Tai Lieu Chat Luong Essentials of Stem Cell Biology Essentials of Stem Cell Biology Third Edition Edited by Robert Lanza Anthony Atala AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 525 B Street, Suite 1900, San Diego, CA 92101–4495, USA 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA Copyright © 2014 Elsevier Inc All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights, Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information Notice No responsibility is assumed by the publisher for any injury and/or damage to persons, or property as a matter of products liability, negligence or otherwise, or from any use or, operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978–0-12–409503–8 For information on all Academic Press publications visit our website at elsevierdirect.com Printed and bound in the United States of America 14 15 16 17 10 9 8 7 6 5 4 3 2 1 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 understanding the control and progress of embryonic differentiation, but their in vitro differentiation, despite being magnificent, was overshadowed experimentally 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 program 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 clinical applications This volume provides a timely, up-to-date state-of-the-art reference The ideas behind regenerative medicine, powered by the products of embryonic stem cells, reinvigorated study of committed stem and precursor cells within the adult body The use of such stem cells in regenerative medicine xix 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 transplantation, 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 technologies is realized, and there is every possibility that such hurdles will be circumvented Quite properly, much of this book concentrates on the fundamental 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 differentiation, but as yet need to understand more in detail, more about developmental 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 considered one of the chief architects of the field of stem cell research His ground-breaking discoveries have enabled gene targeting in mice, a technology 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 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 pioneering 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 accessible 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 pluripotent and adult stem cells; the tools and methods needed to study and characterize 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 reference that we believe will be useful to students and experts alike Robert Lanza M.D Boston, Massachusetts xxi 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 xxiii 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 UniversityHadassah 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 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 xxv 666 Index Embryonic stem (ES) cells (Continued) limitations, 587–591 open systems, 583–586, 585f, 586f overview, 581 principles and perspectives, 581–587 scale-up of, 588–590 as totipotent, 21–22 transgenesis, 31–32 X chromosome inactivation (XCI), 92–93 Endothelial cells (ECs), 227 Endothelial colony-forming cells (ECFCs), 231 Endothelial progenitor cells (EPCs), 227 identification and isolation of, 229–232, 230t in vitro expansion of, 232–233 overview, 229–236 role in physiological and pathological neovascularization, 233–235 therapeutic applications, 237–243 tissue engineering, 238–239 tissue regeneration, 240–241 Engraftment delayed time to, with CB, 157–159 of MAPCs in vivo o, 250 Enzyme-linked immunosorbent assay (ELISA), 551–552 EPCs See Endothelial progenitor cells (EPCs) Epiblast-like cells, 24 Epiblast stem cells (EpiSCs), 81–82 Epidermal growth factor (EGF) family, 137, 574 Epidermal proliferative unit (EPU), 45–47, 46f Epidermal stem cells, 502–503 Epidermis, 203–204, 501–502 mammalian, stem cell niches within, 70–71 structures, 502f Epigenetic regulation of ES cells selfrenewal, 88–89 chromatin remodeling, 89 DNA methylation, 88–89 histone marks, 88 Epigenetic reprogramming, in germ cells, 456–458 Epigenetics, iPSCs induction and, 379–380 EpiSCs See Epiblast stem cells (EpiSCs) Epithelial lineage, metanephric mesenchyme stromal lineages vs., 301–303 Epithelial stem cell development of, 39 generalized scheme, 53–55, 55f hierarchically organized populations, 42–45, 44f, 45f intestinal stem cell system, 49–51, 52f–53f organization on tongue, 51–53, 54f overview, 39–40 skin stem cells, 45–49, 46f, 49f See also Skin stem cells stem cells defined, 40–42 Epo See Erythropoietin (Epo) EPU See Epidermal proliferative unit (EPU) ERK mitogen-activated protein kinase (MAPK) pathway, 390–391 ERNI See Early response to neural induction (ERNI) Erythropoietin (Epo), 230–231 ES-cell-derived glia, derivation of, 176–177 astrocytes, 177 oligodendrocytes, 176 ES-cell-derived neurons, derivation of, 171–176 GABA neurons, 174–175 glutamate neurons, 175 midbrain dopaminergic neurons, 172 motor neurons, 173–174 neural crest differentiation, 175–176 other neuronal and neural subtypes, 175 serotonergic neurons, 173 ES cells See Embryonic stem (ES) cells ES cells, self-renewal of epigenetic regulation of, 88–89 chromatin remodeling, 89 DNA methylation, 88–89 histone marks, 88 extracellular signals, 82–84 Fgf4, 84 LIF, 82–83 Wnt, 84 mediator complex, 87–88 miRNA in, 89 molecular mechanisms to retain, 82–90, 83f nuclear receptors, 87 Rex1, 87 Stat3, 87 transcriptional regulation for, 84–87 Klf4, 85–86 Myc, 86–87 Nanog, 85 Oct3/4, 84–85 Sox2, 85 Tbx3, 86 Tcf3, 86 ESL cells See ES-like (ESL) cells ES-like (ESL) cells biology of, 27–32 conditions of culture, 29–30 germ-line competence, 27–28 origin and properties, 28–29 pluripotency, 29 human, 31 therapeutic potential for, 32 in vertebrates (other species), 22–25, 23t Ethical considerations, 595 deliberate creation of embryos for research, 599 embryo research, opposition of, 596–597 embryos cloning, 599–601 donor issues, 602–603 research conduct, 603 human embryos destruction moral acceptability and, 595–596 for other people’s benefit, 597–598 President Bush on, 598 religious considerations, 598 overview, 595 transplantation research, 603 Ethyl nitrosourea (ENU), 349 European Medicines Agency (EMA), 631–632 Evans, Martin, Extra-embryonic endoderm (XEN) cells, 132–133 Extra-embryonic tissues role in patterning mouse embryo, 138–139 Eya1, 296t, 300 Index Eye, sensory epithelium of, 185 cells from optic vesicle, transdifferentiation in, 186–188 overview, 185 progenitor and stem cells in retina, 185–186 retinal neurospheres growth from ciliary margin of mammals, 191–193 rods and cones, 187 stem cell therapy in retina, 193–194 structure, 186f in vivo neurogenesis in posthatch chicken, 188–191 F FACS See Fluorescence activated cell sorting (FACS) Familial adenomatous polyposis (FAP), 352 FAP See Familial adenomatous polyposis (FAP) FDA See Food and Drug Administration (FDA) FDAMA (FDA Modernization Act), 613–614, 625 FDA Modernization Act (FDAMA), 613–614, 625 Federal Food and Drugs Act, 606– 607, 624–625 Fetal bovine serum (FBS), 257 Fetal hepatoblasts liver repopulation with, 317–318 Fetal stem cells from somatic tissue (FSSCs), 247–248 Fgf2 See Fibroblast growth factor (Fgf2) Fgf4 See Fibroblast growth factor (Fgf4) FGFs See Fibroblast growth factors (FGFs) Fiber degeneration, 529–530 Fibroblast growth factor (Fgf2), 81– 82, 302, 391–392, 571–572 Fibroblast growth factor (Fgf4), 132 in ES self-renewal, 84 Fibroblast growth factors (FGFs), 72, 164 Fibroblasts, 309–310 Fibronectin, 231 Ficoll™, 236–237 Filaggrin, 203–204 Fluorescence activated cell sorting (FACS), 275, 315, 503 Food, Drug, and Cosmetic Act (FD&C Act), 606–607 Food and Drug Administration (FDA) legislative history of, 606–607 medical use products defined, 610–611 regulatory process, 605 advisory committee meetings, 627–628 approval mechanisms and clinical studies, 611–613 laws, regulations, and guidance, 607–609 meetings with industry, professional groups, and sponsors, 613–614 organization and jurisdictional issues, 609–611 other communication efforts, 630–632 regulations and guidance for regenerative medicine, 614–624 research and critical path science, 628–630 standards development program, 624–626 Foot ulcers, 501–502 Forkhead family, of transcription factors, 363–364 foxd3, 396–397, 396t FoxD1 expression, 301–302 Freezing, hES cells, 430–431, 430f materials for, 431 medium, 430–431 protocol, 431 FSSCs See Fetal stem cells from somatic tissue (FSSCs) fs(1)Yb gene, 65 G GABA neurons, 174–175 Gap junctions, 519–520 Gastric inhibitory polypeptide (GIP)secreting K-cells, 498 Gastrointestinal tract, stem cells in, 343 bone marrow stem cells, 336f, 353–357 E2F transcription family, 364–366 epithelial cell lineages originate from common precursor cell, 346 gastrointestinal mucosa contains multiple lineages, 344–345 gastrointestinal neoplasms originate in stem cell populations, 366–370, 369f helix-forkhead family, 363–364 Hox genes, 363 mouse aggregation chimeras, 347–349, 348f multiple epithelial cell lineages derived from single stem cell, 351–353 multiple molecules regulate gastrointestinal development, proliferation, and differentiation, 360 niche maintained by ISEMFs in lamina propria, 358–360 overview, 343–344 single intestinal stem cells regenerating whole crypts, 346–347 somatic mutations in stem cells, 349–351, 350f WNT/β-catenin signaling pathway controls intestinal stem cell function, 361–363, 362f Gastrulation from implantation to, 132 Gbx2(Stra7), 396t GDNF See Glial cell line-derived neurotrophic factor (GDNF) Gene-replacement therapy, for MDs, 530–531 Genes’ importance during preimplantation development (mouse), 127–132, 128t–129t, 130t Genes regulating early kidney development, 296–301, 296t Gene therapy approaches in wound healing, 509 bone defects, 568 FDA regulations and guidance for, 620–621 peripheral blood stem cells for, 242–243 using NSCs, 475–476 667 668 Index Genomic reprogramming, 453 in germ cells, 454–460 during early development, 459–460 epigenetic reprogramming in, 456–458 of parental genomes, maternal inheritance and, 458–459 stem cell model for specification in mammals, 454–456, 455f overview, 453–454, 454f somatic nuclei, 460–462 in embryonic stem–somatic and embryonic germ–somatic cell hybrids, 460–461 nuclear transplantation, 460 Germ cells genomic reprogramming in, 454–460 during early development, 459–460 epigenetic reprogramming in, 456–458 of parental genomes, maternal inheritance and, 458–459 stem cell model for specification in mammals, 454–456, 455f to stem cells, 456 Germ-line competence, of ES and ESL cells, 27–28 Germ-line stem cells (GSCs), 60 See also Drosophila germ-line coordinate control of, SSCs maintenance and proliferation and, 64–66 GFP See Green fluorescent protein (GFP) GH See Growth hormone (GH) GIP-secreting K-cells See Gastric inhibitory polypeptide (GIP)secreting K-cells Glial cell line-derived neurotrophic factor (GDNF), 68–69, 294, 470 'Global’ cell replacement using NSCs, 478–480, 479f–480f Glomerular tuft, cells of, 303–305 Glutamate neurons, 175 Glycogen synthase kinase (GSK) 3-β, 378 Glycogen synthase kinase-3 (GSK3), 84, 388–389 Gonocytes, 67 Good Manufacturing Practice, 512 Gp130, 82–83 Graft failure, with CB, 157–159 Grb2–MAPK pathways, 82 Green fluorescent protein (GFP), 109, 206, 223, 242–243, 273–274 Growth factors’ role in mobilization of stem cells, 521–522 Growth hormone (GH), 571–572 GSCs See Germ-line stem cells (GSCs) GSK3 See Glycogen synthase kinase-3 (GSK3) GSK 3-β See Glycogen synthase kinase (GSK) 3-β Guidance documents, 607–609 See also Food and Drug Administration (FDA) Gurdon, John, Gut, to pancreas, 340 H HAC See Human artificial chromosome (HAC) HAECs See Human aortic endothelial cells (HAECs) Hair follicles, 47 cycle in adult mouse skin, 204, 204f mammalian, stem cell niches within, 71–73, 72f morphogenesis, 203, 205 Hair growth, 47 HBC-3 cells, 326 hBMSCs See Human bone-marrowderived stem cells (hBMSCs) HDAC inhibitor See Histone deacetylase (HDAC) inhibitor HDE (Humanitarian Device Exemption), 611–612 Heart AFS cells, 151–152 atrial niche in, 517, 519f CSCs distribution in, 517–520, 518f as self-renewing organ, 515–517, 516f Heart disease, stem cells and, 515 myocardial damage repair by nonresident primitive cells, 520–523, 522f by resident primitive cells, 523–526, 525f myocardial regeneration in humans, 526–527, 527f Heart regeneration See Cardiac regeneration Hedgehog (Hh) signal transduction pathway, 64–65 Heisenberg principle, 208 Hemangioblasts, 221, 227 Hematopoietic stem cells (HSCs), 8, 12, 35, 69, 95–96, 219, 227, 246, 255, 315, 497, 515–516 AFS cells, 152 blood formation in EBs, 220–221 blood formation in vitro with embryonic morphogens, promoting, 225–226 characterization, 219 EB-derived, transformation by BCR/ABL, 221–222 ES cells and, 219–220 hematopoietic engraftment with STAT5 and HOXB4, promoting, 222–225 as hepatocyte precursors, 321–322 mammalian, stem cell niches within, 69–70 for MDs treatment, 523–526 overview, 219–220 Hepatectomy, partial liver regeneration after, 312–313 Hepatic lobule, structure of, 309–310, 310f Hepatoblasts, fetal liver repopulation with, 317–318 Hepatocyte growth factor (HGF), 311, 345, 524, 574 Hepatocytes, 309–310, 544 bridge technique, 549–550 integration of, after transplantation, 546–548, 546b as liver-repopulating cells, 317 precursors, HSCs as, 321–322 progenitors, 315–316 MAPCs as, 322 prospective isolation of, by cell sorting, 325–327 Hepatocyte transplantation See also Orthotopic liver transplantation (OLT) in acute liver failure, 550–552 advantages, 544–545 clinical, 548–549 Index disadvantages, 545 integration of hepatocytes after, 546–548, 546b for metabolic liver disease, 552–556, 552b methods to improve engraftment and repopulation, 558–559 for non-organ transplant candidates, 556–558 novel uses, challenges, and future directions, 556–562 opportunities for, 549b sites selection for, 545–546 stem cells and alternative cell sources for, 559–562 hESC-derived keratinocytes (k-hESC), 511 hES cells See Human embryonic stem (hES) cells hES cells, derivation and maintenance of, 389–390, 409, 581 equipment, 410–411 of established cell cultures, 424–430 adaptation to trypsin, 424–430 freezing, 430–431 materials for, 431 medium, 430–431 protocol, 431 ICM dispersion, 423–424, 423f immunosurgery, 421 procedure of, 422–423 materials needed, 421–422 mitomycin C-treated PMEF plates, 421–422 mechanical passaging of colonies, 418–421 flame-pulled thin capillaries, 418–419 materials required, 418–421 mechanical dispersion, 420 mouth-controlled suction device, 419–420 PMEF plate preparation, 420 overview, 409–410 quality control, 433 reagents preparation and screening, 412–418 FBS, plasmanate and KSR, screening of, 415–416 media components, 413–414 media recipes, 414–415 mitomycin C treatment and plating, 417–418 PMEF feeders preparation, 416–418 screening media components, 415–416 setting up lab, 410–412 equipment, 410–411 quality assurance of equipment, 411–412 sterility, 412 thawing, 431–433 challenging situations, 432–433 preparation, 431–432 Heterogeneity, 502–503 hFLMPCs See Human fetal liver multipotent progenitor cells (hFLMPCs) HGF See Hepatocyte growth factor (HGF) Histone deacetylase (HDAC) inhibitor, 379–380 Histone marks, ES cell self-renewal and, 88 Histopaque™, 236–237 hMADS cells See Human, multipotent, adipose-derived stem (hMADS) cells hMSCs See Human mesenchymal stem cells (hMSCs) Hoechst dye, 468–469 Holoclones, 502–503 Hope vs hype, 640 Hopscotch (hop) gene, 63 Hoxa11, 396t Hox genes, 171, 363 HoxB4, hematopoietic engraftment with, 222–225 HPRT gene, 223 HSCs See Hematopoietic stem cells (HSCs) HUD (Humanitarian Use Device), 612 Human, multipotent, adiposederived stem (hMADS) cells, 537 Human aortic endothelial cells (HAECs), 231–232 Human artificial chromosome (HAC), 532–533 Human bone-marrow-derived stem cells (hBMSCs), 247–248 Human cellular therapies FDA regulations and guidance for, 616–618 Human embryo, 135–137 destruction moral acceptability and, 595–596 for other people’s benefit, 597–598 President Bush on, 598 religious considerations, 598 Human embryonic germ (EG) cells, 435 derivation of, 437–446 evaluation of cultures, 443 feeder layer, 442–444 initial disaggregation and plating, 438 PGCs growth media components, 444 subsequent passage of cultures, 438–441, 439f, 442f overview, 435–437 Human embryonic stem (hES) cells culture of, 391–393 derivation and maintenance of See hES cells, derivation and maintenance of discovery of, 3–4 neural differentiation of, 177–178 Human ESL cells, 31 Human Fertilisation and Embryology Authority, 601 Human fetal liver multipotent progenitor cells (hFLMPCs), 247–248 Humanitarian Device Exemption (HDE), 611–612 Humanitarian Use Device (HUD), 612 Human MAPCs isolation of, 249–251 differentiation ability of, in vitro, 249–250 in vivo engraftment of, 250 Human mesenchymal stem cells (hMSCs), 255–256 Human therapeutic cloning ethical considerations, 599–601 donor issues, 602–603 research conduct, 603 Human umbilical vein endothelial cells (HUVECs), 231–232 669 670 Index Huntington’s disease, 181–182 spinal cord injury and other motor neuron disorders, 181–182 HUVECs See Human umbilical vein endothelial cells (HUVECs) Hydroxyapatite (HA), 567 5-Hydroxymethylcytosine, 89 Hypoxia-ischemia, rodent models of, 483–484 I ICH See International Conference on Harmonization (ICH) ICM cells See Inner cell mass (ICM) cells ICM dispersion, 423–424, 423f, 426f Idebenone, 530 IGF See Insulin-like growth factor (IGF) IGF-1, 524, 571–572 IGF-1R See Insulin-like growth factor-1 receptors (IGF-1R) Ihh See Indian hedgehog (Ihh) IL-1Ra See Interleukin-1 receptor antagonists (IL-1Ra) Immunocytochemical staining, 445 Immunohistochemistry, EBs embedding and, 445–446 Immunoisolation, 257–258 Immunosurgery hES cells, 421–423 Implantation to gastrulation, 132 maternal vs embryonic factors, 137–138 Indian hedgehog (Ihh), 225–226 Indoleamine 2, 3-dioxygenase (IDO), 137–138 Induced pluripotent stem cells (iPSCs), 5, 247, 373, 409, 539 banking, 382 from CB, 160 direct fate switch, 384 generation of, 375–379 cell source, 378–379 culture conditions and cell signaling, 378 reprogramming factors, 375–377 transduction methods, 377–378 induction, molecular mechanisms in, 379–381 epigenetics, 379–380 microRNAs, 380–381 medical application, 383–384 safety concerns for, 382–383 recapitulation of disease ontology and drug screening, 381–382 Inner cell mass (ICM) cells, 122, 245, 387 development to epiblast in mouse, 133–135, 135f Inner ear development and regeneration of tissues derived from, 194–196 Institutional Review Board (IRB), 612–613 Insulin non-β-cells engineering to produce, 498–499 synthesis by constitutive release, 499 Insulin-like growth factor (IGF), 164, 231, 275–276 Insulin-like growth factor-1 receptors (IGF-1R), 524 Insulin-producing cells See also Islet cells adult stem-progenitor cells as source, 491, 492t bone marrow cells as source of, 497 liver as source of, 497–498 shortage of, 491 Integra, 506 Interfollicular epidermis mammalian, stem cell niches within, 74–75, 75f Interleukin-4 (IL-4), 573 Interleukin (IL)-6 cytokine family, 82 Interleukin-1 receptor antagonists (IL-1Ra), 573 International Conference on Harmonization (ICH), 609 International Society for Cellular Therapy, 4, 255–256 International Society of Stem Cell Research, International Standards Organization (ISO), 626 Intervertebral disc (IVD) regeneration by MSCs, 262–263 Intestinal crypts, 49–50, 347–349, 351–353, 364–366 Intestinal stem cells, 49–51, 52f–53f, 361–363, 362f AFS cells, 154 cancer incidence, 53b regenerate whole crypts containing all epithelial lineages, 346–347 transcription factors define regional gut specification and, 363–366 Intestinal subepithelial myofibroblasts (ISEMFs), 345 niche maintained by, in lamina propria, 358–360 Intra-islet progenitors, 336–337 Investigational Device Exemption (IDE), 612–613 Investigational New Drug (IND) application, 612–613 In vitro expansion of EPCs, 232–233 of MSCs, 236–237 In vitro fertilization (IVF), 597 IPE See Iris-pigmented epithelium (IPE) iPSCs See Induced pluripotent stem cells (iPSCs) Iris, 187–188 Iris-pigmented epithelium (IPE), 112–113 ISEMFs See Intestinal subepithelial myofibroblasts (ISEMFs) Islet cells See also Insulin-producing cells ductal origin of, arguments favoring, 494–495, 494f new, formed by neogenesis, 493 non-duct cells as precursors of , arguments favoring, 495–496 transdifferentiation of nonislet cells to, 496–497 Ito cells, 309–310 IVD See Intervertebral disc (IVD) IVF See In vitro fertilization (IVF) J JAK-STAT pathway See Janus kinase–Signal Transducer and Activator of Transcription (JAK–STAT) pathway Janus kinase–Signal Transducer and Activator of Transcription (JAK–STAT) pathway, 63, 82 Jefferson, Thomas, 641 Judgment, 636 Jumonji-family proteins, 88 Index The Jungle, 606–607 Juvenile Diabetes Research Foundation (JDRF), 637, 637f, 639 K Kennedy, John F., 642 Keratinocyte growth factor (KGF), 345 Keratinocytes, 70–71, 203–204, 502, 510 differentiation, markers of, 503, 504f Keratinocyte stem cells (KSCs), 502–503 k-hESC See hESC-derived keratinocytes (k-hESC) Kidney development additional cell lineages, establishment of, 301–305 epithelia vs stroma, 301–303 glomerular tuft, cells of, 303–305 AFS cells, 152–153 anatomy of, 291–296, 292f genes that control early, 296–301, 296t nephrogenic field determination, 297–299, 297f time of metanephric induction, 299–301 Klein, Robert, Klf4, 247, 375–376 in ES cell self-renewal, 85 KSCs See Keratinocyte stem cells (KSCs) Kupffer cells, 309–310 L Label-retaining cells (LRCs), 206 Lamina propria niche maintained by ISEMFs in, 358–360 Laws and regulations, 607–609 See also Food and Drug Administration (FDA) Lef1-Tcf family, 73 Leukemia inhibitory factor (LIF), 24–25, 29–30, 81–82, 390, 399–400 in ES cell self-renewal, 82–83 Leukocytes, 309–310 LIF See Leukemia inhibitory factor (LIF) LIF/STAT3 pathway, 395 Ligaments orthopedic applications of stem cells, 575–578 lim1, 296t LIM mineralization protein-1 (LMP-1), 578–579 LIN28, 375–376 Lineage selection neural differentiation and, 177 Liver adult mammalian, organization and functions of, 309–311 functions, 310–311 hepatic lobule, structure of, 310f normal tissue turnover, cells for, 311–312 to pancreas, 109–111, 338–339 repopulation, 316–324, 316t animals models for, 316t hepatocytes for, 317 See also Hepatocytes nonhepatocytes for, 317–324 See also Nonhepatocytes, as liver-repopulating cells as source of insulin-producing cells, 497–498 stem cells See Liver stem cells Liver disease, cell therapy for, 543 background studies, 545–546 current treatments for, 544b hepatocyte bridge, 549–550 hepatocyte transplantation in acute liver failure, 550–552 clinical, 548–549 integration of hepatocytes after, 546–548, 546b for metabolic liver disease, 552–556, 552b methods to improve engraftment and repopulation, 558–559 for non-organ transplant candidates, 556–558 novel uses, challenges, and future directions, 556–562 opportunities for, 549b sites selection for, 545–546 stem cells and alternative cell sources for, 559–562 overview, 543–545 Liver stem cells, 311–327 defined, 311 for hepatocyte and bile duct epithelial phenotypes production in vitro, 324–327 isolation of hepatocyte progenitors by cell sorting, 325–327 for normal liver tissue turnover, 311–312 for progenitor-dependent regeneration, 313–316, 314t other hepatocyte progenitors, 315–316 oval cells, 313–315 for regeneration after partial hepatectomy, 312–313 transplantable liver-repopulating cells, 316–324, 316t hepatocytes as, 317 nonhepatocytes as, 317–324 Long QT syndrome, 381 LRCs See Label-retaining cells (LRCs) Lung AFS cells, 153–154 Lurie, Carol, 637f M MABs See Mesoangioblasts (MABs) Macrophage inhibitory protein-1α (MIP-1α), 97–98 Macroscopic clonal regeneration techniques, 50–51 Mammalian tissues, stem cell niches within epidermis, 70–71 hair follicle, 71–73, 72f hematopoietic system, 69–70 interfollicular epidermis, 74–75, 75f neural stem cells, 76–77 testis, 67–69, 68f Mammography Quality Standards Act (MQSA), 609–610 MAPCs See Multipotent adult progenitor cells (MAPCs) Markers of BM-derived MSCs, 236 of keratinocytes differentiation, 503, 504f Marrow-isolated adult multilineage inducible (MIAMI) cells, 247–248 Maternal factors vs embryonic factors, 137–138 671 672 Index Maternal inheritance and reprogramming of parental genomes, 458–459 Matrix metaloprotease-2 (MMP-2), 548 MDR1, 515–516 MDs See Muscular dystrophies (MDs) Mechanical dispersion, 420 Mechanical passaging, of hES cells colonies, 418–421 flame-pulled thin capillaries, 418–419 materials required, 418–421 mechanical dispersion, 420 mouth-controlled suction device, 419–420 PMEF plate preparation, 420 Medial collateral ligament (MCL) injuries, 575–576 Mediator complex ES cells self-renewal, 87–88 Medical Devices Amendments, 607 Medical products approval pathways for, 611–613 FDA's definitions, 610–611 Medicine, stem cells applications in, MEFs See Mouse embryonic fibroblasts (MEFs) Memoranda of Understanding (MOU) agreements, 631 Meniscus orthopedic applications of stem cells, 573–575 mESCs See Mouse embryonic stem cells (mESCs) Mesenchymal stem cells (MSCs), 142, 227, 565–566 AFMSCs See AF mesenchymal stem cells (AFMSCs) in bone formation, 567, 569 chondrogenesis, 570–571 defined, 255–256 in gene therapy strategies for ligamentous and tendon injuries, 576 identification and isolation of, 236 immunomodulatory effects, 258–259 in vitro expansion, 236–237 isolation techniques, 257–258 for MDs, 537–538 non-skeletal tissue regeneration by, 263–265 overview, 236–237 skeletal tissue regeneration by, 259–263 bone, 259–261 cartilage, 261–262 intervertebral disc, 262–263 tendon, 262 stem cell nature of, 256 therapeutic applications, 241–242 tissues having, 256–257 Mesoangioblasts (MABs) for MDs, 538–539 Metabolic liver disease hepatocyte transplantation for, 552–556, 552b Metanephric induction genes that function time of, 299–301 Metaplasia, 107–108 Barrett’s, 112 defined, 107 study of, 107–108 theoretical implications, 107 5-Methylcytosine, 88–89 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), 481–483 MIAMI cells See Marrow-isolated adult multilineage inducible (MIAMI) cells Mice developmental potency of early embryo, 126–127 extra-embryonic tissues role in patterning embryo, 138–139 inner cell mass development to epiblast, 133–135, 135f liver cell lines, 326 preimplantation development, 121, 123f axis specification during, 125–126 genes important during, 127–132, 128t–129t, 130t stages of, 125t primitive endoderm cells, 132–133 trophectoderm cells, 132–133 Michael J Fox Foundation for Parkinson's Research, 639 Microfracture technique, 570 MicroRNAs (miRNAs) in ES cell self-renewal, 89 iPSCs induction and, 380–381 Midbrain dopaminergic neurons, 172 MIP-1α See Macrophage inhibitory protein-1α (MIP-1α) miRNAs See MicroRNAs (miRNAs) Mitomycin C treated PMEF plates, preparation of, 421–422 treatment and plating, hES cells derivation and maintenance, 417–418 Mitosis, 81 MMLV (Moloney murine leukemia virus)-based retroviral vectors, 377–378 MMP-2 See Matrix metaloprotease-2 (MMP-2) MNCs See Mononuclear cells (MNCs) Models of activation skin stem cells, 209–212, 210f Molecular fingerprint, of bulge– putative stem cell markers, 212–214 Moloney murine leukemia virus (MMLV)-based retroviral vectors, 377–378 Monocytes, 258 Mononuclear cells (MNCs), 257 Moore, Mary Tyler, 639f, 642f Moral acceptability/permissibility human embryos destruction for research, 595–596 Morula, 121–122, 123f Motor neurons, 173–174 MOU (Memoranda of Understanding) agreements, 631 Mouse See Mice Mouse embryo aggregation chimeras, 346–347, 348f Mouse embryonic fibroblasts (MEFs), 375–376 Mouse embryonic stem cells (mESCs) culture of, 390–391 derivation of, 388–389 neural differentiation of, 167–177 by default, 171 ES-cell-derived glia, derivation of, 176–177 Index ES-cell-derived neurons, derivation of, 171–176 lineage selection, 177 neural induction, 168–171, 169f MPS VII See Mucopolysaccharidosis type VII (MPS VII) MPTP See 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) MQSA See Mammography Quality Standards Act (MQSA) MRF4, 267–268 MRFs See Muscle regulatory factors (MRFs) MRP2 See Multidrug resistance protein2 (MRP2) MSCs See Mesenchymal stem cells (MSCs) Mucopolysaccharidosis type VII (MPS VII), 475 Multidrug resistance protein2 (MRP2), 547–548 Multipotent adult progenitor cells (MAPCs), 227, 245, 265 greater potency of (mechanisms), 250–251 as hepatocyte progenitors, 322 history, 246–247 human, isolation of, 249–251 differentiation ability of, in vitro, 249–250 in vivo engraftment of, 250 recent developments, 251–252 rodent contribution to chimeras, 250 isolation of, 248–249 Multipotent skin stem cells cell signaling in, 214–216, 216f Musashi-1, 51, 468–469 Muscle regulatory factors (MRFs), 267–268 Muscle stem cells (MuSCs) functional and biochemical heterogeneity among, 271–273 niches, 275–277 overview, 267–268 satellite cell, 268–271 Muscular dystrophies (MDs) stem cells for treatment of, 529 future perspectives, 540–541 HSCs, 533–537 mesoangioblasts, 538–539 MSCs, 537–538 myoblast transplantation, 531–533 non-HSCs derived from mesoderm, 537–539 overview, 529–531 pluripotent stem cells for future cell-based therapies, 539–540 unconventional myogenic progenitors, 533–539, 534t, 535f therapeutic approaches, 530–531 cell therapy, 531 gene-replacement therapy, 530–531 mutation-specific strategies, 530 Mutation-specific strategies for MDs, 530 Mybl2, 91 Myc, in ES cell self-renewal, 86 Myf-5, 267–268 Myoblasts, 270–271 transplantation, 531–533 Myocardial damage, repair of by nonresident primitive cells, 520–523, 522f by resident primitive cells, 523–526, 525f Myocardial regeneration, in humans, 526–527, 527f Myocardium, 285 MyoD, 267–268 Myofibers, 267–268 Myogenic progenitors, unconventional for MDs treatment, 533–539, 534t, 535f HSCs, 533–537 mesoangioblasts, 538–539 MSCs, 537–538 non-HSCs derived from mesoderm, 537–539 pluripotent stem cells for future cell-based therapies, 539–540 Myogenin, 267–268 Myosin heavy chain (MyHC) isoforms, 267–268 N Nanog, 245, 247, 395 in ES cell self-renewal, 85 National Health Interview Survey, 569–570 National Heart, Lung and Blood Institute (NHLBI), 631 National Institute of Diabetes Digestive and Kidney Diseases, 638 National Institute of Neurological Disorders and Stroke (NINDS), 631 National Institutes of Health (NIH), 638 National Research Council, 596–597 Natural killer (NK) cells, 258 NDA (New Drug Application), 611–612 Neovascularization physiological and pathological, EPCs role in, 233–235 Nephric duct, 292–293, 293f Nephrogenic field, genes that determine, 297–299, 297f Nerve growth factor (NGF), 470 Nervous system, 163 demyelination, 182–183 developmental perspectives, 178–179 Huntington’s disease, 181–182 spinal cord injury and other motor neuron disorders, 181–182 neural development, 164–165 neural differentiation of human and nonhuman primate ES cells, 177–178 neural differentiation of mouse ES cells, 167–177 by default, 171 ES-cell-derived glia, derivation of, 176–177 ES-cell-derived neurons, derivation of, 171–176 lineage selection, 177 neural induction, 168–171, 169f neural stem cells, 166–167 overview, 163–164 Parkinson’s disease, 179–180 stroke, 182 therapeutic perspectives, 179 Nestin, 336–337, 468–469 Neural crest differentiation, 175–176 Neural development, 164–165 Neural differentiation, of human and nonhuman primate ES cells, 177–178 673 674 Index Neural differentiation, of mouse ES cells, 167–177 by default, 171 ES-cell-derived glia, derivation of, 176–177 astrocytes, 177 oligodendrocytes, 176 ES-cell-derived neurons, derivation of, 171–176 GABA neurons, 174–175 glutamate neurons, 175 midbrain dopaminergic neurons, 172 motor neurons, 173–174 neural crest differentiation, 175–176 other neuronal and neural subtypes, 175 serotonergic neurons, 173 lineage selection, 177 neural induction, 168–171, 169f EB-based protocols, 168–170 stromal feeder-mediated neural induction, 170–171 Neural induction EB-based protocols, 168–170 stromal feeder-mediated, 170–171 Neural stem cells (NSCs), 7–8, 96–97, 467 cell replacement using, 476–478 defined, 468–470 development of, 12–13 gene therapy using, 475–476 ‘global’ cell replacement using, 478–480, 479f–480f as glue that holds multiple therapies together, 484–485 inherent mechanism for rescuing dysfunctional neurons, 481–484, 482f–483f mammalian, stem cell niches within, 76–77 overview, 467–468 therapeutic potential of, 470–475, 471f, 474f–475f Neurogenesis, 76 ear, in postembryonic animals, 196–199 proliferation after destruction of cells, 198–199 proliferation in normals (after growth factor treatment), 196–198, 197f transcription factor requirements, 199 retinal, in posthatch chicken, 188–191 Neuronal progenitor cell (NPC), 96–97 Neurons to pancreas, 339–340 Neurotrophin-3 (NT-3), 470 New Drug Application (NDA), 611–612 NGF See Nerve growth factor (NGF) Niches atrial, in heart, 517, 519f defined, 517 maintained by ISEMFs in lamina propria, 358–360 stem cell See Stem cell niches NISH See Nonisotopic in situ hybridization (NISH) Nitric oxide (NO), 230–231, 233, 530 NK cells See Natural killer (NK) cells Nkx2-5, 287 NMDA See N-methyl-D-aspartate (NMDA) N-methyl-D-aspartate (NMDA), 175 Non-β-cells engineering, to produce insulin, 498–499 Non-duct cells as islet precursor cells, arguments for, 495–496 Non-hematopoietic cells from mesoderm, for MDs, 537–539 mesoangioblasts, 538–539 MSCs, 537–538 Nonhepatocytes, as liverrepopulating cells, 317–324 bone-marrow-derived progenitors, 321–324 HSCs, 321–322 MAPCs, 322 mechanism for formation of, 324 physiologic significance of, 322–324, 323f fetal hepatoblasts, 317–318 oval cells, 318 pancreatic progenitors, 318–320, 320f Nonhuman primate ES cells neural differentiation of, 177–178 Nonislet cells transdifferentiation to islet cells, 496–497 Nonisotopic in situ hybridization (NISH), 352 Non-NMDA receptors, 175 Non-organ transplant candidates hepatocyte transplantation for, 556–558 Nonresident primitive cells myocardial damage repair by, 520–523, 522f Non-skeletal tissue regeneration by MSCs, 263–265 Notch, CKIs and in cell cycle regulation, 104 Notch–Delta signaling pathway, 365f Notch signaling, 74–75 NPC See Neuronal progenitor cell (NPC) NSCs See Neural stem cells (NSCs) NT-3 See Neurotrophin-3 (NT-3) Nuclear receptors in ES cell self-renewal, 87 Rex1, 87 Stat3, 87 Nuclear transplantation, 460 O Oct3/4, 375–376 in ES cell self-renewal, 84–87 Oct4, 245, 247, 395 at morula and blastocyst stages, 131–132, 131f Oculo-Pharyngeal Muscular Dystrophy, 531–532 Office of Combination Products (OCP), FDA’s, 611 Oligodendrocytes, 176 OLT See Orthotopic liver transplantation (OLT) Oocytes genomic reprogramming in, 3, 457–458 Open tissue engineering systems, 583–586, 585f, 586f Optic vesicle transdifferentiation in cells generates from, 186–188 Organ of Corti, 194–196 Index Ornithine transcarbamylase deficiency (OTC), 544–545 Orthopedic applications of stem cells, 565 bone, 566–569 cartilage, 569–573 ligaments and tendons, 575–578 meniscus, 573–575 overview, 565–566 spine, 578–579 Orthotopic liver transplantation (OLT), 543, 549–551, 556–557 See also Hepatocyte transplantation Osteoarthritis, 569–570 Osteoblasts, 567 Osteogenesis imperfecta (OI), 569 Osteogenic protein-1 (OP-1), 578 Osteoporosis, 569 OTC See Ornithine transcarbamylase deficiency (OTC) O2 tension, 378 Otic progenitors, in vitro expansion of, 199–201 Oval cells, 313–315 liver repopulation with, 318 of rat liver, 326 Ovary, Drosophila germ-line stem cell niches in, 60–63, 61f Overexpression selection of method of, 115–116 P P21’s roles in cell cycle regulation, 100–101 P27’s roles in cell cycle regulation, 101–102 PA6 cells, 172 PANC1, 494–495 Pancreas embryonic development of, 330–333, 331f gut to, 340 liver to, 338–339 neurons to, 339–340 Pancreas-derived cell lines, 327 Pancreas-derived multipotent precursors (PMPs), 247–248 Pancreatic progenitors liver repopulation with, 318–320, 320f Pancreatic stem cells, 329 definition of stem cells and of progenitor cells, 329–330 forcing other tissues to adopt pancreatic phenotype, 338–340 gut to pancreas, 340 liver to pancreas, 338–339 neurons to pancreas, 339–340 in vitro studies, 340–341 overview, 329 progenitor cells during embryonic development of pancreas, 330–333, 331f progenitor cells in adult pancreas, 333–338 acini, 336–337 bone marrow, 337 ducts, 334–335 evidence from cell dynamics, 333–336 histology of, 335f intra-islet progenitors, 336–337 lineage labeling, 336f other evidence for, 337–338 Paneth cells, 50 Parental genomes reprogramming of, maternal inheritance and, 458–459 Parietal endoderm (PE), 132–133 Parkinson’s disease, 172, 179–180 stem cell research, 636–637 Partial hepatectomy liver regeneration after, 312–313 Passage culture embryonic stem cell, 403 Patient stories, 643b–644b Pax2, 296t, 297–298, 297f Pax8, 297–298 Pax2/Pax8, 296t PCR analysis See Polymerase chain reaction (PCR) analysis PDGF See Platelet-derived growth factor (PDGF) PDGFR See Platelet-derived growth factor receptor (PDGFR) pdgf(r), 296t Pdx1 protein, 494–495 PE See Parietal endoderm (PE) PECAM-1, 231–232 Peripheral blood stem cells, 227 EPCs, 229–236 identification and isolation of, 229–232, 230t role in physiological and pathological neovascularization, 233–235 in vitro expansion of, 232–233 future perspectives, 243 MSCs, 236–237 identification and isolation of, 236 in vitro expansion, 236–237 overview, 227–228 therapeutic applications, 237–243 EPCs, 237–241 for gene therapy, 242–243 MSCs, 241–242 types and source of, 228–229 mobilization of bone marrow cells, 228–229 Peripheral nervous system (PNS), 163 See also Nervous system Peroxisome, 311 PFIC See Progressive familial intrahepatic cholestasis (PFIC) PGCs See Primordial germ cells (PGCs) P-glycoprotein, 282–283 PHA See Phytohemagglutinin (PHA) Phenotypes of cell, ability to change, 115–117 bone marrow to other cell types, 113 cell type selection, 115 characterization of new phenotype, 116 dedifferentiation as prerequisite for transdifferentiation, 114–115 factor modification, identify need for, 116 metaplasia See Metaplasia overexpression method, selection of, 115–116 potential factors identification to induce transdifferentiation, 115 regeneration, 112–113 transdifferentiation See Transdifferentiation transdifferentiation activity test in other cell types, 116 Phenylketonuria (PKU), 557 Phosphatidylinositol-3-OH kinase (PI3K)–Akt pathway, 82, 91 Photoreceptors (PRs), 186–187 675 676 Index Phytohemagglutinin (PHA), 258–259 PICM-19, 326 Pig cell lines, 326 PI3K-Akt pathway See Phosphatidylinositol-3-OH kinase (PI3K)–Akt pathway Piwi protein, 62–63 PKU See Phenylketonuria (PKU) PLA cells See Processed lipoaspirate (PLA) cells Placental growth factor (PlGF), 228–229 Plasticity, degree of for stem cells, 41–42 Platelet-derived growth factor (PDGF), 230–231, 304–305, 574 Platelet-derived growth factor-α (PDGF-α), 345 Platelet-derived growth factor receptor (PDGFR), 304–305 PlGF See Placental growth factor (PlGF) Pluripotency See also Totipotency concept of, 41, 247–248 defined, 81–82 of ES and ESL cells, 29 molecular control of, 395–397 Pluripotent stem cells (PSCs) ES cells, 245–246 for future cell-based therapies, 539–540 induction of, 3–4 self-renewal of, 81–90 See also ES cells, self-renewal of ES cell, molecular mechanisms, 82–90 from vertebrate embryos, 19 EG cells, 25–26, 26t ES cells, biology of, 27–32 ESL cells, biology of, 27–32 ESL cells in other species, 22–25, 23t future challenges, 26–27 overview, 19–27 stem cell therapy, 32–34 terminology, 21–22 PMA (Premarket Approval Application), 611–612 PMEF feeders See Primary mouse embryo fibroblast (PMEF) feeders PMPs See Pancreas-derived multipotent precursors (PMPs) PNS See Peripheral nervous system (PNS) pod-1, 296t Podocyte cells, 303 Polycomb, 458 Polycomb group complex (PRC) 2, 88 Polymerase chain reaction (PCR) analysis, 551–552 Polytetrafluoroethylene (PTFE), 238–239 Postnatal tissue-specific stem cells, 246–247 Potency, stem cells, 8, 21–22 PRC2 See Polycomb group complex (PRC) Precursor cells, defined, 492–493 Preimplantation blastocyst, 28 Preimplantation development (mouse), 121, 123f axis specification during, 125–126 genes important during, 127–132, 128t–129t, 130t stages of, 125t Premarket Approval Application (PMA), 611–612 Pre-mesenchymal stem cells (preMSCs), 247–248 Pre-MSCs See Pre-mesenchymal stem cells (pre-MSCs) Primary mouse embryo fibroblast (PMEF) feeders preparation, hES cells derivation and maintenance, 416–418, 420 Primitive endoderm cells of mouse, 132–133 Primordial germ cells (PGCs), 9–11, 10f–11f, 62–63, 67, 435–437, 454 vs ES Cells, 437 growth media components, 444 Processed lipoaspirate (PLA) cells, 567 Progenitor cells, in adult pancreas, 333–338 acini, 336–337 bone marrow, 337 ducts, 334–335 evidence from cell dynamics, 333–336 histology of, 335f intra-islet progenitors, 336–337 lineage labeling, 336f other evidence for, 337–338 from CB, 157 defined, 329–330, 492–493 during embryonic development of pancreas, 330–333, 331f in retina, 185–186 Progenitor-dependent liver regeneration, 313–316 hepatocyte progenitors, 315–316 oval cells, 313–315 Progressive familial intrahepatic cholestasis (PFIC), 553 PRs See Photoreceptors (PRs) PSCs See Pluripotent stem cells (PSCs) PTFE See Polytetrafluoroethylene (PTFE) Public Health Service Act (PHS Act), 607 Q Quality assurance of equipment, hES cells derivation and maintenance, 411–412 Quality control hES cells, 433 R RA See Retinoic acid (RA) RARs See Retinoic acid receptors (RARs) Recombinant human bone morphogenetic protein-2 (rhBMP-2), 568 Regeneration See Tissue regeneration Regenerative medicine, FDA regulations and guidance for, 614–624 case study (cell-scaffold wound healing skin constructs), 622–624 clinical development plan, 624 preclinical development plan, 623–624 cell-scaffold combination products, 621–622 gene therapy, 620–621 human cells and tissues intended for transplantation, 614–616 Index human cellular therapies, 616–618 xenotransplantation, 618–619 Religious considerations human embryos destruction, 598 Renal stem cells, 305–307, 306f Reprogramming, genomic See Genomic reprogramming Reprogramming factors iPSCs generation, 375–377 Request for Designation (RFD), 611 Research, stem cell, conduct of, 603 deliberate creation of embryos for, 599 ethical considerations, 595 FDA research and critical path science, 628–630 new therapies, 642 Parkinson’s disease, 636–637 postponing hES cell research, 596–597 promise of, 636–637 religious considerations, 598 therapeutic cloning research, 599–601 transplantation research, 603 type diabetes, 636–637 Resistance, susceptibility vs., 30, PBt Retina neurospheres growth from ciliary margin of mammals, 191–193 progenitor and stem cells in, 185–186 stem cell therapy in, 193–194 in vivo neurogenesis in posthatch chicken, 188–191 Retinal-pigmented epithelium (RPE), 112–113, 186–187 Retinoblastoma (Rb) pathway CKIs and, in cell cycle regulation, 102–103 Retinoic acid (RA), 168 Retinoic acid receptors (RARs), 302–303 Reverse transcriptase polymerase chain reaction (RT-PCR), 272–273 Rex1, 245, 396t in ES cell self-renewal, 87 RFD (Request for Designation), 611 rhBMP-2 See Recombinant human bone morphogenetic protein-2 ( rhBMP-2) RNA-binding protein Esg-1 (Dppa5), 396–397 Rodent MAPCs contribution to chimeras, 250 isolation of, 248–249 Rods, in eye, 187 ROSA26, 222 RPE See Retinal-pigmented epithelium (RPE) RT-PCR See Reverse transcriptase polymerase chain reaction (RT-PCR) S SAGE See Serial analysis of gene expression (SAGE) Sall1, 396t Sall2, 396t Satellite cell, 268–271 evidences for, 269–270 Sca-1, 285, 515–516 Scale-up of ES cells in tissue engineering, 588–590 SCF See Stem cell factor (SCF) Schwarzenegger, Arnold, SDF-1, 230–231 Sebaceous gland (SG), 204 Selective DNA segregation, 51 Self-renewal, stem cell, 7–8 defined, 81 mechanisms, 81 of pluripotent stem cells, 81–90 See also ES cells, self-renewal of ES cell, molecular mechanisms, 82–90 prevention of differentiation, 90–91 proliferation, maintenance of, 91–92 telomere length, maintenance of, 92 X chromosome inactivation, 92–93 Serial analysis of gene expression (SAGE), 186–187 Serotonergic neurons, 173 Sertoli cells, 68–69 Shh signaling pathway See Sonic Hedgehog (Shh) signaling pathway Sinclair, Upton, 606–607 Single-chain insulin, advantage of, 499 Skeletal muscles AFS cells, 151 composition, 267–268 unorthodox origins of, 273–275 Skeletal muscle stem cells, 267 See also Muscle stem cells (MuSCs) overview, 267–268 satellite cell, 268–271 Skeletal tissues regeneration by MSCs, 259–263 bone, 259–261 cartilage, 261–262 intervertebral disc, 262–263 tendon, 262 Skin See also Skin stem cells composition, 203–204 tissue engineering of, 509–511 Skin-derived progenitors (SKPs), 247–248 Skin stem cells, 45–49, 46f, 49f bulge as residence of, 206–209 cell signaling in multipotent, 214–216, 216f future perspective, 217–218 models of activation, 209–212, 210f molecular fingerprint of bulge– putative stem cell markers, 212–214 mouse (overview), 203–205 Skin ulcers, 501–502 stem cells in, 507–508, 508f ES cells, 511–513 gene therapy approaches in wound healing, 509 recent and future developments, 509–513 tissue engineering, 509–511 SKPs See Skin-derived progenitors (SKPs) Slit diaphragm, 303–304 SMA See Spinal muscular atrophy (SMA) Small-intestinal crypts cell lineage for, 45, 45f SMN1 gene See Survival motor neuron (SMN1) gene Somatic mutations, 349–351 Somatic nuclei, genomic reprogramming in, 460–462 in embryonic stem–somatic and embryonic germ–somatic cell hybrids, 460–461 nuclear transplantation, 460 677 678 Index Somatic stem cell (SSCs) maintenance and proliferation, coordinate control of germline stem cell and, 64–66 Sonic Hedgehog (Shh) signaling pathway, 72, 164–165, 225–226 Sox2, 245, 375–376, 396t in ES cell self-renewal, 84–85 Sox3, 164 Spare conceptuses, 31 Spermatogonial stem cells, 35, 67–68, 247 S-phase toxin, 95–96 Spinal muscular atrophy (SMA), 381 Spine orthopedic applications of stem cells, 578–579 Spleen colonies, 39 SSCs See Somatic stem cell (SSCs) SSEA-1 See Stage-specific antigen I (SSEA-1) SSEDs (Summaries of Safety and Effectiveness Data), 623 Stage-specific antigen I (SSEA-1), 236 Standards development program (FDA), 624–626 Stat3, 390–391 in ES cell self-renewal, 87 Stat5, hematopoietic engraftment with, 222–225 Stellate cells, 309–310 Stem cell factor (SCF), 315 Stem cell niches, 59 concept of, 59 in Drosophila germ-line, 60 ovary, 60–63, 61f testis, 63–64 germ-line coordinate control of, and and somatic stem cell maintenance and proliferation, 64–66 hypothesis, 59–60 within mammalian tissues epidermis, 70–71 hair follicle, 71–73, 72f hematopoietic system, 69–70 interfollicular epidermis, 74–75, 75f neural stem cells, 76–77 testis, 67–69, 68f muscle stem cells, 275–277 structural components, 66–67 Stem cell(s) See also specific types adult, ontogeny of, 11–13 from amniotic fluid See Amniotic fluid applications in medicine, from CB, 157 cell cycle regulators in See Cell cycle regulators, in stem cells challenges to use of, 5–6 characterization, 13–14 clonality, 8–9 defined, 7, 9, 40–42, 256, 267, 329–330, 492–493 degree of plasticity for, 41–42 vs dividing transit cells, 42–43 of early embryo, 9–11, 10f–11f elusive cardiac, 284–286 to germ cells, 455–456 growth of sector, organizations in, heart disease and See Heart disease, stem cells and hierarchically organized populations, 42–45, 44f, 45f identification, 13–14 isolation, 13–14 liver, 311–327 molecular processes, 15–16 origin/lineage of, orthopedic applications of See Orthopedic applications of stem cells potency, proliferation, maintenance of, 91–92 research See Research, stem cell in retina, 185–186 self-renewal, 7–8 See also Selfrenewal, stem cell technology, origins of, 3–4 in tongue, 51–53, 54f Stem cell therapy, 32–34 cell-cycle status and, 32 in ear, 201 embryonic vs adult stem cells, 33–34 function of donor cells and, 33 potential hurdles, 32–33 in retina, 193–194 therapeutic cloning, 33 Stemness, 15–16 See also Stem cell(s) defined, 15–16 Steroids, for DMD treatment, 530 Stevens, Barry Pierce, 19 Stevens, Leroy, 19 Streaming liver, 311–312 Stroke, 182, 477–478 Stromal-cell-derived factor-1, 230–231 Stromal feeder-mediated neural induction, 170–171 Stromal lineages, metanephric mesenchyme vs epithelial lineage, 301–303 Stromal vascular fraction (SVF), 257 Subchondral drilling, 570 Subventricular zone (SVZ), 475 Summaries of Safety and Effectiveness Data (SSEDs), 623 Survival motor neuron (SMN1) gene, 381 Susceptibility vs resistance to ES cell derivation, 30, PBt SVF See Stromal vascular fraction (SVF) SVZ See Subventricular zone (SVZ) T TA cells See Transit-amplifying (TA) cells TA muscle See Tibialis anterior (TA) muscle Tbx3 in ES cell self-renewal, 85–86 Tbx-5, 287 T-cell factor (Tcf) family, 86 T-cells, 258–259 Tcf3 in ES cell self-renewal, 86 Tcf family See T-cell factor (Tcf) family TE cells See Trophectoderm (TE) cells Telogen follicle, 47 Telomere length, maintenance of, 92 TEM See Transmission electron microscopy (TEM) Tendons orthopedic applications of stem cells, 575–578 regeneration by MSCs, 262 Teratocarcinomas, 35–36, 387, 404–405 TERF1, 396t Index TERF2, 396t TERT, 396t Testis Drosophila, germ-line stem cell niches in, 63–64 mammalian, stem cell niches within, 67–69, 68f Tet1, 89 TFs See Transcription factors (TFs) TGF-1, 571–572 TH See Tyrosine hydroxylase (TH) Thawing, hES cells, 430f, 431–433 challenging situations, 432–433 preparation, 431–432 Therapeutic cloning, 33 ethical considerations, 599–601 donor issues, 602–603 research conduct, 603 Thomson, James, 3–4 Thrombin, 286–287 Tibialis anterior (TA) muscle, 269 Tissue engineering EPCs in, 238–239, 240f ES cells in, 581 closed systems, 586–587 combinations of cells and materials, using, 583–587 desired cell types for therapy, isolating, 588 directing differentiation of, 587–588 isolated cells/cell substitutes as cellular replacement parts, 582–583 limitations, 590–591 limitations and hurdles of using, 587–591 open systems, 583–586, 585f, 586f overview, 581 principles and perspectives, 581–587 scale-up of, 588–590 of skin, 509–511 Tissue regeneration, 112–113 EPCs in, 240–241 evolving concepts of, 286–289, 288f inner ear, 194–196 by MSCs non-skeletal, 263–265 skeletal, 259–263 myocardial, 526–527, 527f of zebra fish heart, 287 Tongue proliferative units, 51–53 stem cell organization on, 51–53, 54f Totipotency, 21–22 See also Pluripotency concept of, 41 Transcriptional regulation, for ES cell self-renewal, 84–87 Klf4, 85–86 Myc, 86–87 Nanog, 85 Oct3/4, 84–85 Sox2, 85 Tbx3, 86 Tcf3, 86 Transcription factors (TFs), 245 Transdifferentiation, 107–108 activity test in other cell types, 116 bone marrow to other cell types, 113 cell type selection, 115 dedifferentiation as prerequisite for, 114–115 defined, 107 examples, 108–112, 114f liver to pancreas, 109–111 pancreas to liver, 108–109 factor modification, identify need for, 116 of nonislet cells to islet cells, 496–497 pancreatic acinar cell, 497 potential factors identification to induce, 115 regeneration, 112–113 study of, 107–108 theoretical implications, 107 Transduction methods for iPSCs generation, 377–378 culture conditions and cell signaling, 378 Transforming growth factor β-1 (TGFβ-1), 95, 97–98, 275–276 CKIs and, in cell cycle regulation, 103–104 Transgenesis ES cell, 31–32 Transit-amplifying (TA) cells, 503 Transmission electron microscopy (TEM), 268–269 Transplantation EBD cells, 449–450 hepatocyte See Hepatocyte transplantation human cells and tissues intended for, FDA regulations and guidance for, 614–616 myoblast, 531–533 orthotopic liver (OLT), 543, 549–551, 556–557 research, ethical considerations, 603 Trophectoderm (TE) cells, 122 of mouse, 132–133 Trophectoderm stem cells, 11 Trophoblast stem cells, 132 Trypsin adaptation of hES cells to, 424–430, 427f Trypsin-EDTA solution, 438 Trypsinization, 427–429, 428f, 429f TS cells See Trophectoderm stem (TS) cells; Trophoblast stem (TS) cells Tumor necrosis factor (TNF) blockers, 573 Type diabetes complications, 635–636 stem cell research, 636–637 Tyrosine hydroxylase (TH), 172 Tyrosinemia Type 1, 553 U UEA-1 See Ulex Europaeus agglutinin 1(UEA-1) Ulex Europaeus agglutinin 1(UEA-1), 233 Unpaired (Upd), 63 Unrestricted somatic stem cells (USSCs), 247–248 Upd See Unpaired (Upd) US House of Representatives, 601, 607–608 US National Institutes of Health, USSCs See Unrestricted somatic stem cells (USSCs) UTF1, 396t V Valproic acid (VPA), 379–380 Varmus, Harold, 636 Vascular endothelial growth factor (VEGF), 228–231, 242–243, 304, 509, 547, 569 679 680 Index Vascular endothelium, 309–310 Vascular invasion, 569 Vascular permeability factor (VPF), 547 Vasculogenesis, 233–234 VE See Visceral endoderm (VE) VEGF See Vascular endothelial growth factor (VEGF) VEGF receptor 2, 229–230 Venous ulcers, 501–502 Very small embryonic-like cells (VSELs), 247–248 Villus–crypt axis, 364–366 Visceral endoderm (VE), 132–133 Visiting Nurse Association (Boston), 501 VPA See Valproic acid (VPA) VPF See Vascular permeability factor (VPF) VSELs See Very small embryonic-like cells (VSELs) W WB-344 cell line, of rat liver, 325–326 Weismann, Irv, Weldon, James, 601 Wilmut, Ian, Wilson’s disease, 553 wnt4, 296t, 301–302 Wnt, in ES cell self-renewal, 84 Wnt/β-catenin signaling pathway, 72–73, 361–363, 362f Wnt signaling, 164 Wound healing gene therapy approaches in, 509 WT1, 296t X X chromosome inactivation (XCI), 92–93 XCI See X chromosome inactivation (XCI) XEN cells See Extra-embryonic endoderm (XEN) cells Xenotransplantation FDA regulations and guidance for, 618–619 Y Yamanaka, Shinya, 3–4 Z Zero population growth (zpg) gene, 66