Stem Cells in Endocrinology Edited by Linda B. Lester, MD CONTEMPORARY ENDOCRINOLOGY ™ Stem Cells in Endocrinology Edited by Linda B. Lester, MD STEM CELLS IN ENDOCRINOLOGY CONTEMPORARY ENDOCRINOLOGY P. Michael Conn, SERIES EDITOR Stem Cells in Endocrinology, edited by L INDA B. LESTER, 2005 Office Andrology, edited by P HILLIP E. PATTON AND DAVID E. BATTAGLIA, 2005 Male Hypogonadism: Basic, Clinical, and Therapeutic Principles, edited by S TEPHEN J. WINTERS, 2004 Androgens in Health and Disease, edited by C ARRIE J. BAGATELL AND WILLIAM J. BREMNER, 2003 Endocrine Replacement Therapy in Clinical Practice, edited by A. W AYNE MEIKLE, 2003 Early Diagnosis of Endocrine Diseases, edited by R OBERT S. BAR, 2003 Type I Diabetes: Etiology and Treatment, edited by M ARK A. SPERLING, 2003 Handbook of Diagnostic Endocrinology, edited by J ANET E. HALL AND LYNNETTE K. NIEMAN, 2003 Pediatric Endocrinology: A Practical Clinical Guide, edited by S ALLY RADOVICK AND MARGARET H. MACGILLIVRAY, 2003 Diseases of the Thyroid, 2nd ed., edited by L EWIS E. BRAVERMAN, 2003 Developmental Endocrinology: From Research to Clinical Practice, edited by E RICA A. EUGSTER AND ORA HIRSCH PESCOVITZ, 2002 Osteoporosis: Pathophysiology and Clinical Management, edited by E RIC S. O RWOLL AND MICHAEL BLIZIOTES, 2002 Challenging Cases in Endocrinology, edited by MARK E. MOLITCH, 2002 Selective Estrogen Receptor Modulators: Research and Clinical Applications, edited by ANDREA MANNI AND MICHAEL F. V ERDERAME, 2002 Transgenics in Endocrinology, edited by M ARTIN MATZUK, CHESTER W. BROWN, AND T. RAJENDRA KUMAR, 2001 Assisted Fertilization and Nuclear Transfer in Mammals, edited by DON P. W OLF AND MARY ZELINSKI-WOOTEN, 2001 Adrenal Disorders, edited by ANDREW N. MARGIORIS AND GEORGE P. C HROUSOS, 2001 Endocrine Oncology, edited by S TEPHEN P. E THIER, 2000 Endocrinology of the Lung: Development and Surfactant Synthesis, edited by C AROLE R. MENDELSON, 2000 Sports Endocrinology, edited by M ICHELLE P. W ARREN AND NAAMA W. CONSTANTINI, 2000 Gene Engineering in Endocrinology, edited by MARGARET A. SHUPNIK, 2000 Endocrinology of Aging, edited by J OHN E. M ORLEY AND LUCRETIA VAN DEN BERG, 2000 Human Growth Hormone: Research and Clinical Practice, edited by R OY G. SMITH AND MICHAEL O. THORNER, 2000 Hormones and the Heart in Health and Disease, edited by L EONARD SHARE, 1999 Menopause: Endocrinology and Management, edited by D AVID B. SEIFER AND ELIZABETH A. KENNARD, 1999 The IGF System: Molecular Biology, Physiology, and Clinical Applications, edited by RON G. ROSENFELD AND CHARLES T. ROBERTS, JR., 1999 Neurosteroids: A New Regulatory Function in the Nervous System, edited by E TIENNE-EMILE BAULIEU, MICHAEL SCHUMACHER, AND PAUL ROBEL, 1999 Autoimmune Endocrinopathies, edited by ROBERT VOLPÉ, 1999 Hormone Resistance Syndromes, edited by J. L ARRY JAMESON, 1999 Hormone Replacement Therapy, edited by A. W AYNE MEIKLE, 1999 Insulin Resistance: The Metabolic Syndrome X, edited by G ERALD M. REAVEN AND AMI LAW S , 1999 STEM CELLS IN ENDOCRINOLOGY Edited by LINDA B. LESTER, MS, MD Division of Endocrinology, Diabetes and Clinical Nutrition Department of Medicine, Oregon Health and Sciences University Portland, Oregon © 2005 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles,contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699;Fax: 973-256-8341; E-mail: humana@ humanapr.com.com or visit our website at humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. 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Series: Contemporary endocrinology (Totowa, N.J.) QH588.S83S747 2005 616'.02774 dc22 2004017508 v 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 GIBRAN 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. After medical school at Oregon Health Sciences University, Jim completed a pediatric residency and pediatric endocrine fellowship at the University of Iowa. Upon returning to Portland, Oregon, Jim became medical director of the Emanuel Children’s Diabetes and Endocrine Center. There he worked passionately to care for his patients with type 1 diabetes and continued to pursue novel diabetes thera- pies through ongoing clinical research. Jim was actively involved with the Juvenile Diabetes Research Foundation (JDRF) at both the local and interna- tional levels. He was very enthusiastic about the use of stem cells for endocrine therapies, particularly for treating patients with type 1 diabetes. Jim served as the committee 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, and inspiration. He continues to shine for those of us he touched. Preface vii As the world population ages, health care costs are expected to escalate as a result of the increase in age-related, degenerative diseases. Regenerating the failing cells and organs associated with these diseases would preserve quality of life and help curtail the increase in health care costs. Medical scientists today are faced 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 cells and tissues that can be used in regenerative therapies. Stem cells, by definition, can self-replicate and, under the right conditions, differentiate into mature cell phenotypes. Stem cells are a potential source of cells for regenerative medical therapies, and research on defined stem cell populations will facilitate the study of organ development ex vivo. Understanding stem cell growth and development will shed light on the biological process of tissue/organ development and likely lead to novel regenerative therapies. Although all stem cells have a limited capacity for self-replication and differ- entiation, some stem cells are capable of differentiating into multiple cell types, a property known as plasticity. Embryonic stem (ES) cells are derived from the early 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. These cell 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 tool for the study of human development in vitro. In addition, human ES cells have the potential for direct use in therapies; thus, these cell lines represent a major advance in cell biology that will have a broad impact on subsequent medical research. The study of stem cell biology is likely to have profound effects for the near future, affecting the current equilibrium in medical research. The evolution of science and medicine is punctuated by events that are clearly so significant that they 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 on developmental biology and translational research. However, the fundamental importance 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 regenerative therapy. 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 using whole organ transplantation. However, whole organ transplantation is limited to a small percent of patients because of the scarcity of organs for donation and the need for broad spectrum immunosuppressive therapies. As opposed to other systems, degenerative disorders of the endocrine system can currently be treated using exogenous hormonal therapies. These therapies, however, are frequently inadequate, resulting in significant morbidity and mortality to patients. The difficulty in treating endocrine disorders is developing a therapy that mimics the natural feedback mechanisms inherent to functional endocrine organs. Most current exogenous 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 of diabetes in patients on exogenous insulin therapy. Replacing endocrine organ function with functionally responsive cells will allow for the precise regulation of hormone release through natural feedback and should dramatically improve medical care. The recent success of islet transplantation indicates the potential for cell therapies to improve medical care for patients with diabetes. Again, the major drawback is the lack of tissue available for these procedures. The shortage of islets and other endocrine tissues could be overcome by developing alternative tissue sources such as the use of stem cells. Endocrine diseases, in particular diabetes, are therefore prime targets for stem cell therapeutics. The objective of this text is to provide a primary source of information on basic stem cell biology and the application of stem cell research to endocrine diseases. As such, this book should be useful for both clinical endocrinologists and endo- crine researchers alike. The information in this book is divided into two main sections: first, a basic stem cell biology section and second, translational stem cell research with endocrine applications. In the basic science section, each of the major sources of stem cells are discussed, including embryonic, cord blood, germ line, and adult stem cells tissues. Because it is not clear which stem cell types will eventually be used for endocrine therapies discussing all stem cells allows a side-by-side comparison of the different stem cell types and a full understanding of the pros and cons of each. The second section explores how stem cells may be employed 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 discus- 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 currently available. In closing, I would like to thank all the contributing authors for taking time from their research efforts to share their thoughts and ideas in this book. Their collective expertise provides an excellent starting point for the endocrine researcher, illuminating the complexity and potential of stem cell research in endocrinology. I also want to thank Drs. Laura Andrews and Brian Nauert for their thoughts, editorial comments, and efforts in my research lab while I was working on this project. Finally, I would like to thank Dr. Lynn Loriaux for his ongoing support of stem cell research at Oregon Health and Sciences University and my family, for enduring cold dinners and late nights with few complaints. I could not flourish without their support and encouragement. My accomplish- ments are clearly a reflection of all those around me. Linda B. Lester, MS, MD Preface ix [...]... nestin-expressing cells from mouse ES Chapter 1 / Embryonic Stem Cells 11 cells through growth of EBs in serum-free media containing insulin, transferrin, selenium, fibronectin The cells were then grown in N2 serum-free medium with the addition of bFGF and B27 to expand the pancreatic progenitor cells, and the final step was induction of differentiation through removal of bFGF and addition of nicotinamide... PI3 kinase inhibitor (LY294002) to reduce the growth of neuronal cells and promote terminal differentiation to insulin-positive cells The results of these growth conditions were socalled insulin-producing cell clusters, which appear to express insulin, C-peptide, PDX1, GLUT2, and glucokinase and exhibit better insulin release than cells derived through the B27-supplemented protocol Insulin-producing... for insulin, these clusters neither accumulated insulin transcript nor showed staining with an antibody specific for C-peptide, a protein that results from the cleavage of proinsulin to insulin In addition, many of the insulinpositive cells were positive in the TUNEL assay, suggesting that they were undergoing apoptosis Finally, it was demonstrated that cells were capable of taking up exogenous insulin... result in the production of robust glucose-responsive insulinsecreting cells Aside from the question of whether ES cell-derived nestin-positive cells can differentiate into insulin-secreting cells, there has been a great deal of debate as to whether nestin is a marker of islet endocrine progenitors in vivo Lineage tracing experiments have recently readdressed this question (69–72) In these lineage tracing... Medicine, Macon, GA Chapter 1 / Embryonic Stem Cells I BASIC STEM CELL BIOLOGY 1 2 Browning and Odorico Chapter 1 / Embryonic Stem Cells 1 3 Embryonic Stem Cells Derivation, Properties, and Therapeutic Implications Victoria L Browning and Jon S Odorico CONTENTS INTRODUCTION DERIVATION OF EMBRYONIC STEM CELLS GENERAL GROWTH CHARACTERISTICS OF ES CELLS DIFFERENTIATION OF ES CELLS INTO PANCREATIC LINEAGES... Efforts to generate insulin-producing islet cells from murine and human embryonic stem (ES) cells followed the establishment of these ES cell lines In this review we will discuss the derivation proceFrom: Contemporary Endocrinology: Stem Cells in Endocrinology Edited by: L B Lester © Humana Press Inc., Totowa, NJ 3 4 Browning and Odorico dures and growth characteristics of ES cell lines from these two... Endocrine Disorders 16 5 Sanjeev Gupta xi xii Contents 10 The Manipulation of Mesenchymal Stem Cells for Bone Repair 18 3 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 2 21 Jody Schumacher and Ewa Carrier 13 Preclinical Trials for Stem. .. ES cells have a doubling time of roughly 35–40 hours (36,37) and are passaged approximately once per week using collagenase to dislodge and disrupt colonies Regardless of the species, undifferentiated ES cells express several cell surface markers; these include stage-specific embryonic antigens, SSEA -1 in mouse and SSEA-3 and SSEA-4 in human, and well as tumor-recognition antigens TRA- 1- 6 0 and TRA- 1- 8 1. .. perhaps explaining their staining patterns and their failure to reverse hyperglycemia in streptozotocin-induced diabetic animals Other investigators have used a similar differentiation protocol involving insulin, transferrin, selenium, fibronectin serum-free media and bFGF, B27, and nicotinamide (67,68) Hori et al (67) used similar conditions for the initial stages of differentiation, but in the last... nonselective culture Chapter 1 / Embryonic Stem Cells 9 protocol including EB formation for 5–7 days followed by plating and further differentiation in the presence of FBS In these differentiated cultures, foci of pancreatic lineage cells emerge, including cells that stain positively for PDX1 (pancreatic duodenal homeobox 1, a homeodomain protein absolutely required for pancreas development in both humans and . Reporting Service is: [ 1- 5 882 9-4 0 7-2 /05 $30.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 e-ISBN: 1- 5 925 9-9 0 0 -1 Library of Congress Cataloging -in- Publication Data Stem cells in. Stem Cells in Endocrinology Edited by Linda B. Lester, MD CONTEMPORARY ENDOCRINOLOGY ™ Stem Cells in Endocrinology Edited by Linda B. Lester, MD STEM CELLS IN ENDOCRINOLOGY CONTEMPORARY ENDOCRINOLOGY P in endocrinology / edited by Linda B. Lester. p. cm. (Contemporary endocrinology) Includes bibliographical references and index. ISBN 1- 5 882 9-4 0 7-2 (alk. paper) 1. Stem cells. 2. Endocrinology,