

Medical Center, Los Angeles, CA, USA

Dan Gazit Skeletal Biotechnology Laboratory, Hebrew University –

Hadassah Faculty of Dental Medicine, Jerusalem, Israel and Department

of Surgery and Cedars-Sinai Regenerative Medicine Institute, Cedars-Sinai

Medical Center, Los Angeles, CA, USA

John D. Gearhart Johns Hopkins University, School of Medicine,

Baltimore, MD

Victor M. Goldberg Department of Orthopedics, University Hospitals Case

Medical Center Cleveland, Ohio, OH, USA

List of Contributors xxv

Rodolfo Gonzalez Joint Program in Molecular Pathology, The Burnham

Institute and the University of California, San Diego, La Jolla, CA, USA

Deborah Lavoie Grayeski M Squared Associates, Inc., Alexandria, VA, USA

Ronald M. Green Department of Religion, Dartmouth College, Hanover,

Nrt, USA

Markus Grompe Oregon Health & Science University, Papé Family Pediatric

Institute, Portland, OR, USA

Stephen L. Hilbert Children’s Mercy Hospital, Kansas City, MO, USA

Marko E. Horb Center for Regenerative Medicine, Department of Biology &

Biochemistry, University of Bath, Bath, UK

Jerry I. Huang Departments of Surgery and Orthopedics Regenerative

Bioengineering and Repair Laboratory, UCLA School of Medicine, Los

Angeles, CA, USA

Jaimie Imitola Department of Neurology, Brigham and Women's Hospital,

Boston, MA, USA

D. Leanne Jones Department of Developmental Biology, Stanford

University School of Medicine, Stanford, CA, USA

Jan Kajstura Department of Anesthesia, Brigham and Women's Hospital,

Boston, MA, USA

David S. Kaplan Center for Devices and Radiological Health, Food and

Drug Administration, Silver Spring, MD, USA

Pritinder Kaur Epithelial Stem Cell Biology Laboratory, Peter MacCallum

Cancer Center, Melbourne, and Sir Peter MacCallum Department of

Oncology, The University of Melbourne, Parkville, Australia

Kathleen C. Kent Johns Hopkins University, School of Medicine, Baltimore,

MD

Candace L. Kerr Department of Gynecology and Obstetrics, Johns Hopkins

University, School of Medicine, Baltimore, MD

Ali Khademhosseini Division of Biological Engineering, Massachusetts

Institute of Technology, Cambridge, MA

Nadav Kimelman Skeletal Biotechnology Laboratory, Hebrew University –

Hadassah Faculty of Dental Medicine, Jerusalem, Israel

Irina Klimanskaya Advanced Cell Technology, Inc., Marlborough, MA, USA

Jennifer N. Kraszewski Johns Hopkins University, School of Medicine,

Baltimore, MD

Mark A. LaBarge Cancer & DNA Damage Responses, Berkeley Laboratory,

Berkeley, CA, USA

Robert Langer Department of Chemical Engineering, Massachusetts

Institute of Technology, Cambridge, MA

Robert Lanza Advanced Cell Technology, MA, USA and Wake Forest

University School of Medicine, Winston Salem, NC, USA

Ellen Lazarus Center for Biologics Evaluation and Research, Food and Drug

Administration, Rockville, MD, USA

xxvi List of Contributors

Jean Pyo Lee Department of Neurology, Beth Israel Deaconess Medical

Center, Boston, MA, USA

Mark H. Lee Center for Biologics Evaluation and Research, Food and Drug

Administration, Rockville, MD, USA

Annarosa Leri Department of Anesthesia, Brigham and Women's Hospital,

Boston, MA, USA

Shulamit Levenberg Langer Laboratory, Department of Chemical

Engineering, Massachusetts Institute of Technology, Cambridge, MA

S. Robert Levine Juvenile Diabetes Research Foundation, NY, USA

John W. Littlefield Johns Hopkins University, School of Medicine,

Baltimore, MD, USA

Richard McFarland Center for Biologics Evaluation and Research, Food and

Drug Administration, Rockville, MD, USA

Jill McMahon Harvard University, Cambridge, MA, USA

Douglas A. Melton Department of Molecular and Cellular Biology, Harvard

University, and Howard Hughes Medical Institute, Cambridge, MA, USA

Mary Tyler Moore Juvenile Diabetes Research Foundation, NY, USA

Franz-Josef Mueller Program in Developmental and Regenerative Cell

Biology, The Burnham Institute, La Jolla, CA, USA

Christine L. Mummery Department of Anatomy and Embryology, Leiden

University Medical Center, Leiden, The Netherlands

Bernardo Nadal-Ginard The Stem Cell and Regenerative Biology Unit

(BioStem), Liverpool, John Moores University, Liverpool, UK

Hitoshi Niwa Laboratory for Pluripotent Stem Cell Studies, RIKEN Center

for Developmental Biology, Tokyo, Japan

Keisuke Okita Center for iPS Cell Research and Application, Institute for

Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan

Jitka Ourednik Department of Biomedical Sciences, lowa State University,

Ames, IA, USA

Vaclav Ourednik Department of Biomedical Sciences, lowa State University,

Ames, IA, USA

Kook I. Park Department of Pediatrics and Pharmacology, Yonsei

University College of Medicine, Seoul, Korea

Ethan S. Patterson Johns Hopkins University, School of Medicine,

Baltimore, MD, USA

Gadi Pelled Skeletal Biotechnology Laboratory, Hebrew University –

Hadassah Faculty of Dental Medicine, Jerusalem, Israel and Department

of Surgery and Cedars-Sinai Regenerative Medicine Institute, Cedars-Sinai

Medical Center, Los Angeles, CA, USA

Christopher S. Potten University of Manchester, Manchester, UK

Sean Preston Histopathology Unit, Cancer Research UK, London, UK

Philip R. Roelandt Interdepartmental Stem Cell Institute Leuven, Catholic

University Leuven, Leuven, Belgium

List of Contributors xxvii

Valerie D. Roobrouck Interdepartmental Stem Cell Institute Leuven,

Catholic University Leuven, Leuven, Belgium

Nadia Rosenthal National Heart and Lung Institute, Imperial College,

London, UK

Janet Rossant Mount Sinai Hospital, Toronto, Ontario, Canada

Maurilio Sampaolesi Translational Cardiomyology Laboratory, Stem Cell

Institute, Department of Development and Regeneration, Catholic University

of Leuven, Belgium, and Human Anatomy Institute IIM and CIT, Department

of Public Health, Neuroscience, Experimental and Forensic Medicine,

University of Pavia, Italy

Maria Paola Santini National Heart and Lung Institute, Imperial College,

London, UK

David T. Scadden Harvard University, Massachusetts General Hospital,

Boston, MA, USA

Holger Schlüter Epithelial Stem Cell Biology Laboratory, Peter MacCallum

Cancer Center, Melbourne, and Sir Peter MacCallum Department of

Oncology, The University of Melbourne, Parkville, Australia

Gunter Schuch Institute for Regenerative Medicine, Wake Forest University

School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA

Michael J. Shamblott Institute for Cell Engineering, Johns Hopkins

University, School of Medicine, Baltimore, MD

Dima Sheyn Skeletal Biotechnology Laboratory, Hebrew University –

Hadassah Faculty of Dental Medicine, Jerusalem, Israel

Richard L. Sidman Harvard Medical School, Boston, MA, USA

Evan Y. Snyder The Burnham Institute, La Jolla, CA, USA

Shay Soker Institute for Regenerative Medicine, Wake Forest University

School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA

Stephen C. Strom Department of Pathology, University of Pittsburgh, PA,

USA

Lorenz Studer Developmental Biology and Neurosurgery, Memorial Sloan

Kettering Cancer Center, New York, NY, USA

M. Azim Surani Wellcome Trust Cancer Research UK Gurdon Institute,

University of Cambridge, Cambridge, UK

Francesco Saverio Tedesco Department of Cell and Developmental Biology

and Center for Stem Cells and Regenerative Medicine, University College

London, London, UK, Division of Regenerative Medicine, Stem Cells and

Gene Therapy, San Raffaele Scientific Institute, Milan, Italy, and University

College London Hospitals NHS Foundation Trust, London, UK

Yang D. Teng Department of Neurosurgery, Harvard Medical School/

Children's Hospital, Boston/Brigham and Women's Hospital, Boston, USA,

and SCI Laboratory, VA Boston Healthcare System, Boston, MA, USA

David Tosh Center for Regenerative Medicine, Department of Biology &

Biochemistry, University of Bath, Bath, UK

xxviii List of Contributors

Alan Trounson California Institute for Regenerative Medicine, San

Francisco, CA, USA

Tudorita Tumbar Department of Molecular Biology and Genetics, Cornell

University, Ithaca, NY, USA

Edward Upjohn Epithelial Stem Cell Biology Laboratory, Peter MacCallum

Cancer Center, Melbourne, Australia

George Varigos Epithelial Stem Cell Biology Laboratory, Peter MacCallum

Cancer Center, Melbourne, Australia

Catherine M. Verfaillie Interdepartmental Stem Cell Institute Leuven,

Catholic University Leuven, Leuven, Belgium

Zhan Wang Institute for Regenerative Medicine, Wake Forest University

School of Medicine, Medical Center Blvd, Winston-Salem, NC, USA

Gordon C. Weir Harvard Stem Cell Institute, Cambridge, MA, USA

Kevin J. Whittlesey California Institute for Regenerative Medicine, San

Francisco, CA, USA

J. Koudy Williams Institute for Regenerative Medicine, Wake Forest

University School of Medicine, Medical Center Blvd, Winston-Salem, NC,

USA

James W. Wilson EpiStem Limited, Incubator Building, Manchester, UK

Celia Witten Center for Biologics Evaluation and Research, FDA, Rockville,

MD, USA

Nicholas A. Wright Histopathology Unit, Cancer Research UK, London, UK

Shinya Yamanaka Center for iPS Cell Research and Application, Institute

for Integrated Cell-Material Sciences, Kyoto University, Department of Stem

Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto,

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

Kawaguchi, Japan, and Gladstone Institute of Cardiovascular Disease, San

Francisco, CA, USA

Jung U. Yoo Oregon Health & Science University, Portland, Oregon, OR,

USA

3

R. Lanza & A. Atala (Eds): Essentials of Stem Cell Biology, Third edition.

DOI:

© 2014 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/B978-0-12-409503-8.00001-9

Why Stem Cell Research?

Advances in the Field

CHAPTER 1

Alan Trounson

California Institute for Regenerative Medicine, San Francisco, CA, USA

1.1 THE ORIGINS OF STEM CELL TECHNOLOGY

Stem cell research, which aims to develop new cell therapies, has accelerated

at an astonishing pace; both in terms of the breadth of interests and the dis￾coveries that continue to evolve. Research in stem cell biology is opening new

platforms to launch even more spectacular developments, crowding the pages

of major journals each month. One might wonder why the field took so long

to explode in such an incredible fashion.

The studies of John Gurdon and colleagues on reprogramming amphibian

cells using oocytes stand as a very significant milestone that was emphati￾cally amplified by Ian Wilmut and colleagues, who unexpectedly repro￾grammed mammalian somatic cell nuclei into totipotent embryos when the

nuclei were introduced into oocytes of the same species. Martin Evans and

colleagues showed that cells isolated from the blastocyst stage of an embryo

could be converted to pluripotent embryonic stem cells. Traveling on an

independent plane of discovery were many great scientists, among whom Irv

Weismann stands out for his discoveries of adult hematopoietic stem cells in

mice and humans. Bone marrow transplants have a well-established history

as a therapeutic strategy for cancer and other diseases of the blood.

What a melting pot of ingredients for James Thomson to launch the discov￾ery of human embryonic stem cell lines, cloning for stem cells in the mouse

by members of my own group, and most significantly the demonstration by

Shinya Yamanaka of the ability to reprogram somatic cells to pluripotency

(induced pluripotent stem cells) using four critical transcription factors.

Again independently, Arthur Caplan isolated mesenchymal stem cells from

bone marrow, showing their multipotent capacities to form bone, cartilage,

and adipose tissue. Now we have the ingredients to explore the possibil￾ity of applying stem cell discoveries to regenerative medicine. The potential

4 Chapter 1: Why Stem Cell Research? Advances in the Field

for using living cells to regenerate whole organs was quickly underscored by

Anthony Atala’s demonstration of engineering bladders for patients.

1.2 ORGANIZATIONS THAT ADVOCATE AND

SUPPORT THE GROWTH OF THE STEM

CELL SECTOR

Basic scientists gathered around Len Zon to form and launch the International

Society of Stem Cell Research. Cell therapy and tissue transplant scientists

have remained largely separate but have become another effective science and

therapeutic organization under the International Society for Cell Therapy.

Separately, the stem cell biotechnology industry has joined together under

the umbrella of the Alliance for Regenerative Medicine to become an effective

advocate for the emerging industry interests in cell and tissue therapies.

The Bush administration in the USA raised concerns within the fledgling

stem cell science community by restricting the funding of embryonic stem

cell research and limiting the number of embryonic stem cell lines that could

be studied with federal funding. Key scientists in California coopted Robert

Klein, a financier and lawyer, to their cause and he was able to galvanize

the Californian voters to pass Proposition 71 (with 59% support) – a game￾changing state bond initiative that required California to sell general obli￾gation bonds up to $3 billion to fund pluripotent stem and progenitor cell

research. This extremely clever approach to funding intellectual capital was

supported by the Republican Governor Arnold Schwarzenegger, and estab￾lished the Californian Institute for Regenerative Medicine (CIRM).

California has since become a major hub for stem cell research, attracting

many of the world’s best scientists and rivaling the well-established biotech￾nology hubs around Boston and New York. Twelve new research institutes

have been built in California under CIRM sponsorship, assembling a criti￾cal mass of intellectual excellence and driving an incredible productivity of

discovery research. Both Thompson and Yamanaka have appointments in

California institutions. Two clusters of biotechnology companies involved in

cell therapies have evolved in the Bay Area and San Diego, with a third form￾ing in Los Angeles. Companies are relocating to California and are actively

opening offices and labs to contribute to the energized environment there.

CIRM has also developed a very major network of collaborations with 12

international countries and states, a number of US states, foundations, and,

most recently, with the US National Institutes of Health. These collaborations

are driving globally a vast array of basic research and translational medicine,

and changing the quality and depth of global research to find solutions to the

world’s most feared and intractable diseases.