Stem Cells in Endocrinology - part 1 pdf

Stem cells are a potential source of cells for regenerative medicaltherapies, and research on defined stem cell populations will facilitate the study of organ development ex vivo.. Embry

S TEM C ELLS IN E NDOCRINOLOGY

C ONTEMPORARY E NDOCRINOLOGY

P Michael Conn, S ERIES E DITOR

Stem Cells in Endocrinology, edited by

LINDA B LESTER, 2005

Office Andrology, edited by P HILLIP E.

PATTON AND DAVID E BATTAGLIA, 2005

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Therapeutic Principles, edited by

STEPHEN J WINTERS, 2004

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by C ARRIE J BAGATELL AND WILLIAM J.

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edited by R OBERT S BAR, 2003

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edited by J ANET E HALL AND LYNNETTE

K NIEMAN, 2003

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RADOVICK AND MARGARET H.

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MARTIN MATZUK, CHESTER W BROWN,

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Adrenal Disorders, edited by A NDREW N MARGIORIS AND GEORGE P CHROUSOS, 2001

Endocrine Oncology, edited by S TEPHEN P ETHIER, 2000

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and Surfactant Synthesis, edited by CAROLE R MENDELSON, 2000

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by M ARGARET A SHUPNIK, 2000

Endocrinology of Aging, edited by J OHN E MORLEY AND LUCRETIA VAN DEN BERG, 2000

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Clinical Practice, edited by ROY G SMITH AND MICHAEL O THORNER, 2000

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edited by D AVID B SEIFER AND ELIZABETH A KENNARD, 1999

The IGF System: Molecular Biology,

Physiology, and Clinical Applications,

edited by R ON G ROSENFELD AND CHARLES T ROBERTS, JR., 1999

Neurosteroids: A New Regulatory Function

in the Nervous System, edited by ETIENNE-EMILE BAULIEU, MICHAEL SCHUMACHER, AND PAUL ROBEL, 1999

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Stem cells in endocrinology / edited by Linda B Lester.

p cm (Contemporary endocrinology)

Includes bibliographical references and index.

ISBN 1-58829-407-2 (alk paper)

1 Stem cells 2 Endocrinology, Experimental I Lester, Linda B II.

Series: Contemporary endocrinology (Totowa, N.J.)

QH588.S83S747 2005

616'.02774 dc22

Dedication

The lights of stars that were extinguished ages ago still reach us.

So it is with great men who died centuries ago, but still reach us

with the radiations of their personalities.

— K HALIL G IBRAN

The recent death of James R Hansen, MD (August 24, 1951 to May 27, 2003)cut short a life dedicated to family, patients, and a cure for type 1 diabetes Aftermedical school at Oregon Health Sciences University, Jim completed a pediatricresidency and pediatric endocrine fellowship at the University of Iowa Uponreturning to Portland, Oregon, Jim became medical director of the EmanuelChildren’s Diabetes and Endocrine Center There he worked passionately to carefor his patients with type 1 diabetes and continued to pursue novel diabetes thera-pies through ongoing clinical research Jim was actively involved with theJuvenile Diabetes Research Foundation (JDRF) at both the local and interna-tional levels He was very enthusiastic about the use of stem cells for endocrinetherapies, particularly for treating patients with type 1 diabetes Jim served as thecommittee chair for the JDRF’s Human Stem Cell Research Committee up until

a few weeks before his death

This book is dedicated to Dr James Hansen, in memory of his life, vision, andinspiration He continues to shine for those of us he touched

vii

As the world population ages, health care costs are expected to escalate as aresult of the increase in age-related, degenerative diseases Regenerating thefailing cells and organs associated with these diseases would preserve quality oflife and help curtail the increase in health care costs Medical scientists today arefaced with the challenge of developing new and innovative regenerative thera-pies to meet this need A major focus of this research is to identify sources of cellsand tissues that can be used in regenerative therapies Stem cells, by definition,can self-replicate and, under the right conditions, differentiate into mature cellphenotypes Stem cells are a potential source of cells for regenerative medicaltherapies, and research on defined stem cell populations will facilitate the study

of organ development ex vivo Understanding stem cell growth and developmentwill shed light on the biological process of tissue/organ development and likelylead to novel regenerative therapies

Although all stem cells have a limited capacity for self-replication and entiation, some stem cells are capable of differentiating into multiple cell types,

differ-a property known differ-as pldiffer-asticity Embryonic stem (ES) cells differ-are derived from theearly blastocyst and contain stem cells capable of generating all adult tissues.This makes ES cells the most pluripotent, or plastic, of the available stem cells.Recently, ES cell lines were derived from animal and human blastocysts Thesecell lines are capable of self-replication and can be expanded in culture to provide

a renewable source of cells Human ES cell lines are an invaluable research toolfor the study of human development in vitro In addition, human ES cells havethe potential for direct use in therapies; thus, these cell lines represent a majoradvance in cell biology that will have a broad impact on subsequent medicalresearch

The study of stem cell biology is likely to have profound effects for the nearfuture, affecting the current equilibrium in medical research The evolution ofscience and medicine is punctuated by events that are clearly so significant thatthey alter the future course of scientific and medical discovery The derivation

of human ES cell lines, in my mind, is clearly such an event Human ES cell lines,along with other stem cell lines, will have broad and long-lasting effects ondevelopmental biology and translational research However, the fundamentalimportance of ES cell lines does not necessarily imply that ES cells will become

viii Preface

the cell source for regenerative medicine The appropriate stem cells will need

to be evaluated for each disease system that may benefit from regenerativetherapy

Many disease processes stand to benefit from regenerative medical therapies,including disorders of the central nervous system, cardiovascular, gastrointestinal,and hematologic systems Currently, some of these disorders can be treated usingwhole organ transplantation However, whole organ transplantation is limited to

a small percent of patients because of the scarcity of organs for donation and theneed for broad spectrum immunosuppressive therapies As opposed to othersystems, degenerative disorders of the endocrine system can currently be treatedusing exogenous hormonal therapies These therapies, however, are frequentlyinadequate, resulting in significant morbidity and mortality to patients Thedifficulty in treating endocrine disorders is developing a therapy that mimics thenatural feedback mechanisms inherent to functional endocrine organs Most currentexogenous endocrine therapies fail to mimic the precise metabolic control of endog-enous hormone release, resulting in under- or overtreatment and thereby leading

to complications This is clearly illustrated by the persistent complications ofdiabetes in patients on exogenous insulin therapy Replacing endocrine organfunction with functionally responsive cells will allow for the precise regulation

of hormone release through natural feedback and should dramatically improvemedical care The recent success of islet transplantation indicates the potentialfor cell therapies to improve medical care for patients with diabetes Again, themajor drawback is the lack of tissue available for these procedures The shortage

of islets and other endocrine tissues could be overcome by developing alternativetissue sources such as the use of stem cells Endocrine diseases, in particulardiabetes, are therefore prime targets for stem cell therapeutics

The objective of this text is to provide a primary source of information on basicstem cell biology and the application of stem cell research to endocrine diseases

As such, this book should be useful for both clinical endocrinologists and crine researchers alike The information in this book is divided into two mainsections: first, a basic stem cell biology section and second, translational stemcell research with endocrine applications In the basic science section, each of themajor sources of stem cells are discussed, including embryonic, cord blood, germline, and adult stem cells tissues Because it is not clear which stem cell types willeventually be used for endocrine therapies discussing all stem cells allows aside-by-side comparison of the different stem cell types and a full understanding

endo-of the pros and cons endo-of each The second section explores how stem cells may beemployed to develop endocrine-related cells or tissues This includes discus-sions on directed differentiation using transgenes and development of endocrine-specific phenotypes including β-cells, hepatocytes, bone, and sperm Because

many endocrine disorders are autoimmune mediated, we also include a sion of stem cell therapy for the treatment of autoimmune disorders In the future,stem cell therapies for thyroid and other endocrine disorders may be available,but these areas are not discussed given the limited amount of research currentlyavailable.

discus-In closing, I would like to thank all the contributing authors for taking timefrom their research efforts to share their thoughts and ideas in this book Theircollective expertise provides an excellent starting point for the endocrineresearcher, illuminating the complexity and potential of stem cell research inendocrinology I also want to thank Drs Laura Andrews and Brian Nauert fortheir thoughts, editorial comments, and efforts in my research lab while I wasworking on this project Finally, I would like to thank Dr Lynn Loriaux for hisongoing support of stem cell research at Oregon Health and Sciences Universityand my family, for enduring cold dinners and late nights with few complaints Icould not flourish without their support and encouragement My accomplish-ments are clearly a reflection of all those around me

Linda B Lester, MS , MD

Contents

Dedication vPreface viiContributors xiii

PART I: BASIC STEM CELL BIOLOGY

1 Embryonic Stem Cells: Derivation, Properties,

and Therapeutic Implications 3 Victoria L Browning and Jon S Odorico

2 Germ Line Stem Cells 23

Makoto C Nagano

3 Umbilical Cord Stem Cells 49

Kathy E Mitchell

4 Differentiation Potential of Adult Stem Cells 67

Henry E Young and Asa C Black, Jr.

5 Growth Conditions for Primate vs Murine Embryonic

Stem Cells 93

Gillian M Beattie, Nathan Bucay, Rohan Humphrey, Ana D Lopez, and Alberto Hayek

PART II: TRANSLATIONAL RESEARCH

6 Islet Precursor Cells in Adult Pancreatic Islets 115

Gladys Teitelman and Irem Nasir

7 Transcription Factor-Directed Differentiation

of Stem Cells Along an Endocrine Lineage 133

William L Lowe, Jr.

8 Generation of Islet-Like Structures From ES Cells 147

Nadya Lumelsky

9 The Therapeutic Potential of Liver Repopulation

for Metabolic or Endocrine Disorders 165

Sanjeev Gupta

xii Contents

10 The Manipulation of Mesenchymal Stem Cells

for Bone Repair 183

Shelley R Winn

11 Spermatogenesis From Transplanted

Spermatogenic Stem Cells 207

Michael D Griswold and Derek McLean

12 Hematopoietic Stem Cell Transplant in the Treatment

of Autoimmune Endocrine Disease 221

Jody Schumacher and Ewa Carrier

13 Preclinical Trials for Stem Cell Therapy 243

Linda B Lester, K Y Francis Pau, and Don P Wolf

Index 263

GILLIAN M BEATTIE, P D • Whittier Institute, University of California San

Diego, La Jolla, CA

ASA C BLACK, JR., MD • Division of Basic Medical Science, Department

of Obstetrics and Gynecology, Mercer University School of Medicine, Macon, GA

VICTORIA L BROWNING, P D • Department of Surgery, University of Wisconsin,

MICHAEL D GRISWOLD, P D, DVM • School of Molecular Biosciences, Washington

State University, Pullman, WA

SANJEEV GUPTA, MD • Marion Bessin Liver Research Center, Albert Einstein

College of Medicine, Bronx, NY

ALBERTO HAYEK, MD • Whittier Institute, University of California San Diego,

La Jolla, CA

ROHAN HUMPHREY, P D • Whittier Institute, University of California San Diego,

La Jolla, CA

LINDA B LESTER, MS, MD • Division of Endocrinology, Diabetes and Clinical

Nutrition, Department of Medicine, Oregon Health and Sciences University, Portland, OR

ANA D LOPEZ, P D • Whittier Institute, University of California San Diego,

La Jolla, CA

WILLIAM L LOWE, JR., MD • Feinberg School of Medicine, Northwestern

University, Chicago, IL

NADYA LUMELSKY, P D • Islet and Autoimmunity Branch, National Institute

of Diabetes and Digestive and Kidney Diseases, National Institutes

of Health, Bethesda, MD

DEREK MCLEAN, P D • Department of Animal Sciences, Center for Reproductive

Biology, Washington State University, Pullman, WA

KATHY E MITCHELL, P D • Department of Pharmacology and Toxicology,

University of Kansas, Lawrence, KS

MAKOTO C NAGANO, P D, DVM • Department of Obstetrics and Gynecology,

McGill University, Montreal, Quebec, Canada

xiii