18
LIVER GROWTH AND REPAIR
LIVER GROWTH AND REP AIR
LIVER GROWTH ANDREPAIR
Edited by
ALASTAIR STRAIN and
ANNE MAE DIEHL
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
First edition 1998
© 1998 Springer Science+Business Media Dordrecht Originally published by Chapman & Hali Ltd in 1998 Softcover reprint ofthe hardcover Ist edition 1998
Thomson Science is a division of International Thomson Publishing
Typeset in 10/12pt Palatino by Best-set Typesetter Ltd., Hong Kong
ISBN 978-94-010-6069-1 ISBN 978-94-011-4932-7 (eBook) DOI 10.1007/978-94-011-4932-7
Ali 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 publishers. Applications for permission should be addressed to the rights manager at the London address of the publisher.
The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made.
A catalogue record for this book is available from the British Library
Library of Congress Catalog Card Number: 97-69617
€9Printed on acid-free text paper, manufactured in accordance with ANSI/ NISa Z39.48-1992 (Permanence of Paper).
Contents
ContributorsForewordPreface
Part One Molecular and Cellular Analysis of Liver Growth
xiixvi
xviii
1
Chapter 1 Liver regeneration following partial hepatectomy: genes andmetabolism 3Nancy L.R. Bucher and Stephen R. Farmer
1.1 Introduction1.2 Growth initiation and progression through G) phase1.3 Physiological considerations1.4 Source of mitogenic signals1.5 Priming1.6 Non-surgical, non-necrotizing induction of liver growth1.7 Signals for liver regeneration1.8 Hepatocyte cultures1.9 The C/EBP gene family: involvement with stress, metabolism
and growth1.10 Conclusion
Chapter 2 Liver regeneration following hepatic injuryMark J. Czaja
3466789
12
1519
28
Chapter 3 Epithelial stem-like cells of the rodent liverWilliam B. Coleman and Joe W. Grisham
2.12.22.32.4
2.52.62.7
2.82.9
3.13.2
IntroductionPotential differences in hepatic regeneration after injuryTiming and characteristics of post-injury regenerationAlterations in membrane-mediated events duringregeneration after injuryEffects of liver injury on immediate-early gene expressionRole of polyamine synthesisEffects of liver injury on growth factors and growth inhibitorsinvolved in liver regenerationRole of cytokinesFuture prospects
IntroductionLiver epithelial stem-like cells in embryonic development
282930
343537
404244
50
5052
vi Contents
3.33.43.5
3.6
Liver epithelial stem-like cells in postnatal liver growthIsolation and culture of rodent liver epithelial stem-like cellsEvidence for the differentiation potential of cultured liverepithelial stem-like cellsDiscussion
5966
7180
Chapter 4 Transgenic animals as models for hepatocarcinogenesis 100Eric Santoni-Rugiu and Snorri S. Thorgeirsson
4.1 Introduction 1004.2 Hepatitis B virus transgenic mice 1014.3 Other transgenic models of hepatocarcinogenesis associated
with liver damage 1084.4 Liver carcinogenesis in transgenic mice expressing viral oncogenes 1104.5 Growth factors and their interaction with nuclear oncogenes 1154.6 Conclusions and future prospectives 129
Chapter 5 Gene knockout animal models 143Bonnie Burgess-Beusse, Humberto E. Soriano andGretchen J. Darlington
5.1 Introduction 1435.2 The development of knockout mice from ES cells 1445.3 Knockout models with altered liver function 1455.4 Conclusions 156
Chapter 6 Biological activity ofgrowth factors in vivo 163Kenji Fujiwara and Sumiko Nagoshi
6.1 Introduction 1636.2 Detection of growth factors for hepatocytes in vivo 1636.3 Role of putrescine production in liver regeneration 1646.4 Use of normal liver in detection of growth factors for hepatocytes 1666.5 Regulatory factors of liver growth reported in vivo 1716.6 Proposed mechanisms of liver regeneration 1756.7 Summary 176
Part Two Growth Factors 183
Chapter 7 The EGFf[GFafamily ofgrowth factors and their receptors 185William E. Russell and Robert S. Carver
7.17.27.37.4
The EGF family of ligands and their receptors: an overviewThe EGF receptor, the ErbB (HER) proteins and their ligandsEGF jTGFa family physiology in liverConclusions
185188197205
Chapter 8 Hepatocyte growth factor in liver growth and differentiation 219George Michalopoulos
8.1 Introduction 2198.2 HGF structure 220
8.3 HGF gene organization8.4 HGF gene expression8.5 HGF and the extracellular matrix8.6 HGF activation8.7 HGF receptor8.8 General biological effects of HGF8.9 Other kringle-bearing growth factors8.10 HGF and liver regeneration8.11 HGF and fulminant hepatitis8.12 HGF and its receptor in carcinogenesis8.13 HGF and activation of the hepatic stem cell compartment8.14 HGF and embryogenesis8.15 HGF and regeneration of other tissues8.16 Summary and speculations
Chapter 9 The fibroblast growth factor familyMikio Kan and Wallace 1. McKeehan
Contents vii
221222222222223224225226229230231231232232
240
9.19.29.39.4
9.5
9.69.79.89.9
IntroductionThe fibroblast growth factor familyDiversity of the fibroblast growth factor receptor (FGFR) kinaseHeparan sulfate and its role in assembly of the FGF receptorcomplexSpecificity of ligand binding and signal transduction activity amongFGFR variantsFGF in liver regeneration and diseaseTyrosine kinase receptors for FGF in liverHeparan sulfate receptors for FGF in liverFGF interaction with other growth factors in liver growth andrepair
240241242
244
245247251252
254
Chapter 10 Growth inhibitory signals and liver regeneration:the TGFf3 superfamilyRaymond N. DuBois, David Myers andR. Daniel Beauchamp
10.1 Introduction10.2 Liver regeneration as an experimental model10.3 Growth inhibitory signals: TGFp10.4 Growth inhibitory signals: activin10.5 Summary
Chapter 11 CytokinesGiuliano Ramadori and Thomas Armbrust
11.1 Introduction11.2 Liver damage and repair11.3 Liver regeneration11.4 Cytokines in liver repair and liver regeneration11.5 Other cytokines11.6 Cytokine receptors in liver repair and liver regeneration
261
261261265272275
283
283283284284290290
viii Contents
Part Three Signaling Events
Chapter 12 Proto-oncogenes/transcription factorsJ.K. Westwick and D.A. Brenner
12.1 Signaling cascades and transcriptional responses inthe regenerating liver
12.2 Immediate-early transcription factors12.3 The AP-1 family12.4 Pathways mediating AP-1 induction12.5 NF-KB12.6 CCAAT/ enhancer binding proteins12.7 c-Myc12.8 Cross-talk
Chapter 13 Cyclins and gap junctions in liver growth and repairJaneen H. Trembley, Betsy T. Kren andClifford J. Steer
295
297
297298298300303305306307
311
13.113.213.313.413.513.613.713.813.913.1013.1113.12
13.1313.1413.1513.1613.1713.1813.1913.20
IntroductionHistory of cyelinsCyclins in the cell cycleThe family of cyclinsCyclins in liver regenerationCyclins in development and differentiationTranscriptional control and cyclinsCyclins in cancerCyclins and apoptosisCyclins in growth repairSummary for cyelinsGap junctions and cyelins - partners in regulation of the cellcycle?Liver-specific gap junctionsProperties of hepatic gap junctionsConnexin gene expression in hepatocytesRole of gap junctions in the liverExpression of gap junctions during developmentGap junctions in the regenerating liverGap junction expression during cholestasis in rat liverGap junction expression during tumorigenesis
311311312317324328329330332333333
334334337339346348348350351
Chapter 14 Intracellular signal transduction in liver regenerationJan B. Hoek and Emanuel Rubin
14.1 Introduction14.2 The network of intracellular signaling processes14.3 Signal transduction during liver regeneration14.4 Summary and outlook
366
366368385394
Contents ix
Part Four Biology of the Extracellular Matrix andNon-Parenchymal Cells 403
Chapter 15 Proteoglycans 405Malcolm Lyon
15.1 Introduction 40515.2 Glycosaminoglycan structure 40615.3 Proteoglycans 41015.4 Proteoglycan expression in liver 41315.5 Changes in GAG/PG expression during development, regeneration
and pathological conditions 41715.6 Heparan sulfate and the regulation of growth factor activity 41815.7 Additional activities of liver HS PG 42215.8 Concluding remarks 423
Chapter 16 Regulation of collagen gene expression 430Mario Chojkier
16.1 Introduction 43016.2 Regulation of gene expression 43116.3 Mechanisms of transcriptional activation 43216.4 Regulatory cis-elements of the collagen a1(I) gene 43316.5 Stimulation of collagen gene expression by lipid peroxidation 43516.6 Mechanisms by which lipid peroxidation modulates collagen
gene transcription 43716.7 Alcohol-induced liver fibrogenesis 43916.8 Iron overload induces collagen gene expression 44016.9 Oxidative stress activates hepatic stellate cells 44116.10 Conclusion 443
Chapter 17 The extracellular matrix in liver regeneration 451Jacquelyn J. Maher
17.1 Introduction 45117.2 The hepatic extracellular matrix 45117.3 Changes in the peri-sinusoidal matrix during liver regeneration 45417.4 Functional implications of matrix remodeling in the regenerating liver 45817.5 Comparisons among liver regeneration, liver development and
liver fibrosis 46017.6 Summary 461
Chapter 18 Hepatocyte co-culture, three-dimensional culture models andthe extracellular matrix 465Marcus K.H. Auth and Akira Ichihara
18.1 Introduction18.2 Co-culture models18.3 Other three-dimensional culture models for hepatocytes
465466476
x Contents
Chapter 19 Kupffer cells and endothelial cellsPaul J. Winwood and Michael J.P. Arthur
19.1 Introduction19.2 Kupffer cells19.3 Endothelial cells19.4 Summary
482
482482496501
Chapter 20 Hepatic stellate cells 512Victor Ankoma-Sey and Scott L. Friedman
20.1 Introduction 51220.2 Anatomy and ultrastructure of hepatic stellate cells 51320.3 Cytoskeletal phenotype and cell type of hepatic stellate cells 51520.4 Isolation and culture models of hepatic stellate cells 51620.5 Functions of hepatic stellate cells 51720.6 Role of hepatic stellate cells in liver diseases 52620.7 Conclusions and future prospects 527
Part Five Human Liver Growth and Clinical Applications 539
Chapter 21 Human liver growth and development 541Tania Roskams, Peter Van Eyken and Valeer Desmet
21.1 Introduction 54121.2 Development of the liver parenchyma and intra-hepatic bile
ducts 54121.3 Development of sinusoids, sinusoidal cells, hepatic vasculature
and innervation 54921.4 Hematopoiesis 55021.5 Hepatic lobular development 55121.6 Development of the extra-hepatic bile ducts and the gall bladder 551
Chapter 22 Human liver growth in fibrosis and cirrhosis 558Jian Wu, Gerald S. Kuncio and Mark A. Zem
22.1 Introduction 55822.2 Important factors in modulation of hepatic fibrosis/cirrhosis 55922.3 Factors modulating liver regeneration during fibrosis and cirrhosis 56222.4 Regenerative activity in chronic liver disease 56822.5 Proto-oncogenes, hyperplasia and carcinogenesis 56922.6 Therapeutic implications 570
Chapter 23 Hepatocyte transplantation: novel applications 577Sanjeev Gupta
23.1 Introduction 57723.2 Survival of hepatocytes in non-hepatic sites 58023.3 Survival of transplanted hepatocytes in liver 58923.4 Applications of hepatocyte transplantation in liver injury 598
23.5 Further prospects23.6 Conclusions
Contents xi
598599
Chapter 24 Hepatic gene therapy 608Karen K. Kormis and George Y. Wu
24.1 Introduction 60824.2 Gene delivery: ex vivo versus in vivo 60924.3 Methods of gene transfer 60924.4 Clinical applications 61424.5 Conclusion 619
Chapter 25 Artificial liver support 627Achilles A. Demetriou and Jacek Rozga
25.1 Introduction 62725.2 Non-biological liver support systems 62925.3 Biological liver support systems 63325.4 Hepatocyte-based artificial liver: selected bioengineering aspects 63625.5 Bioartificialliver: Cedars-Sinai experience 64125.6 Artificial liver: the future 646
Index 653
Contributors
Victor Ankoma-SeyDivision of Gastroenterology, Hepatology and Nutrition, University of TexasMedical School, MSB 4.248, 6431 Fannin, Houston, TX 77030, USA
Thomas ArmbrustDepartment of Gastroenterology and Endocrinology, Center of Internal Medicine,Georg-August University, Robert Koch StraBe, 37075 G6ttingen, Germany
Michael J.P. ArthurMedicine, University of Southampton, Southampton, UK
Marcus K.H. AuthDepartment of General Surgery, Transplant Immunological Laboratory, JohannWolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main,Germany
R. Daniel BeauchampDepartment of Cell Biology , Vanderbilt University School of Medicine, Nashville,TN 37232-2279, USA
D.A. BrennerDepartment of Medicine, University of North Carolina, Chapel Hill, NC 27599,USA
Nancy 1.R. BucherBoston University School of Medicine, 80 East Concord Street, Boston, MA 02118,USA
Bonnie Burgess-BeusseDepartment of Molecular and Human Genetics, Baylor College of Medicine,Houston, TX 77030, USA
Robert S. CarverDepartment of Cell Biology, Vanderbilt University, Nashville, TN 37232, USA
Mario ChojkierDepartment of Medicine and Center for Molecular Genetics, University ofCalifornia, San Diego, CA 92161, USA
William B. ColemanDepartment of Pathology and Laboratory Medicine, University of North CarolinaSchool of Medicine, Chapel Hill, NC 27599, USA
Contributors xiii
Mark J. CzajaMarion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300Morris Park Avenue, Bronx, NY 10461, USA
Gretchen J. DarlingtonDepartments of Molecular and Human Genetics, Pediatrics and Pathology, BaylorCollege of Medicine, Houston, TX 77030, USA
Achilles A. DemetriouDepartment of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048-1865,USA
Valeer J. DesmetDepartment of Pathology, University of Leuven Minderbroederstraat 12, B-3000Leuven, Belgium
Raymond N. DuBoisDepartment of Medicine, Vanderbilt University School of Medicine, Nashville, TN37232-2279, USA
Peter Van EykenDepartment of Pathology, University of Leuven, Minderbroederstraat 12, B-3000Leuven, Belgium
Stephen R. FarmerBoston University School of Medicine, 80 East Concord Street, Boston, MA 02118, USA
Scott L. FriedmanDivision of Gastroenterology, University of California, San Francisco, CA USA, andLiver Center Laboratory, 94110, San Francisco, CA Bldg 40, Room 4102, SF GeneralHospital, USA
Kenji FujiwaraThird Department of Internal Medicine, Saitama Medical School, 38 Morohongo,Moroyama, lrumagun, Saitama 350-04, Japan
Joe W. GrishamDepartment of Pathology and Laboratory Medicine, University of North CarolinaSchool of Medicine, Chapel Hill, NC 27599, USA
Sanjeev GuptaMarion Bessin Liver Research Center and Gastroenterology Division, Departmentof Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx,NY 10461, USA
Jan B. HoekDepartment of Pathology, Anatomy and Cell Biology, Jefferson Medical College,Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
Akira IchiharaDepartment of Environmental Science, Tokushima Bunri University, Tokushima770, Japan
xiv Contributors
Mikio KanCenter for Cancer Biology, Albert B. Al1<ek Institute of Biosciences and Technology,Texas A & M University, 2121 W. Holcombe Boulevard, Houston, TX 77030-3303,USA
Karen K. KormisDepartment of Medicine, Division of Gastroenterology-Hepatology, University ofConnecticut Health Center, Farmington, CT 06032, USA
Betsy T. KrenDepartment of Medicine, University of Minnesota, 516 Delaware Street S.£.,Minneapolis, MN 55455, USA
Gerald S. KundoDepartment of Medicine, Division of Gastroenterology and Hepatology, JeffersonMedical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia,PA 19107-5083, USA
Malcolm LyonCancer Research Campaign/University of Manchester Department of MedicalOncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust,Wilmslow Road, Manchester M20 4BX, UK
Wallace L. McKeehanCenter for Cancer Biology, Albert B. Alkek Institute of Biosciences andTechnology and Department of Biochemistry and Biophysics, Texas A & M University, 2121 W. Holcombe Boulevard, Houston, TX 77030-3303, USA
Jacquelyn J. MaherLiver Center Laboratory, San Francisco General Hospital, 1001 Potrero Avenue,San Francisco, CA 94110, USA
George MichalopoulosDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
David MyersDepartment of Surgery, Vanderbilt University School of Medicine, Nashville, TN37232-2279, USA
Sumiko NagoshiFirst Department of Internal Medicine, Faculty of Medicine, University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
Giuliano RamadoriDepartment of Gastroenterology and Endocrinology, Center of Internal Medicine,Georg-August University, Robert Koch StraBe, 37075 G6ttingen, Germany
Tania RoskamsDepartment of Pathology, University of Leuven Minderbroederstraat 12, B-3000Leuven, Belgium
Contributors xv
Jacek RozgaDivision of Surgical Research, Cedars-Sinai Medical Center, Los Angeles, CA90048-1865, USA
Emanuel RubinDepartment of Pathology, Anatomy and Cell Biology, Jefferson Medical College,Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
William E. RussellDivision of Pediatric Endocrinology, Vanderbilt University Medical Center,Nashville, TN 37232-2579, USA
Eric Santoni-RugiuLaboratory of Experimental Carcinogenesis, National Cancer Institute, NationalInstitutes of Health, 37 Convent Drive, Bethesda, MD 20892-4255, USA
Humberto E. SorianoDepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
Clifford J. SteerDepartments of Medicine and Cell Biology, University of Minnesota, 516 DelawareStreet S.E., Minneapolis, MN 55455, USA
Snorri S. ThorgeirssonLaboratory of Experimental Carcinogenesis, National Cancer Institute, NationalInstitutes of Health, 37 Convent Drive, Bethesda, MD 20892-4255, USA
Janeen H. TrembleyDepartment of Genetics and Cell Biology, University of Minnesota, 516 DelawareStreet S.E., Minneapolis, MN 55455, USAPresent address: St Judes Children's Research Hospital, Department of Tumor CellBiology, 332 North Lauderdale, Memphis, TN 38105, USA
J.K. WestwickDepartment of Medicine, University of North Carolina, Chapel Hill, NC 27599,USA
Paul J. WinwoodUniversity Medicine, University of Southampton, Southampton, UK
George Y. WuDepartment of Medicine, Division of Gastroenterology-Hepatology, University ofConnecticut Health Center, Farmington, CT 06032, USA
Jian WuDepartment of Medicine, Division of Gastroenterology and Hepatology, JeffersonMedical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia,PA 19107-5083, USA
MarkA. ZemDepartment of Medicine, Division of Gastroenterology and Hepatology, JeffersonMedical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia,PA 19107-5083, USA
ForewordNelson Fausto
The Greek myth of Prometheus with its picture of a vulture feasting on its chainedvictim has traditionally provided a visual image of liver regeneration. It is a powerfuland frightening representation but if one were to substitute the vulture by a surgeonand Prometheus by a patient laying on a properly prepared operating table, theoutcome of the procedure would not differ significantly from that described by Greekpoets. Yet few of us who work in the field have stopped long enough to ask wherethis myth originated. Did the poet observe a case of liver regeneration in a humanbeing? Was it brilliant intuition or perhaps, literally, just a 'gut feeling' of a poetlooking for good rhymes that led to the prediction that livers grow when part of thetissue is removed? This book does not attempt to solve these historical issues. It does,instead, cover in detail some of the major modem themes of research on liver regeneration, injury and repair.
As indicated in Dr. N. Bucher's chapter, the modem phase of experimental studieson liver regeneration started in 1931 with the publication by Higgins and Andersonof a method to perform a two-thirds resection of the liver of a rat. The techniquedescribed has 3 remarkable features: 1) it is highly reproducible, resulting in theremoval of 68% of the liver, 2) it has minimal if any mortality, and 3) it consists onlyof blood vessel ligation and does not involve cutting through or wounding hepatictissue. These simple features of the operation, which has not been modified morethan 65 years after its original description, have made possible the study of liverregeneration both as a biological process of growth regulation as well as a systemwith important clinical applications.
The main focus of studies on liver regeneration has changed through the years,reflecting the scientific fashions of the day or the availability of suitable techniquesthat could be applied to in vivo studies. From these studies much has been learnedabout liver morphology, biochemistry and physiology. Morphological and biochemical techniques were used more than 30 years ago to describe the main features of liverregeneration, to analyze the time course of DNA synthesis and mitosis inparenchymal and non-parenchymal cells and to determine the relationship betweenthe amount of tissue removed and DNA synthesis. These studies defined the majorlandmarks of liver regeneration after partial hepatectomy and their conclusions havenot been challenged. Not surprisingly, during the last 10 years the emphasis has beenon studies involving molecular techniques and analysis of liver regeneration intransgenic and knockout mice.
It took some time for 'pure' basic scientists to be convinced that liver regenerationin vivo is an excellent system for the study of cell cycle regulation. This recognition isrelatively recent and has brought an influx of new investigators and added new
Foreword xvii
vitality to the field. However, this growth also has some inevitable drawbacks. In thepast, scientists working on hepatic regeneration were primarily fascinated by theamazing regenerative capacity of the liver. While this fascination has not been lost,liver regeneration is increasingly seen as a convenient system in which the propertiesof a particular gene can be evaluated. These different ways of approaching thesystem are not mutually exclusive. Just the opposite, to understand the mechanismsof liver regeneration we need both detailed gene by gene analyses as well as moregeneral integrative studies. Alastair Strain and Anna Mae Diehl bring together inLiver Growth and Repair chapters dealing with general and specialized approaches toliver regeneration and injury. Through a careful selection of subjects and authorsthey are very successful in their efforts.
The book is divided into 5 parts. The first presents more general discussions onmechanisms of regeneration after partial hepatectomy, on the transgenic and knockout mouse models that have been utilized in these studies, and on cells in adult liverthat may function as stem cells. It also includes a chapter on liver regeneration afterliver injury, a topic of major importance that has been less studied than regenerationafter surgical resection and needs to receive more emphasis. Part 2 focuses on specificgrowth factors that participate in liver regeneration, namely the EGF/TGFa system,HGF, the FGF family, and the TGFb family and includes a study of cytokines in livergrowth and repair. Part 3 deals with signal transduction and cell cycle regulation inreplicating hepatocytes. Part 4 contains chapters on collagen, proteoglycans andhepatic extracellular matrix as well as detailed reviews on Kupffer cells, endothelialcells and stellate cells. The last part of the book presents discussions on human liverdevelopment, fibrosis and cirrhosis and chapters on therapeutic strategies involvinghepatocyte transplantation, gene therapy and liver assist devices.
The chapters review the main aspects of the selected topics but, as is the case forany good book, they open new questions that need to be answered by future research.Because knowledge about liver growth, injury and repair is being acquired at a rapidpace, the latest developments in these areas will be found in current journals. However, it would be difficult to place the emerging literature into an appropriate contextwithout the information contained in this book. Here are some questions, eachrelated to a part of this book, that the new research should seek to answer:
• Can cytokines initiate hepatocyte proliferation after partial hepatectomy as wellas chemical injury?
• Are the multiple growth factors that can stimulate hepatocyte proliferation redundant or does each of them have a unique mode of action?
• Which among the more than 50 genes expressed during the immediate earlygene response after partial hepatectomy are essential for hepatocyte DNA replication?
• What are the precise molecular mechanisms that trigger collagen synthesis byliver stellate cells in vivo during the development of fibrosis and cirrhosis?
• Considering that few if any patients with liver disease have benefited from thespectacular advances in gene therapy techniques, are we on the right track or dofurther advances require new conceptual and technological breakthroughs?
Readers of Liver Growth and Repair will acquire essential information and be motivated to find answers to these and other important questions raised throughout thisbook. They may even feel curious enough to find out how the myth of Prometheusoriginated.
Preface
Liver regeneration following partial hepatectomy in the adult rat has been used fordecades as the favoured model with which to study liver growth. Rightly, it wasrecognized as a tightly regulated proliferative response, where normally quiescentand highly differentiated epithelial cells (which unlike some other epithelia are notterminally differentiated) retained the propensity to enter the growth cycle, divideand arrest again. This of course resulted in full restoration of liver mass and placedthe liver as unique amongst other organs, with its capability of complete repair.
However it is clear that the complexity of the process and its control goes wellbeyond that which was originally envisaged. Until the 1970s, much intensive research using animal models including surgically joining pairs of animals to demonstrate the now well known systemic effects, ablation of various organs, and infusionof often complex mixtures of hormones, nutrients and electrolytes, was performed.As a consequence of the ever-increasing complexity of the surgical techniques required and indeed of the subsequent interpretation of the data which accrued, someinvestigators attempted to 'simplifiy' the system and to study isolated liver cellsunder a plethora of conditions in vitro. The rationale behind this approach was toenable the investigation of the direct actions of hormones and growth factors onhepatocytes.
It is probably true to say that (some 20 years on) this 'simplification' has onlyrelatively recently led to significant clarification of our knowledge of the process as awhole. This has involved not just work with hepatocyte cultures, but of course thewhole gamut of information accumulating which relates to the numerous solublefactors and extra-cellular matrix compononents implicated and the increasing awareness of the importance of the other liver cell types, in particular, the sinusoidal cells.Molecular biology has moved on apace and it has sometimes been difficult to preventit running too far ahead of the physiology and/or pathology. This has been solvedpartly with the impressive recent advances in transgenic animal technology which isproviding new insights into the control mechanisms in vivo. Additionally, there isnow a real optimism that application of this knowledge to clinical hepatology willbring about both a better understanding of the pathogenesis of liver disease andultimately better therapies.
The idea for this book came from a desire to create a single volume which wouldencompass the many aspects of liver growth and which in the context of the rapid andexciting advances in cellular and molecular biology would give the reader a comprehensive coverage of both the past and current literature. It also aimed to highlight thefact that we now recognize that different models of liver growth have revealeddifferent cellular and molecular controls. In attempting to put together such avolume, the aim of which is to be comprehensive, inevitably some overlap will occurwhen covering aspects which include separate chapters on the many components offor example fibrosis; control of collagen synthesis, the cell types responsible for itsproduction, the growth factors and cytokines which regulate the process and thehuman angle of liver fibrogenesis are covered. We see this as a strength giving
Preface xix
different perspectives upon the whole subject. Different investigators naturally approach the same conceptual problem in different ways. Following an internationllyagreed consensus published in letter form in Hepatology in 1996 (23, 193) ,throughoutthis volume we have used the recently approved nomenclature, namely thesinusoidal cell type previously known as the Ito Cell, Fat-Storing Cell or Lipocyte isnow known as the HEPATIC STELLATE CELL (HSC).
In summary, the combination of molecular and cellular coverage and its relation toclinical hepatology is perhaps unique. The individual chapter contributors are allworking at the cutting edge of their respective fields of expertise. We hope thereforethat this will be a useful source of information and provide a comprehensive bibliography to the overall field of hepatic growth with a consideration of the clinicalperspective which continually comes closer to bridging the gap bewteen basic scienceand clinical problems. It will appeal to scientists of every discipline who concernthemselves with closing this gap in hepatology.
AJSOctober 1997
