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Human stem cell toxicology 1st Edition
James L Sherley
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Published on 09 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782626787-FP001
Human Stem Cell Toxicology

View Online
Issues in Toxicology
Series Editors:
Professor Diana Anderson, University of Bradford, UK
Dr Michael D. Waters, Michael Waters Consulting, N. Carolina, USA
Dr Timothy C. Marrs, Edentox Associates, Kent, UK
Advisor to the Board:

Professor Alok Dhawan, CSIR-Indian Institute of Toxicology Research,
Lucknow, India
Titles in the Series:

1: Hair in Toxicology: An Important Bio-Monitor
2: Male-mediated Developmental Toxicity
3: Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and
other Xenobiotics
4: Bile Acids: Toxicology and Bioactivity
5: The Comet Assay in Toxicology
6: Silver in Healthcare
7: In Silico Toxicology: Principles and Applications
8: Environmental Cardiology
9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs
and Exposures
10: Biomarkers and Human Biomonitoring, Volume 2: Selected Biomarkers
of Current Interest
11: Hormone-Disruptive Chemical Contaminants in Food
12: Mammalian Toxicology of Insecticides
13: The Cellular Response to the Genotoxic Insult: The Question of
Threshold for Genotoxic Carcinogens
14: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 1
15: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 2
16: Aging and Vulnerability to Environmental Chemicals: Age-related
Disorders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-Across
18: The Carcinogenicity of Metals: Human Risk Through Occupational and
Environmental Exposure
19: Reducing, Refining and Replacing the Use of Animals in Toxicity Testing
20: Advances in Dermatological Sciences
21: Metabolic Profiling: Disease and Xenobiotics
22: Manganese in Health and Disease
23: Toxicology, Survival and Health Hazards of Combustion Products
24: Masked Mycotoxins in Food: Formation, Occurrence and Toxicological
Relevance
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25: Aerobiology: The Toxicology of Airborne Pathogens and Toxins

26: Chemical Warfare Toxicology, Volume 1: Fundamental Aspects
27: Chemical Warfare Toxicology, Volume 2: Management of Poisoning
28: Toxicogenomics in Predictive Carcinogenicity
29: Human Stem Cell Toxicology
How to obtain future titles on publication:

A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For further information please contact:

Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: þ44 (0)1223 420066, Fax: þ44 (0)1223 420247
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Published on 09 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782626787-FP001 View Online
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Edited by
James L. Sherley
Asymmetrex, LLC, Boston, MA, USA
Email: jsherley@asymmetrex.com
Issues in Toxicology No. 29
Print ISBN: 978-1-78262-421-9

PDF eISBN: 978-1-78262-678-7
EPUB eISBN: 978-1-78262-873-6
ISSN: 1757-7179
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2016
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Apart from fair dealing for the purposes of research for non-commercial purposes or for
private study, criticism or review, as permitted under the Copyright, Designs and Patents
Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not
be reproduced, stored or transmitted, in any form or by any means, without the prior
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appropriate Reproduction Rights Organization outside the UK. Enquiries concerning
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Published by The Royal Society of Chemistry,

Thomas Graham House, Science Park, Milton Road,
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Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK
Contents
Chapter 1 Addressing Challenges to Progress in Human Stem Cell

Toxicology Concepts and Practice 1
James L. Sherley
1.1 Filling in the Stem Cell Gap in Human Toxicology 1

1.2 Historical Impact of the Hierarchical, Anatomical,
Sub-disciplinary Structure of Toxicological Sciences 2
1.3 Human Stem Cell Toxicology as a Stem Cell Exact
Science 3
1.4 Health and Medical Applications for Human Stem
Cell Toxicological Sciences 5
1.5 Introducing the Future Diverse Impacts of Human
Stem Cell Toxicology 6
Acknowledgements 7
References 7
Chapter 2 Alternative Methods in Haematopoietic Stem Cell

Toxicology 9
Navneet Kumar Yadav, Pooja Shukla and R. K. Singh
2.1 Introduction 9
2.2 Haematopoietic Stem Cell Toxicity or
Hematotoxicity 11
2.2.1 Sources of Haematopoietic Stem Cell Toxicity 12
2.2.2 Importance of Studying Haematopoietic
Stem Cell Toxicity 13

Edited by James L. Sherley
Published by the Royal Society of Chemistry, www.rsc.org
vii
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viii Contents
2.2.3Haematopoietic Stem Cell Toxicity in Drug

Development 14
2.3 Colonogenic Assays as Predictors of Haematopoietic
Stem Cell Toxicity 14
2.3.1 CFU-GM Colonogenic Assay 15

2.3.2 CFU-Mk Colonogenic Assay 16
2.3.3 BFU-E Colonogenic Assay 18
2.3.4 Lymphoid Lineage Based Colonogenic
Assays 18
2.4 Conclusions 21
Acknowledgements 22
References 22
Chapter 3 High-throughput Screening of Toxic Chemicals on Neural

Stem Cells 31
Kurt Farrell, Pranav Joshi, Alexander Roth, Chandrasekhar
Kothapalli and Moo-Yeal Lee
3.1 Neural Stem Cells 31

3.2 Toxic Chemicals in the Environment 32
3.3 Mechanisms of Neural Stem Cell Toxicity 33
3.3.1 Ion Channel Blocking 34
3.3.2 Drug Metabolism Effects 37
3.3.3 Oxidative Stress 40
3.3.4 DNA/RNA Denaturation 42
3.3.5 Membrane Compromise 42
3.3.6 Other Mechanisms of
Neurotoxicity 43
3.4 NSC Differentiation 43
3.5 Conventional In vitro Assays for Toxicity Screening
against Neural Stem Cells 45
3.5.1 Well Plate Assays 45
3.5.2 Cellular Microarray Assays 47
3.5.3 Microfluidic Assays 49
3.5.4 Other Assays 51
3.6 Challenges of Conventional In vitro Approaches
in Neurotoxicity Screening 51
3.7 Conclusions and Future Directions 52
Acknowledgements 53
References 53
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Contents ix
Chapter 4 The Role of Catecholamines in Stem Cell Mobilisation 64

Brı́d M. Ryan and Oscar Vidal
4.1 Introduction 64
4.2 Catecholamines 64
4.3 Catecholamines and Stem Cell Mobilisation 67

4.3.1 Endothelial Progenitor Cells 70
4.3.2 Mesenchymal Stem Cells 71
4.3.3 Catecholamines and Stem Cell Biology 72
4.4 Consequences of Catecholamine-modulating
Agents for Stem Cell Toxicity 73
4.4.1 Other Considerations 78
4.5 Concluding Comments 80
References 81
Chapter 5 Toxicological Risk Assessment – Proposed Assay Platform

Using Stem and Progenitor Cell Differentiation in
Response to Environmental Toxicants 94
John W. Ludlow, Alexander Kinev, Michael VanKanegan,
Ben Buehrer, Nick Trotta and Joydeep Basu
5.1 Introduction 94
5.1.1 Toxicity 95
5.1.2 Environmental Toxicology 95
5.1.3 Predictive Toxicology 95
5.1.4 Automated High Content Imaging and
High Throughput, or High Content,
Screening 96
5.1.5 Risk Assessment 97
5.1.6 Components of Risk Assessment 97
5.2 Environmental Toxicological Risk Assessment
Employing an Assay Platform That Uses Stem and
Progenitor Cell Differentiation 98
5.2.1 Endothelial Colony Forming Cells (ECFCs) 99
5.2.2 ECFCs are Sensitive to Low-dose Ionizing
Radiation (LDIR) 100
5.2.3 Individual ECFC Cultures Exhibit
Donor-related LDIR Responses 100
5.2.4 The Profiling of Intracellular Signal
Transduction Pathways Provides an Insight
into the Mechanism of LDIR Toxicity 101
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x Contents
5.3 Current State of ECF Platform Development 102

5.3.1 Impedance-based Analysis of ECFC Viability
after Exposure to Environmental Toxicants 102
5.3.2 ECFCs Exhibit Lot-to-lot Variability in
Toxicant Response 105

5.3.3 Development of a Novel ROS Assay Using
ECFCs 105
5.3.4 Density-dependent ROS Levels in Cultured
ECFCs 106
5.3.5 Signal Transduction Assays in Toxicant-
treated ECFCs 108
5.4 Bioanalytical Method Validation 110
5.4.1 Development of a Quantitative High
Content Imaging (QHCA) Platform Using
ECFCs 112
5.4.2 Optimize Culture Conditions for
High-throughput Screening 112
5.4.3 Initiate Translation of Assay to 384-Well
Plates 113
5.4.4 Incorporation of Automation to Increase
Throughput 114
5.4.5 Validation of the ECFC QHCA 114
5.4.6 Determining the Z 0 factor of the Cell Death
Assays Using Positive and Negative Controls 115
5.4.7 Assessing Sources of Assay Variability
Including Manual Pipetting, Plating and
Edge Effects 116
5.4.8 Determining Day-to-day Variability of EC50
for Each Assay 116
5.4.9 Determining Significant Biological
Replicate Power 117
5.4.10 Perform the High-throughput Assay Using
Compounds from the ToxCastt Phase I
Library 117
5.4.11 Incorporation of the Toxicant-induced
ECFC Differentiation Assays into the QHCA
Screen 118
5.4.12 Establish a Repository of ECFCs from
Various Donors 120
5.5 Final Thoughts 121
References 121
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Contents xi
Chapter 6 Current Developments in the Use of Human Stem Cell

Derived Cardiomyocytes to Examine Drug-induced
Cardiotoxicity 124
Varun Ahuja, Sharad Sharma and Raj Kamboj
6.1 Introduction 124

6.2 Constraints Due to Species Differences 125
6.3 Stem Cells and iPSC-CMs 127
6.4 Limitations with Stem Cells 128
6.5 Stem Cells in Cardiovascular Safety
Pharmacology 129
6.6 Disease Models Based on iPSC-CMs 135
6.7 Generation of iPSC-CMs – Considerations on
Differentiation, Maturity, Heterogeneity and
Purification Protocols 137
6.7.1 Differentiation 137
6.7.2 Maturity 138
6.7.3 Heterogeneity 138
6.7.4 Purification 138
6.8 Use of iPSC-CMs in Phenotypic Assays 139
6.9 Assay Technologies Incorporating iPSC-CMs
and hESC-CMs 140
6.9.1 Manual Patch Clamp 140
6.9.2 Automated Patch Clamp 142
6.9.3 MEA (Microelectrode Array) 142
6.10 CiPA: Comprehensive In vitro Proarrhythmia
Assay 144
6.11 Conclusion 146
References 147
Chapter 7 Pesticides and Hematopoietic Stem Cells 160

Sujata Law and Malay Chaklader
7.1 Pesticide Toxicity-induced Disorders of

Hematopoietic System 160
7.1.1 Hematopoietic System and Hematotoxic
Pesticides 160
7.1.2 Pesticide-induced Aplastic Anemia: A Rare
but Severe Hematopathology due to Stem
Cell Failure 162
7.1.3 Assessment of Hematotoxicity 166
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xii Contents
7.2 Pesticide Toxicity on Hematopoietic Stem Cells and

their Microenvironment 167
7.2.1 Oxidative Stress Induction 167
7.2.2 Apoptosis Induction 167
7.2.3 Alteration of Developmental Signaling

Pathways 168
7.3 Experimental Medicine Against Pesticide
Toxicity-induced Hematopoietic Failure 170
7.4 Future Direction 171
References 171
Chapter 8 Epigenetic Impact of Stem Cell Toxicants 178

Anup Kumar Singh, Akhilesh Singh, Rakesh Kumar Arya,
Navneet Kumar Yadav and Dipak Datta

8.2 Epigenetic Regulation of Stem Cells 181
8.3 Stem Cell Toxicants as Modulators of Epigenetic
Programming 182
8.3.1 Heavy Metals 183
8.3.2 Pharmaceuticals 185
8.4 Conclusion 187
Acknowledgements 187
References 187
Chapter 9 Metakaryotic Cancer Stem Cells are Constitutively

Resistant to X-Rays and Chemotherapeutic Agents, but
Sensitive to Many Common Drugs 196
Elena V. Gostjeva, Vera V. Koledova, Liyuan Bai, Kailin C.
Duan, Tushar Kamath, Meghan Nelson, Parul Agnihotri,
Deborah J. Moshinski, Li Ping Wu, Lawrence Zukerberg,
Daniel C. Chung, Susan Tsai, Douglas B. Evans, Aoy
Tomita-Mitchell, Michael Mitchell and William G. Thilly

9.1.1 Introduction to Metakaryotic Biology 197
9.2 Materials and Methods 200
9.2.1 Methods for Studies of Metakaryotic Cancer
Stem Cells In vivo and In vitro 200
9.3 Results 204
9.3.1 Observations in Tumors after Radiation
Therapy and Chemotherapy 204
9.3.2 Observations in Cell Cultures 206
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Contents xiii
9.4 Discussion 233

9.4.1 Stem Cells in Human Tumors and Tumor-
derived Cell Lines are Amitotic,
Metakaryotic Cells 233
9.4.2 Assays that Recognize and Measure the

Toxicity of Radiation and Chemicals
to Metakaryotic Stem Cells 235
9.4.3 Growth and Development of Turnover Units
in HT-29 Cultures 235
9.4.4 Metakaryotic Stem Cells are Resistant to
Doses of X-Rays and Drug Classes
Commonly in Use for Cancer
Chemotherapy 237
9.4.5 Metakaryotic Stem Cells are Sensitive to
Many Drugs in Common Use:
Verapamil, Metformin, NSAIDS
and Antibiotics 237
9.4.6 Hypotheses about Metakaryocidal
Mechanisms, e.g. Inhibition
of Mitochondrial Function 239
9.4.7 Other Potential Targets for Metakaryocides:
Genome Replication and Segregation 241
9.4.8 Translation into Clinical Practice 242
9.4.9 Potential Use of Metakaryocides in
Prevention of Cancers and Other Clonal
Diseases 244
9.4.10 Other Considerations 244
References 246
Chapter 10 Distributed Stem Cell Kinetotoxicity: A New Concept to

Account for the Human Carcinogenicity of Non-genotoxic
Environmental Toxicants 250
Krishnanchali Panchalingam, Minsoo Noh, Yang Hoon Huh
and James L. Sherley

10.2 Results and Discussion 253
10.2.1 Development of a High-throughput Cell
Kinetics Assay for Kinetotoxicity 253
10.2.2 Use of High-throughput Screening to
Detect Benzene and Hydroquinone as
Kinetotoxic Agents 256
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xiv Contents
10.2.3Confirmation Studies for Benzene and

Hydroquinone Kinetotoxicity 262
10.2.4 Validation of Benzene and Hydroquinone
Kinetotoxicity with DSCs 265
10.2.5 Use of Microarray Analyses to Discover a

Potential Molecular Biomarker for
Kinetotoxicity 268
10.3 Conclusions and Closing Thoughts 270
10.3.1 Kinetotoxicity, An Extended Concept in
Human Stem Cell Toxicology for
Carcinogens 270
10.3.2 Development of a High-throughput Screen
for Kinetotoxic Agents 271
10.3.3 Mechanisms of Kinetotoxicity by Benzene
and Hydroquinone 272
10.3.4 The DSC Specification Problem in Human
Stem Cell Toxicology 273
10.3.5 Looking Forward 274
10.4 Materials and Methods 275
10.4.1 Cells 275
10.4.2 Chemicals 275
10.4.3 Development of the High-throughput
Microplate Assay for Kinetotoxicity 276
10.4.4 Assays for Self-renewal Kinetics Pattern
Determination 276
10.4.5 Microarray Analyses 276
References 277
Chapter 11 Cancer Stem Cells as Therapeutic Targets 280

Shinji Tanaka

11.2 CSC Markers and Therapeutic Targets 282
11.3 Signal Transduction in CSCs and Targeted
Agents 283
11.4 Asymmetric Cell Divisions: The Dilemma of
Studies on CSCs 284
11.5 Asymmetric Cell Divisions: Visualization of
CSCs and Toxicology 286
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Contents xv
11.6 Asymmetric Cell Divisions; Potential Therapeutics

Targeting CSCs 289
11.7 Closing Remarks 291
References 291
Subject Index 295

Published on 09 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782626787-00001
CHAPTER 1
Addressing Challenges to
Progress in Human Stem Cell
Toxicology Concepts
and Practice
JAMES L. SHERLEY
Asymmetrex, LLC, P.O. Box 301179, Boston, MA 02130, USA

Email: jsherley@asymmetrex.com
1.1 Filling in the Stem Cell Gap in Human

Toxicology
One way to gauge the degree of research and practice for a scientific dis-
cipline is to evaluate the number of times that, and the period of time over
which, its quoted name is found in published scholarly reports. Table 1.1
provides such data from PubMed1 and Google Scholar2 searches for the
disciplines of ‘human toxicology’, ‘reproductive toxicology’, ‘stem cell tox-
icology’ and ‘human stem cell toxicology’. For the term ‘stem cell toxicology’,
the results show vastly fewer reports that only appeared in the past several
years; and for ‘human stem cell toxicology’, even more dramatically, there
are none. The recognition of an immediate need to begin filling in the
remarkable gap in knowledge and research disclosed by this analysis was the
inspiration for Human Stem Cell Toxicology.
Human Stem Cell Toxicology was developed with the intention of igniting a
long overdue effort to set an updated, well-informed foundation for ‘human

1
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2 Chapter 1
Table 1.1 Database search results for fields related to human stem cell toxicology.
Field Number of reports Report years (total)
1
PubMed
‘‘Human Toxicology’’ 1101 1960–2016 (56)
‘‘Reproductive Toxicology’’ 1014 1980–2016 (36)
‘‘Stem Cell Toxicology’’ 5 2015 (1)

‘‘Human Stem Cell Toxicology’’ 0 N/A
Google Scholar2
‘‘Human Toxicology’’ 25 400 1908–2016 (108)
‘‘Reproductive Toxicology’’ 24 100 1909–2016 (107)
‘‘Stem Cell Toxicology’’ 27 2010–2016 (6)
‘‘Human Stem Cell Toxicology’’ 0 N/A
stem cell toxicology’ as a subfield of human toxicology, which, based on the

earliest scholarly reports identified by Google Scholar, is more than a cen-
tury-old discipline in human science and research. Knowing that the field of
stem cell biology is at least five decades from its origins, and human tox-
icology is a century or more old, may appear to present quite a conundrum
as to why stem cell toxicology, and human stem cell toxicology in particular,
have such scant and late representation in the scientific literature. However,
there is really no puzzle at all. First, as will be the focus later in this opening
chapter, the explanation is certainly related to scientific and technical
challenges that are unique to postnatal tissue stem cells. However, there are
also important features of the history and nature of toxicological sciences
that are also likely to have played important roles in the seeming neglect of
stem cells in toxicological research.
1.2 Historical Impact of the Hierarchical,

Anatomical, Sub-disciplinary Structure of
Toxicological Sciences
In the literature search results of Table 1.1, the subfield of reproductive
toxicology has a literature representation history that closely follows its parent
field, human toxicology. This is not surprising, as the reproductive system is
just one of the many tissue and organ systems defined by specific training,
research and expertise in human toxicology. ‘Reproductive toxicology’ is
considered here, because its usage often applies to studies that might also be
considered ‘stem cell toxicology’. Generally, the stem cells of focus have been
the germinal stem cells of the ovaries and the testes. To a lesser extent, later
on, embryonic stem cells have been considered as models for reproductive
toxicology focused on environmental and iatrogenic toxicants of embryonic
and fetal development.
The hierarchical, anatomical, sub-disciplinary structure of human tox-
icologicalsciences,whichisbasedonpopulation-,tissue-,organ-,cell-,organelle-
and molecule-specific organization of toxicants and their mechanisms of
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Addressing Challenges to Progress in Human Stem Cell Toxicology Concepts and Practice 3
action, met a pedagogical impasse with tissue stem cells. Although know-
ledge of tissue stem cells and their essential roles in tissue function and
repair is long-standing, the concept of them as critical targets of toxicants
and toxic mechanisms has been largely theoretical in construct. Import-
antly, this toxicology concept has not been readily approachable experi-
mentally. Even the concept that human carcinogens may act by inducing
alterations in tissue stem cells in humans continues to be a point of con-
troversy.3 The essential problem has been the elusive physical nature of
postnatal tissue stem cells. The challenge of distinguishing them from
other tissue cell types has thwarted the science of toxicology’s critical re-
quirement for quantifying effects of toxicants on their biological targets. So,
whereas it has been possible to define and establish toxicological
disciplines specialized for human populations, human organs, human
tissues, and many specifically identifiable other human cell types (e.g.
neurons, epidermal cells, endothelial cells, etc.), the same has not been
possible for postnatal tissue stem cells.
1.3 Human Stem Cell Toxicology as a Stem Cell

Exact Science
The above specification of ‘human stem cell toxicology’ to postnatal tissue
stem cells is not a trivial reference. Instead it is a crucial aspect of this new
toxicology discipline’s foundation. One of the most problematic aspects of
the general field of stem cell biology is the inexact language for ‘stem cells’.
This problem comes in two forms, technical and conceptual. The technical
form of the language problem is an outgrowth of well-informed and well-
intended attempts to accurately denote the cellular make-up of stem cell-
containing tissue compartments and tissue cell preparations. Because there
is often no physical basis for distinguishing postnatal tissue stem cells from
local and usually more abundant lineage-committed progenitor cells, which
are their progeny, terms like ‘stem/progenitor cells’ are widely used, as in
some chapters in this book. This usage is appropriate when the typical un-
certainty about stem cell phenotypic identity is an important consideration
or qualification. However, this terminology has become so dogmatic in the
field of mammalian stem cell biology that it has led to a widely misplaced
attitude that even conceptual or theoretical usage of the term ‘stem cell’
without including progenitors is inappropriate. In marked contrast to this
scientific piety, discussions involving current ‘stem cell biomarkers’ often
completely ignore the stem/progenitor ambiguity and apply and interpret
biomarkers, which clearly identify both stem cells and progenitor cells, as
if they only identified stem cells. As biomarkers with greater specificity
for tissue stem cells become available,4–6 this problem may resolve; but
currently it is an important correction required to set the foundation of
human stem cell toxicology as an exact science with respect to its definition
of ‘stem cell’.
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4 Chapter 1
The second conceptual form of the problem is even more fundamental,

although not known to many stem cell biologists. Stem cells are often
defined as cells that can either self-renew or differentiate. However, this
definition is only applicable to three types of cells in vitro: embryonic ‘stem’
cells, induced pluripotent ‘stem’ cells, and cancer cell lines that retain the
ability to differentiate, usually into one differentiated cell type. A characteristic

property of these cells is that they do not self-renew and differentiate. When
placed under conditions that allow differentiation, whether multiple differ-
entiated cell types are produced or only one, no self-renewing cells are
maintained. All the ‘stem’ cells, in fact, undergo differentiation. Therefore,
fundamentally, these cells are not ‘stem’ cells. They are progenitor cells. Their
conditional self-renewal is not a natural state, but one enforced by their
in vitro culture conditions. Informatively, epiblast cells, the in vivo originators
of embryonic ‘stem’ cells, are also not stem cells in their natural setting, but
instead progenitor cells. They undergo differentiation to develop the embryo,
but their initial phenotype is lost in the process.
The fundamental definition of a stem cell is a cell that can self-renew
and produce differentiating cells simultaneously without loss of its stem
phenotype for the life of the tissue that it renews. This ability, which is
unique to stem cells, is called asymmetric self-renewal.7–10 In marked
contrast to progenitor cells, stem cells preserve their stem cell phenotype.
Although the mathematical form that achieves this balance continues to
be a controversial topic,7,10,11 there is no dispute regarding the preser-
vation of the stemness phenotype being an essential element of stem cell
character.12
Three types of human tissue cells have been described that meet the
fundamental asymmetric self-renewal definition for stem cells. The first two
are well-studied, postnatal tissue-specific stem cells (also called distributed
stem cells in Chapter 10) and eukaryotic cancer stem cells (Chapter 11). The
third type is a more recently discovered remarkable class of asymmetrically
self-renewing stem cells found during the development of fetal organs and
tissues, called metakaryotic stem cells (Chapter 9). In each case, these stem
cells divide to produce differentiating progeny cells while simultaneously
maintaining their stemness properties.
The newly defined discipline of human stem cell toxicology currently
encompasses research with pluripotent cell types (e.g. Chapter 6). This in-
clusion may maintain to the extent that pluripotent cells prove to be able to
produce asymmetrically self-renewing tissue-specific stem cells in large
numbers. However, the enthusiasm for such studies must always be tem-
pered by the inherent genetic and epigenetic alterations that occur when
pluripotent cell types are derived.13 By grounding human stem cell toxi-
cology as an exact stem cell science, defined by investigation of the
toxicology of human stem cells that undergo asymmetric self-renewal, the
new discipline will also encourage increased precision with these essential
concepts in stem cell biology as a whole. Many of the contributed chapters
reflect this ideal foundation.
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1.4 Health and Medical Applications for Human

Stem Cell Toxicological Sciences
Given the ideal foundation in an exact definition for stem cells, human stem
cell toxicology has three immediate areas of application that are directly
derivative of the involvement of the three identified types of asymmetrically

self-renewing stem cells in human health and medicine. As for human
toxicology in general, the foremost application is environmental health
science. Both fetal metakaryotic stem cells and postnatal homeostatic tissue
stem cells figure prominently in this regard. Chapters in this book focus on
the importance of these cells as targets for carcinogenic toxicants, and their
respective key roles in fetal development and postnatal tissue maturation and
aging make them crucial toxicant targets for investigation and elucidation.
The second and third applications reflect a splitting of the personality of
toxicology for medicine. On the one hand, a traditional protective toxicology
pursuit – understanding and eliminating toxic drug candidates – focused
now on postnatal tissue stem cells, is an important need in drug develop-
ment. Currently, tissue stem cell-toxic drug candidates, which are highly
unsafe drugs, are detected by their induction of organ and tissue failure in
expensive preclinical animal studies or in even more costly, in both money
and human suffering, clinical trials. New, less expensive, cell culture-based
assays for detection of tissue stem cell toxicity would accelerate drug dis-
covery and greatly reduce its cost, in terms of both expense and risk to re-
search volunteers and patients. In the case of development of drugs for fetal
disorders or that might be taken during pregnancy, this application also
applies to metakaryotic stem cells. However, as will be noted below, the
biology of metakaryotic stem cells places them in a much greater state of
readiness for achieving these advances in drug development applications.
The third application, the development of anti-cancer stem cell drugs, is
the atypical face of the toxicology personality split. Instead of seeking to
prevent or avoid stem cell toxicity, in the case of new cancer stem cell therapy
paradigms, the goal is to discover drugs with cancer stem cell-specific toxi-
city. By destroying cancer stem cells, which are responsible for the asym-
metric self-renewal of tumors, drug developers hope to induce tumor
failures, much in the way that agents toxic against normal tissue stem cells
induce organ and tissue failure. Cancer stem cell therapeutics faces all the
technical problems inherent to investigations of normal postnatal tissue
stem cells. In fact, it is likely that many cancer stem cells are derived from
mutated variants of tissue stem cells.10 So, no specific quantitative bio-
markers exist, and the cells are a small fraction of total tumor cells. The
pursuit of anti-cancer stem cell drugs has the added challenge of specific
targeting to spare normal tissue cells, and in particular normal tissue stem
cells, which are likely to be targeted often by the same agents because of the
unique properties they share with cancer stem cells.
The recently discovered metakaryotic stem cells provide a new paradigm
that sets the standard for achievement by all future investigations in human
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6 Chapter 1
stem cell toxicology. Unlike postnatal tissue stem cells and previously
described eukaryotic cancer stem cells, metakaryotic stem cells, both normal
and tumor-derived, are specifically and directly identifiable and quantifiable
based on their morphology and molecular expression (Chapter 9). Because of
their unique forms of amitotic cell division and DNA replication by a
RNA:DNA hybrid intermediate that are not shared by other cell types,
metakaryotic stem cells are physically and molecularly distinctive. Given
these ideal properties, it seems very likely that many future standard analysis
paradigms in human stem cell toxicology will be developed first in investi-
gations of the toxicology of metakaryotic stem cells, both normal ones in
fetal development and cancerous ones in fetal and postnatal tumors. Whe-
ther there is a developmental lineage relationship between metakaryotic
stem cells and homeostatic postnatal tissue stem cells or eukaryotic cancer
stem cells is presently unclear. However, if such lineage connections exist,
continued investigations of metakaryotic stem cell biology and toxicology
may reduce some of the current seemingly insurmountable barriers to tox-
icological analyses of the other two human stem cell types.
1.5 Introducing the Future Diverse Impacts of

Beyond setting a foundation of stem cell exactness to the new field of human
stem cell toxicology and highlighting the challenges of identifying stem cell
toxicants and their mechanism of action against human stem cells specif-
ically, this inaugural volume begins the introduction to the diverse aspects
of human stem cell toxicological science, including development of new
technologies for improving stem cell toxicant detection and addressing the
problems of specific stem cell detection; investigations for toxicant targets
that impact stem cell function indirectly; and examples of the investigation
of the effects of previously well-studied human toxicants on tissue stem cells.
As might be expected, the category with the largest number of chapters
contributed (Chapters 2, 3, 5, 9, 10) provides treatments of the progress and
challenges in developing high-throughput screens for stem cell toxicants in
both environmental health science and drug development arenas. In most
cases, developing better assays with greater stem cell definition is the main
objective of these presentations; whereas for others, the main focus is an
advance in human stem cell toxicology that required innovation in assay
technology as well.
In one case, the reported advance is an integration of a new stem cell
toxicology concept with a new technological development (Chapter 10). The
new concept, ‘kinetotoxicity’, is conceptually similar to the long-standing
colony forming unit (CFU) approach to quantifying toxicant effects on
elusive human hematopoietic stem cells (HSCs; Chapters 2 and 7), but
technically distinct. The presence of stem cells is detected indirectly by their
cellular output. In the case of the CFU approach, the scored output, mor-
phologically differentiated cell colonies, provides a largely qualitative
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assessment of stem cell number and is limited to HSCs. Kinetotoxicity is a

quantitative measure of a toxicant’s interference with stem cell asymmetric
self-renewal, a kinetics output, and a highly associated stem cell process,
immortal strand co-segregation (ISC) that can be scored molecularly. These
advances for postnatal tissue stem cells have the potential to provide the
specific and quantitative capabilities of metakaryotic stem cells.

Although stem cells are typically sequestered in access-limited micro-
anatomical niches, these are islands with weather and shores. There are
many aspects of stem cell biology besides the autonomous processes of stem
cells (i.e. metabolism, cell division, mutagenesis, etc.) that determine their
function. Human Stem Cell Toxicology includes chapters on ‘stem cell dif-
ferentiation’ (Chapter 5), catecholamine regulation of stem cell mobilization
(Chapter 4), and stem cell epigenetics as targets for stem cell toxicants
(Chapter 8). This is but a very short list of important stem cell interactions
and regulation that toxicants might disrupt to cause stem cell toxicity.
However, these few examples serve to confirm that a basic axiom of general
human toxicology also applies to human stem cell toxicology. For example,
just as some human toxicants require metabolism by the liver before being
activated to affect a different organ site, stem cell-toxic mechanisms may
involve sites of action distal to the impacted stem cells.
A corollary of the distal action axiom is that investigations of the mech-
anisms of stem cell toxicants can lead to increased understanding of the
function and regulation of one of the most elusive cell types in the body. In
keeping with this concept, some chapters in Human Stem Cell Toxicology
consider the responses of stem cells to well-studied environmental toxicants
like pesticides (Chapter 7) and even household medicines (Chapter 9). From
these inaugural contributions to establish the discipline, as well as other
chapters in this volume, it is certain that human stem cell toxicology
promises many intriguing revelations in the future that will greatly impact
human health and medicine.
Acknowledgements
I thank Professor Diana Anderson, of the University of Bradford, UK and The
Royal Society for Chemistry, for her vision of the timeliness of this volume and
her gracious invitation to me to serve as the editor for its completion. In
addition to my co-authors for their seminal contributions, I also wish to thank
the unseen members of the international human toxicology community who
expresssed genuine enthusiasm for the project and recommended ideal
authors, both of which were crucial elements in its successful completion.
References
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London, 1997, pp. 1–27.
8. J. Sherley, Tissue stem cells, in Encyclopedia of Cancer, ed. M. Schwab,
Springer-Verlag, Berlin, Heidelberg, 2009, DOI: 10.1007/SpringerReference_
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9. J. L. Sherley, Asymmetric self-renewal: the mark of the adult stem cell, in
Stem Cell Repair and Regeneration, ed. N. A. Habib, M. Y. Gordon,
N. Levicar, L. Jiao and G. Thomas-Black, Imperial College Press, London,
2005, pp. 21–28.
10. J. L. Sherley, New cancer diagnostics and therapeutics from a 9th
‘‘hallmark of cancer’’: Symmetric self-renewal by mutated distributed
stem cells, Expert Rev. Mol. Diagn., 2013, 13, 797–810.
11. H. Clevers, STEM CELLS. What is an adult stem cell? Science, 2015, 350,
1319–1320, DOI: 10.1126/science.aad7016.
12. J. L. Sherley, Stem cell differentiation: What does it mean? Proc. Second
Joint EMBS-BMES Conf. Houston, TX, October, 2002, 1, 741–742.
13. J. L. Sherley, Accelerating progress in regenerative medicine by advancing
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Anal. Acta, 2014, 5, 286, DOI: 10.4172/2153-2435.1000286.
CHAPTER 2
Alternative Methods in
Haematopoietic Stem Cell
Toxicology
NAVNEET KUMAR YADAV,*,y POOJA SHUKLAy AND
R. K. SINGH*
Hematological Facility, Division of Toxicology, CSIR-Central Drug

Research Institute, BS-10/1, Sector 10, Jankipuram Extension,
Sitapur Road, P.O. Box 173, Lucknow 226031, India
*Email: navneet17yadav@gmail.com; rk_singh@cdri.res.in
2.1 Introduction
Hematopoietic stem cells are very primitive cells localized in the bone
marrow (BM). They are pluripotent cells, having capacity for self-renewal and
differentiation to produce all kinds of blood cells (e.g. T cells, B cells, natural
killer cells, granulocytes, monocytes, erythrocytes and platelets) to perform
different functional roles in the human body.1,2 The mature blood cells have
a limited lifespan (several days to many years); thus, hematopoietic stem
cells produce a large number of bloods cell every day to replace the dying
cells and ultimately sustain the hematopoietic system of individuals
throughout their lives (Figure 2.1).3–5
The hematopoietic system is a characteristic of all vertebrates. It performs
a plethora of functions. Amongst components of the hematopoietic system,
y
Contributed equally to this chapter.

9
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10 Chapter 2
Figure 2.1 Illustration showing hematopoietic and stromal cell differentiation.
blood stands out as an integral one. Blood, which is the prime connective
tissue, carries out many essential functions. It is the ultimate transport
system for the delivery of oxygen from the lungs to the overall body via the
aorta, and carbon dioxide from the overall body for expiration from the
lungs. Thus, blood follows a pattern of double circulation in humans. It
carries out the transportation of various nutrients, amino acids, fats and
other essential substances to different parts of the body. Blood is vital for
maintaining basal metabolism, as it helps in maintaining optimum body
temperature via thermoregulation. Blood shows a very strict pattern of flow
in the skin that results in thermoregulatory balance. In heat, the blood flow
increases and reaches 6–8 liters per minute. Cooling temperatures lead to a
decrease in blood flow in the skin to minimum levels. The blood also
maintains thermoregulatory balance in health conditions like the meno-
pause and diabetes.6 Thus, blood tends to maintain a constant body
temperature and has a homeostatic role. Such homeostatic functions of
blood make it the ultimate buffer in the body, responsible for maintaining
a pH balance. Proper pH balance is crucial for good health. In the case of
acidic pH, the ability of cells to absorb nutrients deteriorates. The normal
reference range of pH for a healthy person is 7.35 to 7.45.7 Such a narrow
reference range is executed by the blood through various acid–base balance
mechanisms. Deviation from this normal range has been associated with
disease prognosis, e.g. acidosis, formation of tumours.8 Blood is respon-
sible for the collection of harmful and unwanted materials from each part
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Alternative Methods in Haematopoietic Stem Cell Toxicology 11
of the body and their transport to the excretory organs (e.g. kidneys) where
waste products are disposed of. Blood (along with lymph) performs im-
munogenic functions. It is responsible for transportation of the com-
ponents of the immune system to locations in the body where they are
needed. To perform such important functions, blood has to possess the
potential for rapid genesis. This is evident by the fact that a healthy adult
body produces 1–3 million new blood cells per second.9 About 2.4 106 red
blood cells (RBCs) are produced each second and live for about 120 days.
White blood cells (WBCs) have a lifespan of 59 days. There are 5–10 103
leucocytes present in each cubic centimeter. Neutrophils have a lifespan of
1–4 days, but are continuously replenished. The immense cell production
capacity of the hematopoietic system is evident by the fact that in con-
ditions of low oxygen (e.g. at high altitudes), RBC production can be as high
as six times greater compared to normal oxygen conditions. With such
short lifespans and immense proliferative capacities, blood and its cell
components are very susceptible toxicity targets for chemicals that
suppress cell proliferation.
The major breakthroughs in stem cell research started with the advent
of various technological advancements, leading to quantification of stem
cell populations. Major progress was achieved with the observation that
radiation-induced injury could be protected against by intravenous trans-
plantation of normal rat BM cells.10 Other, similar observations implied that
BM consists of adult rat cells, which are capable of repopulating and re-
establishing the destroyed cells.11
It was known that BM is not the only source of haematopoietic cells and
that the spleen also plays a vital role. First, CFUs were obtained from the
spleen.12 These CFUs carried specific biomarkers and were generated by
single parental cells (from the spleen).13 The colonies so obtained were a
cocktail of myeloid and lymphoid lineages. Myeloid are erythroid, mega-
karyocytic, granulocyte, macrophage, whereas lymphoid are the T and B
cells.14 The nature, number and types of these lineage-restricted cells were
variable.15,16 All the cells of the colonies were in the quiescent stage
(Go phase of cell cycle).17,18
Altogether, various observations led to a common notion that inside the
BM of adult mammals there resides quiescent, heterogeneous, dividing,
replenishable haematopoietic cells that can be lymphoid or myeloid in their
lineage. These cells can be used whenever the organism needs to fulfil any of
the requirements of cells throughout its lifetime.18
2.2 Haematopoietic Stem Cell Toxicity or

Hematotoxicity
By definition, hematotoxicity is the effect of chemical exposures (i.e. drugs,
chemicals, pesticides and toxicants) on the hematopoietic system including
blood, its components, and blood-forming organs (Figure 2.2).19
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12 Chapter 2
Figure 2.2 Scheme showing source of hemato-toxicants and various clonogenic

assays.
2.2.1 Sources of Haematopoietic Stem Cell Toxicity

2.2.1.1 Therapeutic Drugs
Many drug and treatment regimens act by mechanisms that suppress the
proliferative potential of the haematopoietic system. This situation occurs
because many diseases and disorders are characterized by either loss or gain
of tissue generative potential. The haematopoietic toxicity of these treatment
regimens is manifested as adverse drug reactions (ADRs). These ADRs are
undesirable side effects of these drugs. Table 2.1 provides a list of well-
known drugs that are associated with induction of haematotoxicity.20–27
2.2.1.2 Disease Conditions

Coeliac disease is correlated with hematotoxicity, which is characterized
by anemia in patients. Other manifestations of coeliac disease include
thrombocytosis, thrombocythemia, leukopenia, thromboembolism, increased
bleeding tendency, IgA deficiency, splenic dysfunction and lymphoma.
2.2.1.3 Occupational Toxicants

Table 2.2 list chemicals that are known to induce hematotoxicity when
contacted.28–31
2.2.1.4 Chemotherapy
Drug treatment regimens against cancer destroy the cancer cells by
obstructing their ability to grow and divide.32 These chemotherapy drugs
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Alternative Methods in Haematopoietic Stem Cell Toxicology 13

Table 2.1 Drugs that induce hematotoxicity as an adverse drug reaction.
S. no. Drug name Therapeutic use
1. Dapsone Leprosy
2. Ziduvidine Anti-HIV
3. Paclitaxel Anti-cancer
4. Bendamustin Anti-chronic lymphocytic leukemia (CLL)

5. Convulex Anti-epileptic
6. Ribavirin Hepatitis
7. Rifampicine Antibiotic
8. Primaquine Antimalarial
Table 2.2 Occupational toxicants causing hematotoxicity.

S. no. Chemical name Use
1. Benzene Industrial solvent for polymer production
2. Nitrocellulose Industrial solvents commonly used in furniture,
paints and automobile spray painting industries
3. Phenylhydrazine Intermediate in agriculture industry
4. Pesticides Agrochemical industry
circulate in the bloodstream and directly damage cells that are actively
growing. Because they generally divide at a higher rate than many normal
cells, cancer cells are somewhat more susceptible to the action of these
drugs. However, damage to actively dividing normal cells occurs as well, and
this damage accounts for the ADRs of these drugs, which in the haemato-
poietic system are manifested as anemia, neutropenia, thrombocytopenia,
agranulocytosis, etc.33
Doxorubicin, carboplatin, cisplatin, lenalidomide, thalidomide, clopido-
grel, cetuximab, oxaliplatin, irinotecan, capecitabine, gemicitabine, irinote-
can, topotecan, tetraplatin and vincristine are all examples of approved,
popular, prescribed anticancer drugs.34 These induce significant hemato-
toxicity as an undesired side effect. These chemotherapy drugs are circulated
throughout the body and lack ideal selectivity for only cancer cells.
Many anticancer drugs act by obstructing the proliferative capacities of the
cells. Haematopoietic cells are one of the most highly adversely affected cell
types. This adverse side effect is evident as hematotoxicity in cancer patients
undergoing chemotherapy.35 Many reports show that this hematotoxicity
becomes a limiting factor during cancer treatment. Only 53–70% of these
treatments are able to be continued to completion.36 Completion of treat-
ment according to the treatment protocol is extremely important in order to
achieve sufficient therapeutic efficacy.
2.2.2 Importance of Studying Haematopoietic Stem Cell

Toxicity
Hematotoxicity is investigated by industrial hygienists, toxicologists and
occupational physicists. Their evaluations involve the study of chemicals
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—— (Virgil’s), xi. 492.
Ænobarbas (in Shakespeare’s Antony and Cleopatra), see
Enobarbus.
Ænone, v. 203.
Æschylus, i. 194; iv. 216; v. 56; vi. III; viii. 12; x. 33; xi. 284, 506; xii.
240, 260.
Æsop. See Fables by Æsop.
Ætna, v. 122.
Afrancesadoes (Spaniards), i. 428.
African (or Negro), i. 69.
Agamemnon (Æschylus), i. 221; v. 54; x. 81, 94, 98; xi. 284, 421; xii.
240, 260.
Agar (Welbore Ellis), vi. 369.
Agatha Friburg (in Kotzebue’s Lovers’ Vows), viii. 335.
Age of Elizabeth, The Lectures on, etc.; Lecture I.—Introductory, v.
175.
Agincourt, i. 285, 289, 425.
Aglaura (Suckling’s), viii. 57.
Agli, Messer, x. 300.
Agnes, or the Triumph of Principle, iv. 243 n.
—— (Mrs Radcliffe’s), viii. 126
—— (in Lillo’s Fatal Curiosity), ii. 212.
—— (in Molière’s School for Wives), viii. 76; xi. 276.
Agnese (opera by Paer), viii. 540.
Agnolo, Andrea d’. See Andrea del Sarto.
Agreeable Surprise, The (O’Keeffe’s), viii. 166, 167, 319, 387, 463.
Agriculture, On (Cowley), viii. 60.
Aickin, James, ii. 197, 199, 201.
Aikin, Dr John (Dr A.), ii. 198; xi. 505.
Ailsa, Craig of, ii. 64.
Aimwell (Farquhar’s Beaux’ Stratagem), viii. 10, 88.
Airy, Sir George, viii. 503.
Ajax, x. 94; xii. 10.
Akenside, Mark, i. 114; ii. 79; iii. 222; v. 68, 119, 375; xi. 573.
Aladdin, ix. 269.
Alastor, or the Spirit of Solitude (Shelley’s), x. 261, 265.
Albano, Francesco, i. 77; vi. 441; ix. 34, 111, 236.
—— Hills of, ix. 234, 254, 376.
Albany, The, xi. 486.
—— Duke of, ii. 80.
Albemarle Street, i. 370; iii. 217; iv. 367; xi. 423, 486, 487.
Albergo di Venezia (an inn), ix. 264.
Alberigi, Frederigo, i. 163, 331; vii. 303; x. 68; xi. 501.
Albigeois, The Civil Wars of the, x. 56.
Alcæus, iv. 271.
Alcamenes (painter), ix. 466.
Alcantara (town), iii. 290 n.
Alceste (in Molière’s Misanthrope), ix. 150–1
Alcestis, vi. 179; x. 97.
Alchymist, The (Ben Jonson’s), viii. 45, 227; x. 117, 171.
Alcibiades, i. 211 seq.; vii. 213; xi. 228.
Alcides, The (acrobats), vi. 442.
Alcinous, Gardens of, ix. 325; xi. 514.
Alderman Gripe (Wycherley’s Love in a Wood), viii. 78.
Aldermanbury, xi. 441.
Aldobrand (in Maturin’s Bertram), viii. 306–7.
Aldridge’s, ii. 174.
Ale-house Door (Wilkie’s), viii. 140; ix. 15; xi. 252.
Aleman, Mateo. See Guzman D’Alfarache.
Aleppo (referred to in Shakespeare’s Othello), xi. 283.
Alexander and Campaspe (John Lyly’s), v. 197, 201, 202.
—— Battle of (a picture), ix. 41.
—— of Aberdeen, ii. 209.
—— I. of Russia, iii. 56, 160, 306; iv. 189; ix. 479; xi. 415.
—— the Great, i. 291; ii. 67, 173; iv. 71; v. 124; vi. 106, 107; x. 15, 17,
26, 329; xi. 3, 234, 553; xii. 37, 204.
Alexander the Great (by Lee, Nathaniel), v. 357; vi. 342; vii. 301.
—— VI., Pope, Bower’s Life of, ii. 172.
—— the Spy, ii. 154 n.
Alexander’s Feast (Dryden’s), iv. 276; v. 81, 372; vi. 204 n.; xii. 347.
Alfieri, Count, x. 45, 232, 241; xi. 424.
Alfred (Wilkie’s), ix. 389.
Algiers, iii. 335, 442.
Alhambra, The, ix. 349.
Alice (in Scott’s Old Mortality), iv. 247.
—— Bridgenorth (in Scott’s Peveril of the Peak), xi. 540.
Alicia (in Rowe’s Jane Shore), viii. 352.
Alien Bill, The Scotch, ix. 214.
—— Office, The, ii. 248.
Alighieri, Family of the, x. 63.
Alithea (in Wycherley’s adaptation of Molière’s School for Wives),
viii. 76, 153, 554; xi. 276.
Allan, The bog of, v. 34.
Allen, Bobbie (Lamb’s schoolfellow), xi. 585.
Allen-a-Dale (in Scott’s Ivanhoe), iv. 209.
Allen, John, M.D., ix. 17.
All Fools (Chapman’s), v. 234.
All for Love (Dryden’s), viii. 190.
All-Foxden, vi. 183; xii. 269, 271.
All in the Wrong (Murphy’s), viii. 164.
Allston, Washington, xi. 189, 190, 456 n.
All’s Well that Ends Well (Shakespeare’s), i. 329;
also referred to, iii. 437; viii. 330; xi. 296.
Allworthy (in Fielding’s Tom Jones), vi. 452.
Almack’s, xi. 343.
Almanach des Gourmands, The, xi. 501.
Almeria (Congreve’s Mourning Bride), viii. 75.
Almeyda (in Dryden’s Don Sebastian), v. 357.
Alonzo (in Maywood’s Zanga), xi. 398.
Alphonso VI. of Castile and Leon, x. 57.
Alps, The, iv. 193; vii. 368; ix. 182, 188, 190, 195, 199, 207, 208, 240,
263, 264, 273, 277, 288, 290, 297, 303, 360; xi. 231; xii. 134.
Alpuente, Romero (Landor’s), x. 251.
Alric (in Holcroft’s The Noble Peasant), ii. 110.
Alsop, Mrs, viii. 252, 355, 361, 369, 370, 412, 524; xi. 277, 305.
Alsop’s Rosalind, Mrs, viii. 252.
Altarpiece of St Mark (Tintoretto’s), ix. 113.
Alton (town), vii. 126.
Altona (town), ii. 256.
Alwyn, or the Gentleman Comedian (Holcroft’s), ii. 95 seq., 280.
Amadis de Gaul (early romance), i. 133; vii. 253; x. 14, 19, 20, 57; xii.
62.
Amadis of Greece, x. 57.
Amanda (Vanbrugh’s Relapse), viii. 83.
Amanthis (in Mrs Inchbald’s Child of Nature), viii. 196.
Amaryllis, vii. 41.
—— (in Fletcher’s Faithful Shepherdess), v. 255.
Ambrogetti, Signor, viii. 365; xi. 308.
Ambrose Lamela (in Le Sage’s Gil Blas), vii. 380.
Ambrose (Wilson’s Noctes Ambrosianæ), xii. 367.
Amelia (Fielding’s), i. 130; vi. 457; vii. 84; viii. 114, 115, 152, 555; x.
32, 33; xi. 501; xii. 64.
—— Mammonton (in Ups and Downs), xi. 385, 387.
Amelia, the Princess (George II.’s daughter), x. 159.
—— Carolina Wilhelmina Skeggs (in Goldsmith’s Vicar of Wakefield),
iii. 313.
—— Wildenheim (in Lovers’ Vows, Mrs Inchbald’s adap. of
Kotzebue’s Natural Son), viii. 249, 336.
American Farmer’s Letters, The, x. 314.
—— Lion (Kean’s), xi. 332.
—— Literature—Dr Channing, x. 310.
—— Revolution, ii. 133; iii. 32 n., 279, 302, 304; vii. 52.
—— War, The, iii. 250, 420, 422, 424; vi. 385; x. 150–2; xii. 263, 293.
Americans, ix. 257.
Amiens, ii. 216; iii. 6, 61, 83, 99; vii. 227 n.
—— (Shakespeare’s As You Like It), xi. 367, 378; xii. 122.
Amine (in Arabian Nights), viii. 14.
Aminta (Tasso’s), x. 73.
Amintor (in Beaumont and Fletcher’s Maid’s Tragedy), v. 251, 252.
Amlet, Mrs (Vanbrugh’s Confederacy), viii. 14, 80.
Ammerbach (philosopher), x. 143.
Amory, John, i. 52.
Amours of Peter the Long (L. E. Billardson de Sauvigny), ii. 107.
Amphion, xi. 282.
Amphitheatre of Titus, ix. 234.
—— The (at Verona), ix. 277.
Amsterdam, vii. 100; ix. 295, 300, 301.
Amy Robsart (in Scott’s Kenilworth), ii. 314; iv. 248, 251.
Anabaptists, x. 360.
Anacharsis (traveller), vii. 255.
Anacreon, iv. 356; vii. 372 n.
Anacreon (Herrick’s translation), v. 312.
Anacreontics (Cowley’s), v. 372; viii. 59.
Anah (Byron’s), vii. 85.
Analogy (Butler’s), vi. 224; ix. 415; xii. 266, 346.
Analytical Review, The, ii. 116.
Ananias (Raphael’s), ix. 272 n.
Anastasius, vii. 220.
Anatomy of Melancholy (Burton’s), iv. 365; vi. 225.
Ancient Britons (the corps), ii. 176.
—— Mariner (Coleridge’s), iii. 205; iv. 218; v. 166, 377; viii. 14; xii.
236, 273, 319, 460.
—— Pistol (Shakespeare’s Henry IV., etc.), i. 425; iii. 54.
—— and Modern Literature, On Spirit of; On German Drama
contrasted with that of Age of Elizabeth, v. 345.
Ancona, View of (Wilson’s), xi. 199.
Andalusia, Castle of (O’Keeffe’s), viii. 329.
Anderson, Dr, v. 124.
Andes, iv. 193; vii. 255; viii. 415.
Andrea del Sarto, vi. 11; ix. 25, 51, 226.
Andromache (Racine’s), viii. 334.
Andromeda (Guido’s), vi. 441; viii. 253; ix. 61, 237.
Andrugio (in Marston’s Antonio and Mellida), v. 225.
Angelica (Congreve’s Love for Love), i. 133; viii. 15, 152, 555.
—— and Medora (a picture), ii. 212, 227; v. 3; x. 71.
Angelo (in Shakespeare’s Measure for Measure), i. 346, 347.
—— Michael. See Michael Angelo.
Angerstein, John Julius, vi. 174, 346; ix. 9, 35, 75, 113, 439.
Angerstein’s Collection, ix. 7.
Angiers, i. 311.
Anglade Family (or Accusation, by Payne), viii. 279.
Anglaises pour rire (a play), xi. 366.
Angler. See Complete Angler.
Angrisani (Signor), viii. 365, 371; xi. 308.
Anhalt (in Lovers’ Vows, Mrs Inchbald’s version of Kotzebue’s
Natural Son), viii. 249.
Anjou, Charles of, x. 56.
Anlaff the Dane (in Holcroft’s The Noble Peasant), ii. 110.
Anna, Verses upon (Gifford’s), iv. 302; vi. 221.
—— St Ives (Holcroft’s), ii. 128, 132, 136, 201, 279.
Annabel (in Holcroft’s The Man of Ten Thousand), ii. 160.
Annabella (in Ford’s ’Tis a Pity She’s a Whore), v. 269.
Anne Page (in Shakespeare’s Merry Wives), i. 350; ix. 36.
—— Queen, i. 8, 138; iii. 405; iv. 212, 217, 367; v. 82, 104, 105; vi. 113,
322, 323, 376, 445; viii. 96; x. 73, 205, 310, 358, 373, 374, 377,
378; xii. 405.
Annecy (town), i. 17; v. 100; vii. 304.
Annesley (a novel), x. 392.
Annual Anthology, iii. 211.
—— Register, ii. 56.
Annunciation (Guido’s), ix. 111.
Annus Mirabilis, The (Dryden’s), v. 81.
Anselme (in Molière’s L’Avare), xi. 379.
Anstey, Christopher, viii. 560.
Antæus, i. 160; iv. 38.
Antigone (Sophocles), x. 81, 97.
Antigonus (Shakespeare’s Winter’s Tale), i. 324.
Anti-Jacobin Review, i. 401; iii. 219, 238, 261, 262, 295; v. 164; x.
139, 158, 225.
Antinous, The (statue), vii. 167; viii. 149; ix. 107, 350, 378; xi. 228,
486, 542.
Antipholis (in Shakespeare’s Comedy of Errors), i. 351; iv. 341; vi. 58;
viii. 401.
Antipodes, xii. 279.
Antiquary (Scott’s), iv. 248; vii. 156; viii. 413, 425; ix. 202; xi. 558.
Antiquaries, Society of, viii. 335.
Antiquity, On, vii. 252.
Antonines, The, ix. 366.
Antonio (in Middleton’s Witch), v. 218.
—— (Shakespeare’s Merchant of Venice), i. 321; viii. 179, 250, 374; xi.
417.
—— (Godwin’s), iv. 210 n.; xii. 326.
—— and Mellida (Marston’s), v. 224, 225.
Antony (Shakespeare’s Julius Cæsar and Antony and Cleopatra), i.
197; iv. 183; vii. 264.
—— and Cleopatra (Shakespeare’s), i. 228; v. 50, 253; viii. 190;
also referred to, i. 195; v. 253; viii. 31, 389; ix. 27.
Antwerp, ix. 110, 300, 302, 492; xii. 48 n.
A. P. E., vii. 124, 207.
Ape, Lines on the Story of the (Merry’s), iv. 309 n.
Apelles (sculptor), vi. 74.
—— (in Lyly’s Alexander and Campaspe), v. 201.
Apemantus (Shakespeare’s Timon of Athens), i. 210 et seq.
Apennines, The, ix. 199, 207, 208, 209, 210, 254, 260, 263, 264, 276,
303; xii. 57, 134.
Apicius, xii. 141.
Apocalypse, The, vii. 199; xii. 280, 441.
Apollo, i. 34, 416; v. 83, 192; vi. 141; vii. 157; x. 349, 350; xi. 544; xii.
341.
—— (statues), iii. 169; v. 164; vi. 141; ix. 28, 107, 147, 164, 165 n., 169
n., 222, 223, 237, 240, 339, 340, 341, 350, 378, 379, 381, 430,
491–2; x. 341, 342, 344; xi. 196, 227, 228, 493.
Apollo and Daphne (Titian’s), ix. 74.
—— giving a Poet a Cup of Water (Poussin’s), vi. 172; ix. 24.
—— and the Seasons (R. Wilson’s), ix. 392; xi. 198.
Apollodorus, x. 100.
Apology for His Own Life (Cibber), viii. 160, 359.
Apostate, The (by Richard Lalor Sheil), v. 345; viii. 538.
Apostates, On Modern, iii. 155.
Apothecary (in Shakespeare’s Romeo and Juliet), ii. 368 n.
Apparitions, History of (Defoe’s), x. 382.
Appeal to Honour and Honesty (Defoe’s), x. 369 n.
—— from the New to the Old Whigs (Burke’s), iii. 32.
Appius and Virginia (Webster’s), v. 234.
Appleby, iii. 423; v. 148.
Application to Study, On, vii. 55.
Apprentice, The (Murphy’s), viii. 514.
Apuleius, Lucius, v. 199; vi. 201; x. 17, 18.
Apullius and Apullia (Turner’s), xi. 190.
Aquapendente (town), ix. 230.
Aquinas, Thomas, iv. 217; xii. 35.
Arabia, v. 88, 340 n.; xi. 560.
Arabian Nights, i. 46; ii. 347; iv. 337; v. 113; vi. 53, 408; vii. 23, 421
n.; viii. 12, 13, 14; ix. 69; x. 46.
Aram, Eugene, vi. 314; xii. 34.
Araminta (Vanbrugh’s Relapse), viii. 83.
Arbaces (in Beaumont and Fletcher’s King and no King), v. 252.
—— (in the opera Artaxerxes), viii. 248, 321, 451.
Arbe, The (river), ix. 292.
Arbela, The Battle of, vi. 107.
Arbuthnot, John, iii. 33; iv. 217; v. 78, 104, 105.
Arcadia, i. 338; ix. 324, 325.
—— Sir Philip Sidney’s, v. 98, 318, 319, 320, 321, 323, 324, 325, 326;
ix. 9, 10, 58; x. 14; xii. 282.
Arch of Constantine (Claude), ix. 54.
—— of Constantine, ix. 232.
Archangel, ii. 251.
Archbishop of Grenada, The (in Le Sage’s Gil Blas), x. 31.
Archer (in Farquhar’s Beaux’ Stratagem), viii. 14, 88; xii. 451, 452.
Archimago (in Spenser), v. 36.
Archimedes, iii. 151; vi. 377; x. 13; xii. 36.
Arcite (Chaucer), v. 21, 29, 30, 258.
Arctic Circle, The, xii. 253.
Arden of Feversham (play), i. 357.
—— Forest of, i. 185, 338, 339; xi. 367; xii. 122.
Arethusa, xii. 200.
—— (in Beaumont and Fletcher’s Philaster), v. 262.
Aretine, Peter, iii. 218; iv. 225; v. 186; viii. 10.
Aretino, Pietro (Titian’s supposed portrait of), ix. 354; xii. 30.
Arezzo, ix. 262, 302.
Argenis (Barclay’s), x. 145.
Arguing in a Circle, xii. 285.
Argus, The (a newspaper), xi. 386.
Argyll, Duke of, vi. 521.
—— 2nd Duke of, John Campbell, iii. 415.
—— The Duchess of, vi. 450.
—— in Prison (Northcote’s), vi. 341.
—— Place, vi. 358.
Ariadne, vi. 238; vii. 125; xii. 203.
Ariel (Shakespeare’s Tempest), i. 23, 238, 241, 245; iv. 216; v. 15, 151;
viii. 235, 236; ix. 177, 463; x. 116; xi. 179.
Ariosto, i. 161; iv. 257, 356; v. 3, 35, 45, 224; vi. 425; vii. 94, 252; ix.
29, 239, 266, 301; x. 9, 13, 16, 20, 45, 69, 70, 71, 73, 77, 409; xi.
235, 492.
Ariosto (Titian’s portrait of), ix. 270; xi. 30.
—— (Harington’s), v. 186; vi. 319 n.
Aristarchus, iv. 307.
Ariste (should be Valère), (in Molière’s L’Ecole des Femmes), xi. 356.
Aristocracy of Letters, On the, vi. 205.
Aristophanes, v. 56; viii. 28, 166; x. 99, 100, 112 n.
—— of Byzantium, i. 183.
Aristotle, i. 13, 123, 139; iv. 9 n., 143, 144, 283, 285; v. 360; vi. 107,
109, 198; vii. 248, 316; viii. 63, 93, 305; x. 143, 248, 249; xi. 97,
262; xii. 164, 326, 361, 370.
Arkwright (Sir Richard), ii. 175; vi. 456; vii. 165, 186; ix. 243 n.
Armelie (in L. Bonaparte’s Charlemagne), xi. 232, 235.
Armida (Ariosto’s), x. 71.
Armitage (racket-player), vi. 89.
Armstrong, John, ii. 169, 183, 194, 195; v. 119, 376; vi. 332.
Arnaud, Anthony, xi. 289.
—— Daniel, x. 55.
Arne, Michael, ii. 86.
—— Dr Thomas Augustine, ii. 86; viii. 451, 452.
Arno, The, ix. 211, 212, 221; xii. 134.
Arnold, S. J., viii. 224, 243, 244, 314, 322, 323, 463, 476.
Arpasia (in Bajazet), xi. 275.
Arragon, x. 56.
Arruntius (in Ben Jonson’s Sejanus), v. 264.
Arsinoe (in Molière’s Misanthrope), ix. 149.
Art, Fragments on, ix. 489.
—— of Walking the Streets. See Trivia.
Artamène (in Mlle. de Scudéry’s Artamène ou Le Grand Cyrus), xii.
61.
Artaxerxes (F. A. Arne’s), viii. 192;
also referred to in viii. 248, 320, 330, 451, 532; xi. 455 n.
Arthur, King, x. 20–21, 56; xii. 221.
—— (in Shakespeare’s King John), i. 306 et seq.; vii. 344.
Arthur’s Seat, ii. 314; ix. 98, 324, 336, 337.
—— —— View of (Nasmyth’s), xi. 247.
Artist, The (a magazine), vi. 416.
Artists, On the Old Age of, vii. 88.
Arts, On the Progress of the, i. 372.
—— are not Progressive, Why the, i. 160; ix. 489;
referred to, ix. 478.
Arundel, Thomas Howard, Earl of, ix. 34.
Arviragus (in Shakespeare’s Cymbeline), i. 182 seq.; v. 258; xi. 293.
Ascham, Roger, x. 236–7.
Ascot Heath, ii. 4, 5, 6.
Ashburton, Baron. See Dunning, John.
—— the Inn at, vi. 407.
Ashby-de-la-Zouch, ii. 14.
Ashmole, Elias, iii. 141.
Asia Minor, v. 199.
Aspasia (Landor’s), ii. 396; vii. 299.
Aspatia (in Beaumont and Fletcher’s Maid’s Tragedy), v. 251.
Aspin, Mr, ii. 205.
Ass (of Apuleius), x. 17, 18.
Assembly of the Just (Raphael’s), iii. 142; xii. 208.
—— of Saints (Raphael’s), ix. 380; xi. 227.
Assignation Scene, The (Hogarth’s), viii. 134.
Assizi, ix. 261.
Ass’s Foal, Ode to an (Coleridge’s), v. 164.
Assumption (Titian’s), ix. 273.
Astley, John, vii. 111.
Astley’s, xii. 49.
Astolpho (Ariosto’s), vii. 252.
Astræa, xi. 384.
Astrea and Cleopatra, Histories of, x. 14.
Astronomical Discourses, Dr Chalmers’s, iv. 230; xii. 279.
Asturias, xi. 317.
As You Like It (Shakespeare’s), i. 338;
also referred to in i. 185; vii. 260 n.; viii. 513; xi. 396.
Atala at the Tomb (Girodet’s), ix. 132.
At-all (in Abbe’s Double Gallant), viii. 162, 360.
Athalie (Racine’s), x. 106; xi. 452.
Athanasius, Creed of St, iii. 139, 269.
Athenæ Oxonienses (Wood’s), iii. 276.
Athenæum, The, xi. 386.
Athenians, xi. 312.
Athens, i. 4, 212; vi. 188, 448; vii. 95, 185, 254; ix. 381, 379, 466, 492;
x. 347; xii. 170.
Atherstone, ii. 14.
Atkins, Mr (actor), viii. 275.
—— Mrs, ii. 219.
Atkinson (in Fielding’s Tom Jones), vii. 214; viii. 114; x. 33.
Atlas (the horse), ii. 22.
—— The, vi. 505, 517, 520, 521, 522; ix. 484–5; x. 403; xii. 320, 339,
342, 346, 348, 350, 353, 354, 357, 360, 363, 364, 367, 369, 370,
377, 381, 386, 391, 394, 402.
Atterbury, Francis, iii. 408; v. 79; vii. 24; viii. 14.
Attica, ix. 325; xi. 495.
Atticus (Pope’s), ii. 79, 199.
Attila, ix. 267.
—— (Raphael’s), ix. 364.
Attributes (Samuel Clarke’s), xi. 118.
Attwood, Mr (actor), ii. 195, 222, 225.
Audrey (in Shakespeare’s As You Like It), i. 185, 340; iv. 348; v. 146;
viii. 167, 252, 319; xi. 367, 397.
Aufidius (in Shakespeare’s Coriolanus), i. 217; iii. 435; viii. 375.
Augustus (in Shakespeare’s Antony and Cleopatra), i. 230.
—— (statue), ix. 165, 221.
Auld Reekie School, The, viii. 478 n.
Auld Robin Gray (ballad), v. 141; vii. 253.
Aumerle (Shakespeare’s Richard II.), i. 273.
Aurelia, Duchess of Pietro Jacomo (in Marston’s Malcontent), v. 230.
Aurelio and Miranda (Boaden’s), ii. 218.
Aurora (newspaper), xi. 386.
—— (in Le Sage’s Gil Blas), xii. 141.
—— (Guido’s), ix. 237; xii. 36.
—— (Poussin’s), vi. 171.
Ausias (Italian author), x. 56.
Austerlitz, i. 415; iii. 99, 112; vi. 13, 237.
Austria, iii. 14, 104, 179.
—— Archduke of, i. 310, 311.
—— Emperor of, iii. 106, 107; ix. 277.
Austrian Catechism, The, xi. 343–4.
—— Troops, ix. 259.
Austrians, ix. 187 n.
Authors, On the Conversation of, vii. 24.
——, The Royal Society of, vii. 105.
Autolycus (in Shakespeare’s Winter’s Tale), i. 155, 326; viii. 230, 388.
Auvergne, Countess of, i. 292.
Avare (Molière). See L’Avare.
Avarice (in Spenser), v. 39.
Avon, v. 297.
Aylesbury, iii. 422.
Ayr, ii. 78.
Ayrton, William, vi. 195, 201; vii. 37.
Ayton, Miss Fanny, xi. 378.
B.
B——, xii. 455 n.

B., Arthur, ii. 211.
B——, Col., ii. 194, 196.
B., Dr, ii. 224.
B., Duke of, ii. 225.
B——ll, ii. 176.
B——r, ii. 215.
Babilonia, La (Salvator’s), x. 301.
Babylon, v. 183, 203, 273; vii. 185; ix. 268; xii. 153.
Baccano (a town), ix. 231.
Bacchus, v. 81; viii. 28, 231; ix. 216, 220.
—— and Ariadne (Titian’s), iv. 276; ix. 72.
Bacon, Lord, i. 23, 82, 123; iii. 293; iv. 45, 200 n., 283, 365; v. 3, 175,
179, 307, 326, 332, 333; vi. 85, 154; vii. 182 n., 262, 306, 320; viii.
58, 100; ix. 28, 186, 243 n.; x. 249, 258, 291, 326; xi. 25, 26, 27,
163, 164, 203, 287, 323; xii. 35 n., 50, 369, 372.
—— Friar, v. 334.
—— Roger, vii. 443 n.
Bacon’s Works, Character of Lord, compared as to Style with Sir
Thomas Brown and Jeremy Taylor, v. 326.
Bagdad, iii. 146.
Bagnigge Wells, iv. 108; vii. 70; viii. 140; xi. 252.
Bagot (Henry VI.), i. 295.
Bagshot, xi. 375; xii. 13.
Bailie Bradwardine (Scott’s Waverley), viii. 129; xi. 534.
—— Nicol Jarvie (Scott’s Rob Roy), iv. 248.
Baillie, Miss Joanna, v. 147, 148, 270; viii. 420 n.
Baird, Mr (a mate), ii. 248, 249, 252.
Baker, Mr (actor), viii. 318; x. 382.
—— Sir George, ii. 174, 175.
Bakewell, ii. 18.
Bakhuysen, Ludolf, ix. 20.
Balaam (in Holcroft’s The Exiles), ii. 201.
—— (in Kotzebue’s Indian in England), ii. 196.
Balafre (in Scott’s Quentin Durward), iv. 248.
Balasteros, Francisco, x. 250.
Bal Champêtre (Watteau’s), ix. 22, 23.
Balfour of Burley (Scott’s Old Mortality), iv. 229, 247; viii. 129; xi.
381, 532.
Ball, John, iii. 194, 303.
Ballad on a Wedding (Sir John Suckling’s), v. 371; viii. 56.
Ballads, On the Old English, v. 123.
Ballantyne Press, vii. 222.
Ballets, Two New, viii. 353.
Balmawhapple (in Scott’s Waverley), xii. 91.
Balmerino, Lord, iii. 285 n.; x. 161, 168.
Baltimore, viii. 473; xii. 377.
—— House, viii. 12.
Banbury, ii. 14.
—— Mutton, ii. 246.
Banchieri, Monsignore, iii. 178.
Bandello, Matteo, x. 9.
Bandinelli, Baccio (Correggio’s), ix. 43.
——, Bartolommeo, ix. 219, 229.
Bank of a River (Gainsborough’s), xi. 203.
Banks, Henry, xi. 473.
—— Sir Joseph, ii. 178, 183, 199, 203; vii. 210.
—— Mr, ix. 56 n.
—— Miss, ii. 206.
—— the Miller (in The Merry Devil), v. 294.
—— of the Thames (J. Wilson’s), xi. 247.
—— of the Wye (Wordsworth’s), v. 156.
Bannister, John, i. 155, 326; ii. 160, 162, 165, 195, 196, 197, 198, 202,
368; vi. 273, 417; vii. 76, 127; viii. 230, 234, 317, 387, 388, 514; xi.
366; xii. 24.
Bannister’s Farewell, viii. 229.
Banquo (in Shakespeare’s Macbeth), vi. 410; xi. 316.
Banstead Downs, vi. 12.
Baptistery, The, at Florence, ix. 212.
Barabbas, v. 210.
Barbara Yellowley (in Scott’s Pirate), xi. 534.
Barbarelli, Giorgio. See Giorgione.
Barbarosa (Brown’s), viii. 372.
Barbaroux, vi. 102.
Barbauld, Mrs (Anna Letitia), v. 147.
Barber, Mrs, xii. 139 n.
—— of Bagdad, The (in Arabian Nights), viii. 13.
Barberigo Palace, The, ix. 269, 270.
Barbieri, Giovanni Francesco. See Guercino.
Barcelona, ix. 185.
Barclay, Captain, viii. 203.
Bard (Gray’s), xi. 326 n.; xii. 223.
—— Bracy (in Coleridge’s Christabel), x. 415.
Bardolph (in Shakespeare), ii. 72; viii. 33; xii. 7.
Barebone’s Parliament, iii. 395.
Baretti, G. M. A., vi. 381.
—— Reynolds’ Portrait of, ix. 399.
Bareuth, the Margravine of, vi. 445.
Barker, Benjamin, xi. 248.
Barkley, Sir Robert, ii. 224.
—— Miss, ii. 224.
Barlow, Joel, iii. 460.
Barmecide, The, iii. 139; iv. 337; vi. 53; viii. 13.
Barnaby Brittle (a play founded on Molière), viii. 28.
Barnard, Mr (actor), viii. 241, 279, 280, 302, 399, 460, 475, 525, 532.
—— Sir John, iii. 413.
Barnard’s Inn, ii. 218.
Barnes, Mrs and Mr, viii. 271, 439.
Barney o’ Mulchesen (in Leigh’s Where to Find a Friend), viii. 258,
260.
Baron of Bradwardine (Scott’s Waverley), iv. 247.
—— Wildenheim (in Mrs Inchbald’s Lovers’ Vows), viii. 335.
Barrés, The, iii. 420; iv. 237; xii. 293.

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Chapter 1 Addressing Challenges to Progress in Human Stem Cell

1.1 Filling in the Stem Cell Gap in Human Toxicology 1

Chapter 2 Alternative Methods in Haematopoietic Stem Cell

Issues in Toxicology No. 29

2.2.3Haematopoietic Stem Cell Toxicity in Drug

2.3.1 CFU-GM Colonogenic Assay 15

Chapter 3 High-throughput Screening of Toxic Chemicals on Neural

3.1 Neural Stem Cells 31

Chapter 4 The Role of Catecholamines in Stem Cell Mobilisation 64

4.3 Catecholamines and Stem Cell Mobilisation 67

Chapter 5 Toxicological Risk Assessment – Proposed Assay Platform

5.3 Current State of ECF Platform Development 102

Toxicant Response 105

Chapter 6 Current Developments in the Use of Human Stem Cell

6.1 Introduction 124

Chapter 7 Pesticides and Hematopoietic Stem Cells 160

7.1 Pesticide Toxicity-induced Disorders of

7.2 Pesticide Toxicity on Hematopoietic Stem Cells and

7.2.3 Alteration of Developmental Signaling

Chapter 8 Epigenetic Impact of Stem Cell Toxicants 178

8.1 Introduction 178

Chapter 9 Metakaryotic Cancer Stem Cells are Constitutively

9.1 Introduction 197

9.4 Discussion 233

9.4.2 Assays that Recognize and Measure the

Chapter 10 Distributed Stem Cell Kinetotoxicity: A New Concept to

10.1 Introduction 250

10.2.3Confirmation Studies for Benzene and

10.2.5 Use of Microarray Analyses to Discover a

Chapter 11 Cancer Stem Cells as Therapeutic Targets 280

11.1 Introduction 280

11.6 Asymmetric Cell Divisions; Potential Therapeutics

Subject Index 295

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1.1 Filling in the Stem Cell Gap in Human

Issues in Toxicology No. 29

‘‘Stem Cell Toxicology’’ 5 2015 (1)

stem cell toxicology’ as a subfield of human toxicology, which, based on the

1.2 Historical Impact of the Hierarchical,