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<ChapterID>114-1</ChapterID>
<ChapterDOI>10.1007/978-3-642-27728-3_114-1</ChapterDOI>
<ChapterTitle Language="En">Stem Cells</ChapterTitle>
<ChapterFirstPage>1</ChapterFirstPage>
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<CopyrightHolderName>Springer-Verlag Berlin Heidelberg</CopyrightHolderName>
<CopyrightYear>2014</CopyrightYear>
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<RegistrationDate>
<Year>2014</Year>
<Month>12</Month>
<Day>16</Day>
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<Year>2014</Year>
<Month>12</Month>
<Day>16</Day>
<Hour>12</Hour>
<Minute>31</Minute>
<Second>52</Second>
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<Month>12</Month>
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<BookID>43401_0_En</BookID>
<BookTitle>Drug Discovery and Evaluation: Pharmacological Assays</BookTitle>
</ChapterContext>
</ChapterInfo>
<ChapterHeader>
<AuthorGroup>
<Author CorrespondingAffiliationID="Aff1" AffiliationIDS="Aff1" SpringerReferenc
eID="176797">
<AuthorName>
<GivenName>Benedikt</GivenName>
<FamilyName>Müller</FamilyName>
</AuthorName>
<Contact>
<Email>muellerb@hs-albsig.de</Email>
</Contact>
</Author>
<Author AffiliationIDS="Aff1" SpringerReferenceID="156829">
<AuthorName>
<GivenName>Suzanne</GivenName>
<FamilyName>Kadereit</FamilyName>
</AuthorName>
<Contact>
<Email>suzanne.kadereit@uni-konstanz.de</Email>
</Contact>
</Author>
<Affiliation ID="Aff1">
<OrgDivision>Faculty of Life Sciences</OrgDivision>
<OrgName>Albstadt-Sigmaringen University</OrgName>
<OrgAddress>
<City>Sigmaringen</City>
<Country>Germany</Country>
</OrgAddress>
</Affiliation>
</AuthorGroup>
<Abstract ID="Abs1" Language="En" OutputMedium="Online">
<Heading>Abstract</Heading>
<Para ID="Par1">In the last 20 years, costs of pharmaceuticals have grown faster
than other parts of health care, with estimated costs for drugs reaching market
ranging around 800 million USD (DiMasi et al. 2003). Accumulating data and nume
rous failed clinical trials indicates that drug development and evaluation on an
imal models, animal-derived in vitro test systems, and standard human cell lines
are not reliably predictive for human efficacy and safety (Perel et al. 2007; L
eist and Hartung 2013). Failed drugs increase the general costs of development,
particularly if failing in very late stages of development, as clinical trial te
sting is extremely expensive with phase III trials generating around 40 %
of overall drug development costs (Roy 2012). Failure in the clinical trial sta
ge can moreover result in unnecessary suffering due to unanticipated severe side
effects, even resulting in life-threatening situations such as in the case of t
esting of TGN1412 (Attarwala 2010). Also, failures such as in the case of Vioxx,
where cardiac toxicity emerged only with large-scale use in humans, are difficu
lt to predict with currently available methodologies (Karha and Topol 2004).</Pa
ra>
</Abstract>
</ChapterHeader>
<Body>
<Section1 Type="Introduction" ID="Sec1">
<Heading>Introduction</Heading>
<Para ID="Par2">In the last 20 years, costs of pharmaceuticals have grown faster
than other parts of health care, with estimated costs for drugs reaching market
ranging around 800 million USD (DiMasi et al. <CitationRef CitationID="CR29">20
03</CitationRef>). Accumulating data and numerous failed <IndexTerm>clinical tri
als<Primary>Clinical trials</Primary></IndexTerm> indicates that drug developmen
t and evaluation on animal models, animal-derived in vitro test systems, and sta
ndard human cell lines are not reliably predictive for human efficacy and safety
(Perel et al. <CitationRef CitationID="CR107">2007</CitationRef>; Leist and Har
tung <CitationRef CitationID="CR84">2013</CitationRef>). Failed drugs increase t
he general costs of development, particularly if failing in very late stages of
development, as clinical trial testing is extremely expensive with phase III tri
als generating around 40 % of overall drug development costs (Roy <Citati
onRef CitationID="CR118">2012</CitationRef>). Failure in the clinical trial stag
e can moreover result in unnecessary suffering due to unanticipated severe side
effects, even resulting in life-threatening situations such as in the case of te
sting of TGN1412 (Attarwala <CitationRef CitationID="CR6">2010</CitationRef>). A
lso, failures such as in the case of Vioxx, where cardiac toxicity emerged only
with large-scale use in humans, are difficult to predict with currently availabl
e methodologies (Karha and Topol <CitationRef CitationID="CR74">2004</CitationRe
f>).</Para>
<Para ID="Par3">Animal models and in vitro systems with animal cells have failed
repeatedly over the years, mainly due to differences in species-specific metabo
lism, neurogenesis, signaling, and immune function (Dohnal et al. <Citatio
nRef CitationID="CR31">2014</CitationRef>; Hengstler et al. <CitationRef Citatio
nID="CR61">1999</CitationRef>; Lazarov and Marr <CitationRef CitationID="CR83">2
013</CitationRef>; Mestas and Hughes <CitationRef CitationID="CR96">2004</Citati
onRef>). Hepatotoxicity is the most frequent reason for withdrawal of already ap
proved drug, followed by hematologic and cardiac toxicity (Fung et al. <Citation
Ref CitationID="CR45">2001</CitationRef>). One of the most prominent examples of
failure of animal models to predict human toxicity was <IndexTerm>thalidomide<P
rimary>Thalidomide</Primary></IndexTerm>, which passed testing in two-species an
imal testing without any indication of teratogenicity, resulting in thousands of
humans born with severe developmental defects in extremity growth (Kim and Scia
lli <CitationRef CitationID="CR75">2011</CitationRef>). The only currently valid
ated in vitro test with stem cells, the <IndexTerm>embryonic stem cell test (EST
)<Primary>Embryonic stem cell test (EST)</Primary></IndexTerm>, also failed to d
etect the teratogenicity of thalidomide in its original format (zur Nieden et al
. <CitationRef CitationID="CR160">2004</CitationRef>). The validated EST is usin
g murine, not human, embryonic stem cells (Heuer et al. <CitationRef CitationID=
"CR62">1993</CitationRef>). When using more sophisticated endpoints or human emb
ryonic stem cells (hESCs), the predictivity of the EST is improved (discussed in
more detail later).</Para>
<Para ID="Par4">Development, particularly of the human brain, is likewise very s
pecies specific. The human brain is much more complex than other vertebrate brai
ns, with its development continuing past birth. Due to the complexity of its dev
elopment, the human brain is particularly sensitive to insults during developmen
t. Moreover, it was shown that some receptors that are important during <IndexTe
rm>brain development<Primary>Brain development</Primary></IndexTerm> are express
ed differently in human and rodent brains. For example, Gassmann and colleagues
investigated the role of the aryl hydrocarbon receptor (AhR) in persistent organ
ic pollutant (POP)-induced <IndexTerm>developmental neurotoxicity (DNT)<Primary>
Developmental neurotoxicity (DNT)</Primary></IndexTerm>. They found that in cont
rast to mouse neural progenitor cells that were susceptible to POP-induced DNT,
human neural progenitor cells were far less susceptible to DNT due to the absenc
e of AhR (Gassmann et al. <CitationRef CitationID="CR47">2010</CitationRef>). Th
us, toxicological pathways are difficult to model with sufficient predictability
in rodent systems.</Para>
<Para ID="Par5">One additional problem arising recently is <IndexTerm>REACH<Prim
ary>REACH</Primary></IndexTerm> (Registration, Evaluation, Authorization of Chem
icals), a new European Union legislation mandating that chemicals produced for,
or imported into, the European market are evaluated for their safety for humans
(Schoeters <CitationRef CitationID="CR121">2010</CitationRef>). The number of ch
emicals that need to be tested under REACH is daunting, with estimates reaching
over 100,000 chemicals, by far exceeding the numbers of available animals requir
ed for this evaluation. It is estimated that testing under REACH will use 20 tim
es more animals and cost 6 times as much as estimated during development of the
legislation. Currently, regulatory testing has neither the high-throughput metho
ds nor <IndexTerm>alternatives to animal testing<Primary>Alternatives to animal
testing</Primary></IndexTerm> to be able to comply under REACH (Hartung and Rovi
da <CitationRef CitationID="CR59">2009</CitationRef>).</Para>
<Para ID="Par6">Drug development and testing taking place in human cells is curr
ently performed on cell lines which are mostly derived from tumor tissues. Accor
dingly, apart from chromosomal anomalies, these cells also harbor defects in nor
mal regulatory pathways of cell cycle, cell death, and senescence and may be mor
e robust to toxicity than cells in vivo, rendering prediction of toxicity for no
rmal cells difficult. On the other hand, drug development and evaluation in norm
al human <IndexTerm>primary cells<Primary>Primary cells</Primary></IndexTerm> ar
e also not desirable; as such cells are associated with a far-too-high batch-tobatch variability. Moreover, human primary material is only scarcely available a
nd does not grow well (if at all) in culture and can certainly not supply the qu
antities of cell materials required to support high- to ultrahigh-throughput scr
eening in drug development, left alone mandatory testing under REACH. This also
holds true for tissue stem cells isolated from human fetal or adult tissue.</Par
a>
<Para ID="Par7">The derivation of <IndexTerm>human pluripotent stem cells (PSCs)
<Primary>Human pluripotent stem cells (PSCs)</Primary></IndexTerm>, which not on
ly are relatively normal but also grow indefinitely in culture and are able to g
enerate all cell types of the human body, has raised high hopes that such cells
could support the demands for the cell numbers needed for drug development and t
esting. Moreover, with such cells, <IndexTerm>human disease models<Primary>Human
disease models</Primary></IndexTerm> can be developed which will not only infor
m on mechanistic aspects of disease etiology but also enable a more targeted dev
elopment of drugs. It is anticipated that PSCs will in the near future replace c
lassical cell lines used in drug development and testing. Although classical cel
l lines are much easier and cheaper to culture, they do not allow for a more sop
histicated cell type-specific testing, as cell type choice is limited. Often, th
e cell type of standard, tumor-derived cell lines is also ill defined and does n
ot correspond to fully differentiated cells in vivo. Moreover, for the two main
target cell types of human drug toxicity, hepatocytes and cardiomyocytes, no ade
quate human cell lines exist.</Para>
<Para ID="Par8">For their better scalability to high throughput, possibility for
disease modeling, and thus applicability to drug development and evaluation, th
is chapter will focus on PSCs. In contrast to fetal and adult stem cells which c
an be grown only to a limited extent in culture, PSCs can generate large amounts
of progeny in culture and can still be differentiated into all cell types of th
e human body. Not only does this alleviate batch-to-batch variability considerab
ly, but PSCs can provide sufficient number of cells for high-throughput <IndexTe
rm>screening<Primary>High throughput screening</Primary></IndexTerm> of the thou
sands of compounds generated through combinatorial chemistry. They can also gene
rate meaningful disease models in which compounds can be screened for efficacy,
moreover with genotype specificity, and thus allow for personalized medicine. As
PSC-derived cell culture models can be (and are already partly) characterized a
s to their molecular underpinnings, they enable identification of target-selecti
ve compounds, as well as function-based approaches, where therapeutic effects ca
n be observed by normalizing a disease-specific abnormality.</Para>
</Section1>
<Section1 ID="Sec2">
<Heading>Pluripotent Stem Cell Properties</Heading>
<Para ID="Par9">Due to their promising properties, human pluripotent stem cells
(PSCs) have raised high hopes for both scientific and medical applications since
the first successful isolation of an <IndexTerm>embryonic stem cell<Primary>Emb
ryonic stem cell</Primary></IndexTerm> (hESC) line from human blastocysts in 199
8 (Thomson et al. <CitationRef CitationID="CR141">1998</CitationRef>). PSCs exhi
bit two unique properties in comparison to all other cells: pluripotency and lon
g-term self-renewal in culture. Pluripotency is the ability to generate cells fr
om all three germ layers (mesoderm, endoderm, and ectoderm) as well as cells of
the germ line, i.e., all cell types of the body (Gao et al. <CitationRef Citatio
nID="CR46">2013</CitationRef>). Hence, PSCs can be used to generate any human ti
ssue. Moreover, as the cells are self-renewing, meaning that they can divide ind
efinitely into identical daughter cells, these cells can be maintained in cultur
e for extended periods of time without losing their <IndexTerm>stem cell propert
ies<Primary>Stem cell properties</Primary></IndexTerm>. This enables culturing o
f PSCs over extended passages without loss of their potential to generate all ce
ll types of the body.</Para>
<Para ID="Par10">Importantly, and in contrast to most other cell lines, hESCs ar
e karyotypically normal and maintain this property for extended periods of cultu
re, if maintained properly (Englund et al. <CitationRef CitationID="CR37">2010</
CitationRef>; Wenger et al. <CitationRef CitationID="CR149">2004</CitationRef>).
Differences in the <IndexTerm>karyotype<Primary>Karyotype</Primary></IndexTerm>
of cancer cell lines were demonstrated to lead to high variation in gene expres
sion patterns, thus making it difficult to reproduce results even when using the
same cell line (Abdallah et al. <CitationRef CitationID="CR1">2013</CitationRef
>). In order to generate in vitro models as similar as possible to the in vivo s
ituation, a normal karyotype, as provided by hESCs, is essential.</Para>
<Para ID="Par11">In 2007, the so-called <IndexTerm>induced pluripotent stem cell
s<Primary>Induced pluripotent stem cells</Primary></IndexTerm> (hiPSCs) were gen
erated for the first time from human adult somatic cells, opening even further h
orizons (Takahashi et al. <CitationRef CitationID="CR139">2007</CitationRef>). T
o achieve this, the group of Yamanaka used transcription factors which were alre
ady known to regulate pluripotency in hESCs and influence cell proliferation and
differentiation: Oct4, Sox2, c-Myc, and Klf4 (Niwa et al. <CitationRef Citation
ID="CR103">2000</CitationRef>; Bullejos et al. <CitationRef CitationID="CR19">20
00</CitationRef>; Chen et al. <CitationRef CitationID="CR20">2003</CitationRef>;
Kanazawa et al. <CitationRef CitationID="CR73">2003</CitationRef>; Mitsui et al
. <CitationRef CitationID="CR97">2003</CitationRef>). The introduction of these
<IndexTerm>transcription factors<Primary>Transcription factors</Primary></IndexT
erm> into adult, terminally differentiated, fibroblasts induced the so-called re
programming of the somatic DNA in the fibroblasts and led to cells exhibiting pr
operties very similar to embryonic stem cells. During <IndexTerm>reprogramming<P
rimary>Reprogramming</Primary></IndexTerm>, epigenetic marks accumulated during
development and further maturation to terminally differentiated cells are stripp
ed off the DNA. At the same time, the DNA is reprogrammed to the pluripotent sta
te. The exact processes and mechanisms operating are still largely unknown and i
ncompletely understood. These induced PSCs expressed pluripotency gene expressio
n patterns, had an epigenetic profile similar to hESCs, and could differentiate
into cells of all three germ layers. Thus, by overexpressing only four <IndexTer
m>transcription factors<Primary>Transcription factors</Primary></IndexTerm> invo
lved in the maintenance of the pluripotent network, Yamanaka and colleagues succ
eeded in reprogramming somatic DNA to pluripotency. Since 2007, the approaches u
sed for <IndexTerm>reprogramming<Primary>Reprogramming</Primary></IndexTerm> of
human somatic cells to generate hiPSCs have become more robust and are steadily
being improved (Ma et al. <CitationRef CitationID="CR87">2013</CitationRef>; Dre
ws et al. <CitationRef CitationID="CR33">2012</CitationRef>).</Para>
<Para ID="Par12">The generation of hiPSCs caused widespread enthusiasm, as the u
se of iPSCs for cellular therapies offers a way to prevent immune rejections upo
n transplantation, by generating <IndexTerm>patient-specific hiPSCs<Primary>Pati
ent-specific hIPSCs</Primary></IndexTerm> from the patient’s own cells. S
uch cells can then be used to generate therapeutic cells that presumably would n
ot be rejected by the patient they have been derived from. However, it has also
emerged that not all hiPSC lines are truly pluripotent, likely due to incomplete
reprogramming of the somatic DNA. A deeper look at the molecula
r level has furthermore revealed that hiPSC lines cluster together and separate
from hESC lines, when analyzing global gene expression and methylation patterns
(Kim et al. <CitationRef CitationID="CR76">2010</CitationRef>; Chin et al. <Cita
tionRef CitationID="CR22">2009</CitationRef>). Also, hiPSCs harbor a higher amou
nt of mutations than hESCs, some stemming from the original somatic cells, but m
any induced through the reprogramming process itself (Lister et al. <CitationRef
CitationID="CR86">2011</CitationRef>; Ji et al. <CitationRef CitationID="CR71">
2012</CitationRef>). Some of these mutations may be caused by the introduction o
f viral vectors into the genome during reprogramming and disruption of normal ge
nes or regulatory sequences. Additional <IndexTerm>mutations<Primary>Mutations</
Primary></IndexTerm> include point mutations, nonsense mutations, missense mutat
ions, splice variations, or copy number variations (Hussein et al. <CitationRef
CitationID="CR67">2011</CitationRef>; Gore et al. <CitationRef CitationID="CR53"

>2011</CitationRef>). The type and number of mutations do not seem to correlate
with donor cell age, type of reprogrammed cell, or reprogramming method (Ben-Dav
id and Benvenisty <CitationRef CitationID="CR13">2011</CitationRef>). To address
some of these issues, different methods of reprogramming have been developed, u
sing non-integrating vectors, transposons, plasmids, excisable vectors, transduc
ed proteins, or engineered RNA to reprogram the somatic donor cells. Unfortunate
ly, most of these methods are much less efficient than the transduction of the t
ranscription factors with lentiviral vectors (Bayart and Cohen-Haguenauer <Citat
ionRef CitationID="CR12">2013</CitationRef>). During reprogramming of mouse embr
yonic fibroblast, it could be shown that some mutations could also be traced bac
k to rare somatic cells within the population of starting cells, suggesting sele
ction of rare mutated cells during the reprogramming process (Young et al. <Cita
tionRef CitationID="CR155">2012</CitationRef>). Moreover, it emerged that with i
ncreasing time in culture, the newly derived hiPSCs lose much of their mutationa
l load and become more similar to hESCs (Polo et al. <CitationRef CitationID="CR
109">2010</CitationRef>; Hussein et al. <CitationRef CitationID="CR67">2011</Cit
ationRef>).</Para>
<Para ID="Par13">For cellular therapies with hiPSCs, the use and potential activ
ation of oncogenes have raised concerns of tumor development after transplantati
on (Robbins et al. <CitationRef CitationID="CR114">2010</CitationRef>). Furtherm
ore, due to incorrect reprogramming in certain cells and ensuing defective diffe
rentiation with persistence of undifferentiated cells in the therapeutic cell pr
eparations, there is a potential of <IndexTerm>tumor formation<Primary>Tumor for
mation</Primary></IndexTerm> upon transplantation (Miura et al. <CitationRef Cit
ationID="CR98">2009</CitationRef>). It could also be shown that some cell lines
demonstrate a high frequency of tumor formation upon chimera formation, attribut
able to reactivation of the c-myc oncogene (Okita et al. <CitationRef CitationID
="CR104">2007</CitationRef>).</Para>
<Para ID="Par14">While such properties are certainly not desirable for human cel
lular therapies, mutations may be less relevant for drug screening applications.
As mutations and/or incomplete <IndexTerm>reprogramming<Primary>Reprogramming</
Primary></IndexTerm> as well as aberrant methylation patterns may influence diff
erentiation potential of hiPSCs and have an impact on the quality of the cells o
ne generates for testing, such problems have to be taken into account when devel
oping models and systems for drug testing (Miura et al. <CitationRef CitationID=
"CR98">2009</CitationRef>; Deng et al. <CitationRef CitationID="CR27">2009</Cita
tionRef>; Doi et al. <CitationRef CitationID="CR32">2009</CitationRef>). Moreove
r, due to incomplete reprogramming, hiPSCs retain gene expression patterns of th
e original cells (Ghosh et al. <CitationRef CitationID="CR51">2010</CitationRef>
; Polo et al. <CitationRef CitationID="CR109">2010</CitationRef>; Kim et al. <Ci
tationRef CitationID="CR76">2010</CitationRef>). This <IndexTerm>epigenetic &#x2
01C;memory”<Primary>Epigenetic "memory"</Primary></IndexTerm> can also ha
ve effects on the differentiation potential of an iPSC line, for example, when e
pigenetic properties favor the generation of a specific cell lineage (Feng et al
. <CitationRef CitationID="CR40">2010</CitationRef>). For example, hiPSCs genera
ted from keratinocytes did not differentiate well into hematopoietic lineage, an
d cord-blood-derived hiPSCs generated far less keratinocytes than hiPSCs derived
from keratinocytes (Kim et al. <CitationRef CitationID="CR77">2011</CitationRef
>). Whether or not iPSCs exhibit an overall reduced differentiation <IndexTerm>p
otential<Primary>Differentiation potential, iPSCs</Primary></IndexTerm> compared
to hESCs is still heavily discussed and may be cell line dependent (Hu et al. <
CitationRef CitationID="CR66">2010</CitationRef>; Boulting et al. <CitationRef C
itationID="CR16">2011</CitationRef>). It may also become less of an issue as hiP
SC lines become more hESC-“like” with prolonged culture time.</Par
a>
<Para ID="Par15">Nevertheless, induced PSCs have distinct advantages, compared t
o hESCs. hiPSCs can be generated from readily accessible tissue of patients with
a particular genetic condition and can therefore serve as a platform for <Index
Term>personalized medicine<Primary>Personalized medicine</Primary></IndexTerm>,
drug testing, and predictive toxicology studies (Han et al. <CitationRef Citatio
nID="CR57">2011</CitationRef>; Gross et al. <CitationRef CitationID="CR56">2012<
/CitationRef>; Teoh and Cheong <CitationRef CitationID="CR140">2012</CitationRef
>). Patient-derived hiPSCs can also be used to generate disease models for clini
cal testing, an approach that will be discussed in more detail further down. An
additional advantage of hiPSCs is the avoidance of ethical <IndexTerm>issues<Pri
mary>Ethical issues, hiPSCs</Primary></IndexTerm> raised by the destruction of e
arly embryos to generate hESCs. This has caused research with hESCs to be strict
ly regulated or even completely prohibited in some countries (Teoh and Cheong <C
itationRef CitationID="CR140">2012</CitationRef>). The use of hiPSCs on the othe
r hand is far less regulated and can be carried out in any laboratory that is in
terested in this field, which led to a very large scientific community involved
in hiPSC research in a very short time.</Para>
<Para ID="Par16">The choice of the type of <IndexTerm>pluripotent stem cell<Prim
ary>Pluripotent stem cell</Primary><Secondary>choice of type of</Secondary></Ind
exTerm> (hESC vs. hiPSC) depends on the application in which they are going to b
e used. When developing a patient-specific approach or a disease model, iPSC tec
hnology enables the generation of cells with a particular disease background tha
t cannot always be recreated easily with ESCs. On the other hand, when generatin
g a developmental model or defined target cell types for transplantation, hESCs
are often preferred. Due to the genetic abnormalities discussed above for hiPSCs
, therapeutic cells generated from hESCs would presumably be of higher quality.<
/Para>
<Para ID="Par17">Murine ESCs can be used to faithfully recreate in vivo developm
ent in the dish (Barberi et al. <CitationRef CitationID="CR10">2003</CitationRef
>). Similar behavior is inferred for human ESCs, and accordingly, hESCs now serv
e to model early human development. For example, <IndexTerm>embryoid bodies (EBs
)<Primary>Embryoid bodies (EBs)</Primary></IndexTerm>, small aggregations of PSC
s differentiating in suspension, are used as a model of early embryogenesis as t
he differentiating cells generate spontaneously cells of all three germ layers (
Dvash et al. <CitationRef CitationID="CR34">2004</CitationRef>). EBs can also be
used for toxicological testing (Meganathan et al. <CitationRef CitationID="CR93
">2012</CitationRef>). As EBs can be guided toward specific cell lineages by exp
osure to specific growth factors, they are widely used as the initial step for d
irected differentiation and can be used for the generation of <IndexTerm>develop
mental models<Primary>Developmental models</Primary></IndexTerm> of specific cel
l lineages (Schuldiner et al. <CitationRef CitationID="CR122">2000</CitationRef>
). Cells of the neural cell lineage can be generated by adding growth factors su
ch as retinoic acid, nerve growth factor, or fibroblast growth factor 2 (Schuldi
ner et al. <CitationRef CitationID="CR123">2001</CitationRef>; Reubinoff et al.
<CitationRef CitationID="CR113">2001</CitationRef>). For directed differentiatio
n of human ESCs toward cardiomyocytes, a mix of <IndexTerm>growth factors<Primar
y>Growth factors</Primary></IndexTerm> such as bone morphogenetic protein 4, act
ivin A, and fibroblast growth factor 2 is needed (Murry and Keller <CitationRef
CitationID="CR102">2008</CitationRef>). An overview of growth factors needed to
generate specific cell types was generated by Williams and colleagues (Williams
et al. <CitationRef CitationID="CR150">2012</CitationRef>).</Para>
<Para ID="Par18">In combination, hESCs and hiPSCs are expected to offer an unlim
ited supply of human cells of desired type to generate in vitro models for devel
opmental studies, disease modeling, drug discovery, and development of personali
zed medicine approaches and offer sufficient human cell material for toxicology
and REACH.</Para>
</Section1>
<Heading>Human Versus Animal Models</Heading>
<Para ID="Par19">The major advantage of human PSCs is that they allow to generat
e human models. The value of animal models in correctly predicting the outcome o
f treatment strategies in humans is controversial (Perel et al. <CitationRef Cit
ationID="CR107">2007</CitationRef>). The large number of potential treatment mod
alities that were proven beneficial in animal studies but finally failed in rand
omized clinical trials can only partly be explained by shortcomings in the desig
n of animal studies, such as insufficient statistical power or overoptimistic co
nclusions about efficacy (van der Worp et al. <CitationRef CitationID="CR144">20
10</CitationRef>). More importantly, <IndexTerm>animal models<Primary>Animal mod
els</Primary></IndexTerm> can often times simply not predict human responses to
drugs (Inoue and Yamanaka <CitationRef CitationID="CR68">2011</CitationRef>). On
a genetic level, for example, inflammation-related changes in gene expression i
n mice were often very different from the changes observed in humans (Seok et al
. <CitationRef CitationID="CR129">2013</CitationRef>). Furthermore, as many gene
tic variants of <IndexTerm>human diseases<Primary>Human diseases</Primary></Inde
xTerm> are located in noncoding regions of the genome, which have no similarity
in other organisms, the introduction of these genetic variants into animal genom
es is unlikely to yield a disease phenotype (Merkle and Eggan <CitationRef Citat
ionID="CR95">2013</CitationRef>). Another example that is hard to replicate in a
nimal models is the impact of diseases on the proteome and its complex regulatio
n which often leads to secondary effects. In case of the neurodegenerative Alzhe
imer’s disease, for example, a toxic effect caused by protein misfolding
could not be recapitulated in a transgenic mouse model (Winklhofer et al. <Citat
ionRef CitationID="CR151">2008</CitationRef>).</Para>
<Para ID="Par20">Recently, a large-scale compound drug screen of neural stem cel
ls and rat mixed cortical neurons was performed (Malik et al. <CitationRef Citat
ionID="CR88">2014</CitationRef>). The researchers tested 2,000 compounds for the
ir species and cell type specificity. From these 2,000 substances, 100 were show
n to be specifically toxic for human neural stem cells. In a secondary screen wi
th different human neural cell types, they were able to demonstrate a cell typespecific <IndexTerm>toxicity<Primary>Cell-type specific toxicity</Primary></Inde
xTerm> for more than 80 % of these compounds. These results illustrate cl
early that drugs can have various effects on different cells, depending both on
the species and the target cell type, and that in order to predictably identify
compounds affecting human cells, human in vitro models are needed with, if possi
ble, the cell type of interest.</Para>
<Para ID="Par21">There have also been numerous cases in which drugs that were al
ready approved and commercially available had to be withdrawn from the market, a
fter successful preapproval trials. In these cases, animal models did not predic
t the harmful effects on humans, which were only reported in studies after the d
amage had already been done. Two widely known examples are the drugs <IndexTerm>
rofecoxib (Vioxx)<Primary>Rofecoxib (Vioxx)</Primary></IndexTerm> and <IndexTerm
>thalidomide (Contergan)<Primary>Thalidomide (Contergan)</Primary></IndexTerm>.
Rofecoxib (Vioxx) is a nonsteroidal anti-inflammatory drug (NSAID) inhibiting Co
x-2 that was approved in 1999 for the treatment of osteoarthritis, acute pain, a
nd primary dysmenorrhea (Roth-Cline <CitationRef CitationID="CR116">2006</Citati
onRef>). Shortly after approval, thrombotic side effects were postulated (Title
et al. <CitationRef CitationID="CR142">2003</CitationRef>), and in the following
years, several studies investigating other potential applications for rofecoxib
reported cardiac toxicity, particularly in long-term studies (Bombardier et al.
<CitationRef CitationID="CR14">2000</CitationRef>; Graham et al. <CitationRef C
itationID="CR54">2005</CitationRef>; Juni et al. <CitationRef CitationID="CR72">
2004</CitationRef>; Mukherjee et al. <CitationRef CitationID="CR100">2001</Citat
ionRef>). In 2004, the drug was finally withdrawn due to increased cardiovascula
r risk following long-term use. In this case, cardiac toxicity was only noticed
after long-term use and this in millions of users. Such effects are difficult to
detect in animal models and initial clinical trials due to small-size samples.
In case of thalidomide, the outcome was also severe as it caused malformation of
the limbs of around 10,000
infants worldwide in the 1950s and 1960s. The drug was approved in Germany in 19
57 and used as a sedative or hypnotic. Later on, it was commonly used by pregnan
t women to alleviate morning sickness. It then emerged that thalidomide had tera
togenic effects during a very narrow time window of pregnancy, between 20 and 36
days postfertilization (Kim and Scialli <CitationRef CitationID="CR75">2011</Ci
tationRef>). The strong teratogenic effect of thalidomide could not be detected

in in vivo reproductive or developmental studies in rodents (Fratta et al. <Cita
tionRef CitationID="CR44">1965</CitationRef>; Schumacher et al. <CitationRef Cit
ationID="CR124">1968</CitationRef>; zur Nieden et al. <CitationRef CitationID="C
R160">2004</CitationRef>). Even the validated and commonly used mouse <IndexTerm
>embryonic stem cell test (EST)<Primary>Embryonic stem cell test (EST)</Primary>
</IndexTerm>, a developmental in vitro model to specifically test embryotoxicity
by evaluating the effects on cardiac differentiation of murine embryonic stem c
ells, is not able to detect the teratogenic effect of thalidomide (zur Nieden et
al. <CitationRef CitationID="CR160">2004</CitationRef>). Just recently, researc
hers have developed an EST based on human hiPSCs with molecular endpoints (Aikaw
a et al. <CitationRef CitationID="CR5">2014</CitationRef>), which was able to de
monstrate the teratogenic effect of thalidomide. This finding highlights the sup
eriority of human stem cell-based models compared to traditional models based on
animal models and cells.</Para>
<Para ID="Par22">One last aspect also worth considering is that it is very possi
ble that a certain number of potential drugs is discarded during development due
to lack of efficacy in animal models but might have beneficial effects in human
s, as molecules are more and more designed to impact specific pathways in human.
</Para>
</Section1>
<Heading>PSCs for Human Disease Modeling and Drug Development</Heading>
<Para ID="Par23">For many human diseases, etiology and molecular mechanisms are
still poorly understood since they can only be studied to a limited extent in vi
vo in human. For the first time, modern techniques now allow for the generation
of <IndexTerm>disease-specific cell models<Primary>Disease-specific cell models<
/Primary></IndexTerm> derived from PSCs. This is particularly the case with <Ind
exTerm>hiPSCs<Primary>hiPSCs</Primary></IndexTerm>. Cells can be taken from a pa
tient affected by a genetic disease and hiPSCs generated by reprogramming. These
hiPSCs can then be differentiated into any cell type of the body and the cells
analyzed carefully for disease phenotype and molecular underpinnings (Dimos et a
l. <CitationRef CitationID="CR30">2008</CitationRef>). By now, a large variety o
f hiPSC lines has been generated, including disease-specific lines from genetica
lly inherited and sporadic diseases (Onder and Daley <CitationRef CitationID="CR
105">2012</CitationRef>). For in vitro models based on disease-specific hiPSCs,
it is most important that the cells exhibit an easy observable cellular or molec
ular disease phenotype. Examples for neuronal disease-related phenotypes in hiPS
C-derived models are the generation of motor neurons with a selective deficit in
a model of spinal muscular atrophy (Ebert et al. <CitationRef CitationID="CR35"
>2009</CitationRef>). A model with hiPSCs derived from <IndexTerm>Rett syndrome<
Primary>Rett syndrome</Primary></IndexTerm> patients revealed a smaller soma siz
e and altered calcium signaling in neurons derived from these hiPSCs (Marchetto
et al. <CitationRef CitationID="CR90">2010</CitationRef>). Further, Rett syndrom
e symptoms that were detected in this model were fewer synapses, reduced spine d
ensity, and electrophysiological defects when compared to hiPSCs from normal cel
ls. In case of metabolic diseases, patient-specific hiPSCs that were differentia
ted into hepatocytes were found to recapitulate key pathological features of the
diseases affecting the patients from which they were derived. The symptoms of t
hese inherited metabolic diseases observed in the cells included altered protein
aggregation, deficient receptor function, and elevated lipid and glycogen accum
ulation (Rashid et al. <CitationRef CitationID="CR111">2010</CitationRef>). The
cardiovascular disease <IndexTerm>long-QT syndrome<Primary>Long-QT syndrome</Pri
mary></IndexTerm> was also shown to be recapitulated in hiPSC-derived cells. Car
diac myocytes of long-QT patients exhibited prolonged action potentials and an i
ncreased susceptibility to catecholamine-induced tachyarrhythmia compared to non
-disease control cells (Moretti et al. <CitationRef CitationID="CR99">2010</Cita
tionRef>).</Para>
<Para ID="Par24">Another significant advantage of using hiPSCs for drug developm
ent and testing is the availability of already a large variety of cell lines wit
h genetic defects. In addition, more cell lines are generated in international e

fforts to generate large banks of <IndexTerm>hiPSC lines<Primary>hiPSC lines</Pr
imary><Secondary>large banks of</Secondary></IndexTerm> from normal cells as wel
l as from genetically affected cells (McKernan and Watt <CitationRef CitationID=
"CR92">2013</CitationRef>). Since all these cell lines have different genetic ba
ckgrounds, development and testing on a multitude of different hiPSC lines can c
over the broad genetic variability in humans and can mimic the various reactions
due to <IndexTerm>genetic predispositions<Primary>Genetic predispositions</Prim
ary></IndexTerm> of patients to a drug. A substance that might not show an effec
t in one cell line might have effects in another line with a different genetic b
ackground. As of today, large banks with stored <IndexTerm>cord-blood cells<Prim
ary>Cord-blood cells</Primary></IndexTerm> exist. Cord-blood cells have been sho
wn to be particularly amenable to reprogramming and moreover harbor fewer mutati
ons than skin cells from a 60-year-old adult (Rocha et al. <CitationRef Citation
ID="CR115">2004</CitationRef>; Giorgetti et al. <CitationRef CitationID="CR52">2
009</CitationRef>). In the foreseeable future, these banks could be used to gene
rate banks of hiPSC lines, which could then be used to evaluate the effects of a
drug for a whole population. The results from such studies would provide far mo
re significant data than any traditional in vitro method used in clinical trials
today.</Para>
<Para ID="Par25">Another new development in the field of drug discovery is the u
se of disease-specific hiPSC lines in <IndexTerm>high-throughput drug screening<
Primary>High-throughput drug screening</Primary></IndexTerm> approaches. hiPSCs
can be grown and differentiated into the target cell type in multiwell microtite
r plates. Cells in each well can then be exposed to different compounds, allowin
g for fast testing of a high amount of substances in a single step. Possible rea
douts could include cell proliferation, gene expression, protein levels, or enzy
me activity. When including control lines in the assay, the outcome of these tes
ts can be immediately compared to the non-disease phenotype.</Para>
<Para ID="Par26">One condition that is probably better modeled with hESCs than w
ith hiPSCs is <IndexTerm>developmental neurotoxicity (DNT)<Primary>Developmental
neurotoxicity (DNT)</Primary></IndexTerm>. DNT is the developmental exposure to
neurotoxicants, i.e., toxicants to the nervous system. The <IndexTerm>nervous s
ystem<Primary>Nervous system</Primary></IndexTerm> as one of the most complex or
gans is particularly susceptible to insults during development. During developme
nt, cells have to proliferate extensively but in an orchestrated manner; express
appropriate receptors and signaling and effector molecules, within the right ti
me frame and in the right location; migrate to their destination; and differenti
ate and, in the case of neurons, establish complex and far-reaching neuronal net
works. These processes are highly regulated and thus prone to impact of only sli
ght changes within the cellular environment potentially leading to neurodevelopm
ental disorders in the absence of noticeable cell death or changes in gross brai
n morphology. In recent years, it has emerged that environmental pollution and o
ther types of exposure are contributing to a rise in <IndexTerm>neurodegenerativ
e diseases<Primary>Neurodegenerative diseases</Primary></IndexTerm> and <IndexTe
rm>behavioral problems<Primary>Behavioral problems</Primary></IndexTerm> includi
ng aggressivity, learning disabilities, attention deficit disorder, and autism s
pectrum disorders (Grandjean and Landrigan <CitationRef CitationID="CR55">2006</
CitationRef>; Boulet et al. <CitationRef CitationID="CR15">2009</CitationRef>).
Also of concern is the possibility that <IndexTerm>DNT<Primary>DNT</Primary></In
dexTerm> may result in an acceleration of age-related decline in cognitive funct
ion. Animal models and regular human cell lines can only inform to a very limite
d extent about DNT-induced subtle changes in neural functioning and behavior in
human. Stuttering, for example, a neurodevelopmental disorder, would be difficul
t to model in mice. Current, more elaborate in vitro models based on primary neu
rons, neural cell lines, and immortalized neural precursor cells are only partly
satisfactory (Radio and Mundy <CitationRef CitationID="CR110">2008</CitationRef
>). While such models have allowed elucidation of molecular mechanisms underlyin
g impairment of differentiation and neurite outgrowth, such models contain usual
ly only one cell type and as such can only poorly model the complex intercellula
r interactions taking place during <IndexTerm>in vivo development<Primary><Empha

sis Type="Italic">In vivo development</Emphasis></Primary></IndexTerm>.</Para>
<Para ID="Par27">As <IndexTerm>hESCs<Primary>hESCs</Primary></IndexTerm> can be
differentiated into neural progenitors, neurons and glial cells, while recapitul
ating crucial steps in in vivo neural development, they are particularly attract
ive for <IndexTerm>modeling neurodevelopment in vitro<Primary>Modeling neurodeve
lopment <Emphasis Type="Italic">in vitro</Emphasis></Primary></IndexTerm> (Barbe
ri et al. <CitationRef CitationID="CR10">2003</CitationRef>; Conti and Cattaneo
<CitationRef CitationID="CR25">2010</CitationRef>). hESCs differentiating in cul
ture to neural cells better reflect the sensitivity of developing neural cells t
o insult than assays based on fetal or perinatal cells, such as neurons. Within
the same cellular test system derived from embryonic stem cells, terminally diff
erentiated neurons are far less susceptible to toxicity than the still different
iating neurons (Zimmer et al. <CitationRef CitationID="CR157">2011</CitationRef>
). Accordingly, hESCs are used increasingly to model DNT, with different assay s
ystems covering different stages during neural development, ranging from very ea
rly stages of neural induction and specification of the first progenitors of the
brain (Balmer et al. <CitationRef CitationID="CR8">2012</CitationRef>) over sta
ges where neural crest cells migrate to generate peripheral neurons (Zimmer et a
l. <CitationRef CitationID="CR158">2012</CitationRef>) to the stages where neuro
ns develop (Stummann et al. <CitationRef CitationID="CR138">2009</CitationRef>;
Hoelting et al. <CitationRef CitationID="CR64">2013</CitationRef>; Colleoni et a
l. <CitationRef CitationID="CR24">2012</CitationRef>).</Para>
</Section1>
<Heading>Limitations to Human Disease Modeling with hiPSCs</Heading>
<Para ID="Par28">Although <IndexTerm>hiPSC-derived disease models<Primary>hiPSCderived disease models</Primary></IndexTerm> are promising to generate human dis
ease phenotypes in vitro, there are also limitations. hiPSCs cannot necessarily
be generated from all genetic diseases. In the case of <IndexTerm>Fanconi anemia
(FA)<Primary>Fanconi anemia (FA)</Primary></IndexTerm>, a genetic disease cause
d by deficient DNA repair (FANC pathway) leading to bone marrow failure and canc
er, researchers reported a failure of reprogramming of fibroblasts derived from
two different FA patients (Raya et al. <CitationRef CitationID="CR112">2009</Cit
ationRef>). After repair of the genetic defect with lentiviral vectors encoding
the affected FANC genes, <IndexTerm>reprogramming efficiency<Primary>Reprogrammi
ng efficiency</Primary></IndexTerm> was restored to normal, non-disease levels.
Müller et al. were able to generate iPSCs from somatic FA cells albeit wi
th a decreased efficiency due to an increase in double-strand breaks and senesce
nce (Müller et al. <CitationRef CitationID="CR101">2012</CitationRef>). T
hey as well concluded that complementation of the FA gene defect rescues reprogr
amming efficiency of somatic FA cells to normal levels. These studies demonstrat
e that iPSC models for diseases related to <IndexTerm>DNA damage repair and sene
scence<Primary>DNA damage repair and senescence</Primary></IndexTerm> are not al
ways easily developed and might demand prior repair of the genetic defect.</Para
>
<Para ID="Par29">Another challenge is the modeling of <IndexTerm>epigenetic diso
rders<Primary>Epigenetic disorders</Primary></IndexTerm> during development, suc
h as deficient imprinting. For example, in fragile X syndrome (FXS) patients, th
e disorder is caused by an expanded CGG trinucleotide repeat in the fragile X me
ntal retardation (FMR1) gene locus, resulting in epigenetic silencing and the lo
ss of expression of the FMR1 protein. Neural cells derived from reprogrammed FXS
patient fibroblast lines showed variations in CGG-repeat lengths, with some hav
ing shorter repeats than the input population of fibroblasts (Sheridan et al. <C
itationRef CitationID="CR130">2011</CitationRef>). This indicates that epigeneti
c predispositions are not necessarily transferred after reprogramming of somatic
cells. Moreover, in various studies, a <IndexTerm>clone-to-clone variability<Pr
imary>Clone-to-clone variability</Primary></IndexTerm> of hiPSC lines in exhibit
ing or developing a disease phenotype was demonstrated. Particularly, two studie
s carried out by Agarwal et al. and Batista et al. showed that their hiPSC model
s of dyskeratosis congenita (DC), a premature aging syndrome caused by mutations

in telomerase components, displayed different disease phenotypes. Whereas the h
iPSCs from Agarwal et al. recovered telomerase activity and were able to regrow
<IndexTerm>telomeres<Primary>Telomeres</Primary></IndexTerm>, the hiPSCs from Ba
tista et al. retained the disease-related deficiency and showed telomere shorten
ing (Agarwal et al. <CitationRef CitationID="CR4">2010</CitationRef>; Batista et
al. <CitationRef CitationID="CR11">2011</CitationRef>). These studies illustrat
e the need to keep the variations in viral integration sites, starting cell hete
rogeneity, passage numbers, and culture conditions from one hiPSC cell line to a
nother in mind when using them as disease models. To alleviate discrepancies bet
ween different cell lines, multiple hiPSC lines from multiple patients with the
same disease should be generated when developing a disease model. While this clo
ne-to-clone variability can be beneficial in large-scale studies, it does compli
cate the process of initially developing a reliable disease model.</Para>
<Para ID="Par30">One approach to address this problem is the generation of genet
ically defined clones by genome editing. Modern genetics tools such as engineere
d <IndexTerm>zinc finger nucleases (ZFNs)<Primary>Zinc finger nucleases (ZFNs)</
Primary></IndexTerm> and <IndexTerm>transcription activator-like effector nuclea
ses (TALENs)<Primary>Transcription activator-like effector nucleases (TALENs)</P
rimary></IndexTerm> allow for either a directed correction of an affected gene o
r the introduction of a disease-specific mutation into the genome (Hockemeyer et
al. <CitationRef CitationID="CR63">2009</CitationRef>). This technique has alre
ady been successfully used to model <IndexTerm>susceptibility variants<Primary>S
usceptibility variants</Primary></IndexTerm> for familial Parkinson’s dis
ease, by introducing two different point mutations in the α-synuclein gen
e which led to the generation of two models with differing susceptibility levels
(Soldner et al. <CitationRef CitationID="CR132">2011</CitationRef>). TALENS hav
e also been successfully used to correct disease phenotypes. X-linked chronic gr
anulomatous disease is a defect of neutrophil microbicidal reactive oxygen speci
es (ROS) generation caused by a mutation in CYBB gene. By introducing a single-c
opy CYBB minigene into X-CGD hiPSCs without off-target insertions, Zou et al. co
uld restore ROS production (Zou et al. <CitationRef CitationID="CR159">2011</Cit
ationRef>). Another example is the <IndexTerm>in situ correction<Primary><Emphas
is Type="Italic">In situ correction</Emphasis></Primary></IndexTerm> of sickle c
ell anemia. Sebastiano et al. generated hiPSC lines from sickle cell anemia pati
ents and corrected the disease-related mutation by using three ZFN pairs and the
reby generating transgene and disease-free hiPSC lines (Sebastiano et al. <Citat
ionRef CitationID="CR125">2011</CitationRef>).</Para>
<Para ID="Par31">Additional limitations to hiPSC-derived disease models are a la
ck of efficient protocols for the generation of certain cell types affected by a
disease, the lack of sensitive detection methods for disease phenotypes, the pr
oblems with modeling late-onset diseases, or the inability to model interactions
between different cell types. This holds also true for model derivation from hE
SCs. An example for the lack of suitable differentiation protocols are models fo
r <IndexTerm>hematological disorders<Primary>Hematological disorders</Primary></
IndexTerm>. The establishment of models for sickle cell anemia, β-thalass
emia, and ADA-SCID has proven difficult as the blood cell lineages most relevant
to these diseases cannot be generated with satisfying efficiency and purity (On
der and Daley <CitationRef CitationID="CR105">2012</CitationRef>). Generation of
models for <IndexTerm>late-onset diseases<Primary>Late-onset diseases</Primary>
</IndexTerm> such as sporadic Parkinson’s disease, for example, which not
only require the genetic predisposition but also environmental queues, might re
quire experimental induction of the disease as well as an acceleration of the co
urse of the disease (Kim et al. <CitationRef CitationID="CR78">2013</CitationRef
>; Cherry and Daley <CitationRef CitationID="CR21">2012</CitationRef>). Finally,
in pursuance of modeling <IndexTerm>non-cell autonomous deficits<Primary>Non-ce
ll autonomous deficits</Primary></IndexTerm> as occurring, for example, in ALS (
amyotrophic lateral sclerosis), a disease where motor neurons die, a disease mod
el derived from cocultures of motor neurons derived from hESCs and mutated astro
cytes showed that the motor neurons die due to oxidative stress elicited in the
mutated astrocytes (Di Giorgio et al. <CitationRef CitationID="CR28">2008</Citat

ionRef>; Marchetto et al. <CitationRef CitationID="CR89">2008</CitationRef>). Wh
ile in this case protocols for the generation of motor neurons are well develope
d, many other cell types have yet to be derived with higher efficacy.</Para>
</Section1>
<Heading>Pluripotent Stem Cell Handling</Heading>
<Para ID="Par32">As discussed above, PSCs can be a valuable source of cells for
in vitro models, but they require a very meticulous handling, including stringen
t <IndexTerm>quality control<Primary>Quality control</Primary></IndexTerm>. In c
omparison to other more robust cell lines, pluripotent stem cell lines are highl
y susceptible to environmental changes and can quickly lose their pluripotent qu
alities. Heterogeneous cell populations can develop with spontaneous differentia
tion from PSCs entailing that cells do not necessarily reach developmental stage
s in a synchronized manner during directed differentiation (Kitaoka et al. 2011<
!--<query ID="Q5"><query_paragraph>Please provide details of Kitaoka et al. (201
1) and Estevan et al. (2011) in the reference list.</query_paragraph></query>-->
). Crucial for high-quality PSC populations are feeder cells of constant quality
, defined media and additives, <IndexTerm>standardized passaging<Primary>Standar
dized passaging</Primary></IndexTerm> and seeding techniques, substrate, and par
ticularly the cell or tissue microenvironment. The latter is very complex and pl
ays an important role in the generation of appropriate in vitro models (Viswanat
han et al. <CitationRef CitationID="CR147">2014</CitationRef>). In contrast to m
ouse PSCs, hPSCs cannot be passaged as single cells as the absence of <IndexTerm
>cell-cell contacts<Primary>Cell-cell contacts</Primary></IndexTerm> leads to ap
optosis. Thus, successful passaging of hPSCs depends on the generation of small
clusters of defined and, importantly, constant size. The addition of ROCK inhibi
tor to the culture medium allows for single-cell passaging for a limited number
of passages (Watanabe et al. <CitationRef CitationID="CR148">2007</CitationRef>)
. Another important factor of hPSC culture is <IndexTerm>oxygen tension<Primary>
Oxygen tension</Primary></IndexTerm>. Physiological oxygen tension reduces the i
ncidence of chromosomal aberrations without altering hESC pluripotency marker ex
pression while improving maintenance of pluripotency (Forsyth et al. <CitationRe
f CitationID="CR43">2006</CitationRef>; Forristal et al. <CitationRef CitationID
="CR42">2010</CitationRef>; Zachar et al. <CitationRef CitationID="CR156">2010</
CitationRef>). Lastly, the choice of substrate for stem cell culturing plays an
important role in cell quality. Viswanathan et al. have extensively discussed th
e different choices of substrates, with a focus on synthetic materials and their
effect on self-renewal and differentiation (Viswanathan et al. <CitationRef Cit
ationID="CR146">2012</CitationRef>, <CitationRef CitationID="CR147">2014</Citati
onRef>).</Para>
<Para ID="Par33">hiPSC lines show high disparities between cell lines, due to in
complete reprogramming, genetic background variability (Soldner and Jaenisch <Ci
tationRef CitationID="CR131">2012</CitationRef>), epigenetic memory (Kim et al.
<CitationRef CitationID="CR76">2010</CitationRef>), or erosion of X-chromosome i
nactivation (Mekhoubad et al. <CitationRef CitationID="CR94">2012</CitationRef>)
. These disparities in cell quality can have a great impact on the outcome of in
vitro tests and should be characterized very carefully. To fully realize the po
tential of human PSCs and to benefit from all the potential these versatile cell
s have, robust differentiation and cell purification protocols, optimal control
settings, and validation with human samples and/or other disease models are need
ed (Inoue et al. <CitationRef CitationID="CR69">2014</CitationRef>).</Para>
</Section1>
<Heading>The Embryonic Stem Cell Test (EST)</Heading>
<Para ID="Par34">As outlined above, the availability of PSCs provides new approa
ches for disease modeling and drug testing. Yet, despite all the advantages of t
hese cells compared to traditional models and the extensive research regarding t
he development of more defined cell models, as of date, only one stem cell-based
assay has been validated on the regulatory level: the mouse <IndexTerm>embryoni
c stem cell test (EST)<Primary>Embryonic stem cell test (EST)</Primary></IndexTe

rm>. The EST is a validated assay for potential <IndexTerm>embryotoxicants<Prima
ry>Embryo toxicants</Primary></IndexTerm> (Seiler and Spielmann <CitationRef Cit
ationID="CR126">2011</CitationRef>). For regulatory purposes, it can however not
be used on its own, but rather incorporated into an integrated test strategy. T
he official standard operation procedure (SOP) of the EST can be accessed at the
EURL ECVAM online database (<ExternalRef>
<RefSource>http://ecvam-dbalm.jrc.ec.europa.eu/</RefSource>
<RefTarget TargetType="URL" Address="http://ecvam-dbalm.jrc.ec.europa.eu/"/>
</ExternalRef>, accessed December 8, 2014).</Para>
<Para ID="Par35">This test was originally developed because of the need for a re
liable, cellular in vitro test for <IndexTerm>embryotoxicity<Primary>Embryo toxi
city</Primary></IndexTerm> of chemicals. The reasons for the development of this
new cellular assay were the high costs and ethical concerns associated with anim
al testing, a toxicological study for one chemical which was estimated to requir
e around 4,700 animals, and a paucity of tests specific for early embryonic deve
lopment (Höfer et al. <CitationRef CitationID="CR65">2004</CitationRef>).
Already established in vitro methods such as the frog embryo teratogenesis assa
y (Bantle et al. <CitationRef CitationID="CR9">1990</CitationRef>), the chicken
embryotoxicity screening test (Jelinek et al. <CitationRef CitationID="CR70">198
5</CitationRef>), or assays based on murine embryos (Sadler et al. <CitationRef
CitationID="CR119">1982</CitationRef>; Flint <CitationRef CitationID="CR41">1993
</CitationRef>; Schmidt et al. <CitationRef CitationID="CR120">2001</CitationRef
>; Cicurel and Schmid <CitationRef CitationID="CR23">1988</CitationRef>) are bas
ed on <IndexTerm>somatic cells<Primary>Somatic cells</Primary></IndexTerm> rathe
r than on stem cells and developing cells and thus do not reflect early developm
ental stages.</Para>
<Para ID="Par36">The EST was developed in the group of Spielmann and his coworke
rs in 1993 and was validated in 2002 (Heuer et al. <CitationRef CitationID="CR62
">1993</CitationRef>; Genschow et al. <CitationRef CitationID="CR49">2002</Citat
ionRef>). The test is based on the assumptions that in vitro tests of basal <Ind
exTerm>cytotoxicity<Primary>Cytotoxicity</Primary></IndexTerm> are able to accur
ately determine rodent in vivo LD<Subscript>50</Subscript> (Ekwall <CitationRef
CitationID="CR36">1999</CitationRef>; Spielmann et al. <CitationRef CitationID="
CR135">1999</CitationRef>) and that exposure of ESCs to embryotoxic substances l
eads to alterations in the <IndexTerm>differentiation patterns<Primary>Different
iation patterns</Primary></IndexTerm> during embryoid body (EB) formation (Wobus
et al. <CitationRef CitationID="CR154">1994</CitationRef>). In this test, two m
ouse cell lines are used that represent both the embryonic and the adult tissue:
the <IndexTerm>mouse ESC line D3<Primary>Mouse ESC line D3</Primary></IndexTerm
> and the <IndexTerm>mouse 3T3 fibroblast cell line<Primary>Mouse 3T3 fibroblast
cell line</Primary></IndexTerm>. The D3 ESCs are differentiated to EBs in the a
bsence of the pluripotency cytokine leukemia inhibitory factor (LIF), leading to
the formation of beating clusters of cardiomyocytes. The first endpoint investi
gated in the EST is the concentration of the test substance that is needed to in
hibit cardiac differentiation by 50 % after 10 days of exposure (ID<Subsc
ript>50</Subscript>). Further, the concentrations of this substance needed to in
hibit proliferation of both D3 ESCs and 3T3 fibroblasts by 50 % after 10
days of exposure lead to two additional endpoints. The three endpoints are used
to generate a biostatistical prediction model that assigns the tested substance
to an embryotoxicity category (strong, weak or non-embryotoxic) (Genschow et al.
<CitationRef CitationID="CR48">2000</CitationRef>, <CitationRef CitationID="CR4
9">2002</CitationRef>; Spielmann and Liebsch <CitationRef CitationID="CR134">200
1</CitationRef>).</Para>
<Para ID="Par37">The EST became widely recognized when the <IndexTerm>European C
entre for the Validation of Alternative Methods (ECVAM)<Primary>European Centre
for the Validation of Alternative Methods (ECVAM)</Primary></IndexTerm> began se
eking for new toxicity tests as alternatives to animal experiments in the mid-19
90s and initiated <IndexTerm>validation studies<Primary>Validation studies</Prim

ary></IndexTerm> for various in vitro assays. In 2002, the EST was validated as
a screening assay for potentially embryotoxic chemicals by the <IndexTerm>Europe
an Scientific Advisory Committee<Primary>European Scientific Advisory Committee<
/Primary></IndexTerm> (ESAC <CitationRef CitationID="CR38">2002</CitationRef>).
In the first study, a set of 20 substances with known embryotoxicity were tested
. For weak and nontoxic substances, the embryotoxicity was predicted with an acc
uracy of 78 %, whereas strongly embryotoxic substances were predicted wit
h 100 % accuracy (Genschow et al. <CitationRef CitationID="CR49">2002</Ci
tationRef>, <CitationRef CitationID="CR50">2004</CitationRef>). The poorest accu
racy was recorded for the detection of non-embryotoxic compounds.</Para>
<Para ID="Par38">Although the EST was sufficiently accurate at predicting embryo
toxicologic <IndexTerm>effects<Primary>Embryo toxicologic effects</Primary></Ind
exTerm> and was ready to be accepted by regulatory commissions (Balls and Hellst
en <CitationRef CitationID="CR7">2002</CitationRef>), the ESAC ultimately did no
t recognize the EST as qualified to replace the already established animal exper
iments (Spielmann <CitationRef CitationID="CR133">2009</CitationRef>). One of th
e reasons was that the amount of tested substances was not large enough. In a fo
llow-up study with 13 additional substances, the EST failed to correctly predict
the embryotoxic effect of the tested compounds, indicating that the test requir
ed further optimizations (Hareng et al. <CitationRef CitationID="CR58">2005</Cit
ationRef>). Further limitations of the original <IndexTerm>mouse EST<Primary>Mou
se EST</Primary></IndexTerm> have been extensively discussed, including the lack
of molecular endpoints, such as differentiation markers for all cell lineages,
for example (Schmidt et al. <CitationRef CitationID="CR120">2001</CitationRef>;
Piersma <CitationRef CitationID="CR108">2004</CitationRef>), the inability of mo
use D3 ESC to detect toxic effects of substances that require metabolic activati
on (Marx-Stoelting et al. <CitationRef CitationID="CR91">2009</CitationRef>; Ver
wei et al. <CitationRef CitationID="CR145">2006</CitationRef>) and the inability
of the EST to detect teratogenic effects past the early embryonic differentiati
on stages.</Para>
<Para ID="Par39">In the past few years, many of these concerns have been address
ed, and new variations of the original EST have been proposed. Early on, the use
of reporter genes under control of cardiac-specific promoters was discussed whe
n a lineage-dependent effect of retinoic acid on ESC differentiation was reporte
d (Wobus et al. <CitationRef CitationID="CR154">1994</CitationRef>; Kolossov et
al. <CitationRef CitationID="CR80">1998</CitationRef>). <IndexTerm>Reporter gene
assays<Primary>Reporter gene assays</Primary></IndexTerm> for developmental tox
icity have since been implemented (Bremer et al. <CitationRef CitationID="CR17">
2001</CitationRef>) and have replaced the rather subjective and poorly quantitat
ive determination of the embryotoxic effect of a substance by microscopical obse
rvation of beating EBs. Instead, the expression of the <IndexTerm>cardiac marker
genes<Primary>Cardiac marker genes</Primary></IndexTerm> α-myosin heavy
chain (MHC) and α-actinin is quantified by flow cytometry in labeled cell
s (Seiler et al. <CitationRef CitationID="CR127">2004</CitationRef>, <CitationRe
f CitationID="CR128">2006</CitationRef>). This <IndexTerm>flow cytometry-based E
ST<Primary>Flow cytometry-based EST</Primary></IndexTerm> has successfully been
adopted for assessing developmental toxicity and has reduced the test duration w
hile providing a more reproducible screening for developmental toxicity (Buesen
et al. <CitationRef CitationID="CR18">2009</CitationRef>). Even more biomarker g
enes of embryotoxicity have been identified that displayed a significant decreas
e in expression after exposure to a nontoxic dose of the embryotoxic 5-fluoroura
cil (Estevan et al. 2011). This effect was already measured 5 days after exposur
e, reducing the time needed to evaluate the embryotoxic potential of a substance
by 50 % compared to the usual 10 days needed to observe beating cardiomy
ocyte clusters.</Para>
<Para ID="Par40">In addition to cardiac markers, additional lineages were added
to the <IndexTerm>endpoints<Primary>Endpoints, EST</Primary></IndexTerm> of the
EST (Spielmann et al. <CitationRef CitationID="CR136">2006</CitationRef>). The i
nclusion of parameters for neuronal differentiation led to the positive detectio
n of the highly embryo and neurotoxic substance methylmercury, which had not bee
n successfully classified in the conventional EST previously, with cardiac endpo
int alone (Stummann et al. <CitationRef CitationID="CR137">2007</CitationRef>).
Hayess et al. have developed a test for determining DNT of substances by inducin
g neural differentiation of mouse ESCs. They were able to determine <IndexTerm>D
NT<Primary>DNT</Primary></IndexTerm> with a 100 % predictivity and accura
cy for nine substances (Hayess et al. <CitationRef CitationID="CR60">2013</Citat
ionRef>). Another endpoint that has been established successfully is testing for
the expression of three genes involved in <IndexTerm>osteogenesis<Primary>Osteo
genesis</Primary></IndexTerm>. The results of this osteoblast differentiation as
say (ESTo), testing 19 substances, showed a high correlation to results of the c
onventional EST and allowed for the detection of 2,3,7,8-tetra-chlorodibenzo-<Em
phasis Type="Italic">p</Emphasis>-dioxin (TCDD), an embryotoxic substance that c
ould not be detected otherwise (de Jong et al. <CitationRef CitationID="CR26">20
14</CitationRef>). These examples show the importance of a broad range of geneti
c markers for successfully identifying embryotoxic compounds.</Para>
<Para ID="Par41">Apart from endpoints based on gene expression, <IndexTerm>prote
in markers<Primary>Protein markers</Primary></IndexTerm> and metabolic activity
can potentially indicate embryotoxic properties. A proteomics approach carried o
ut by Osman and coworkers showed that EBs exposed to the embryotoxic monobutyl p
hthalate for 25 h showed a shift in the intracellular levels of 33 protei
ns, including cardiac markers and chromatin modulator enzymes (Osman et al. <Cit
ationRef CitationID="CR106">2010</CitationRef>). A recent study investigated the
impact of embryotoxic substances on genes of the <IndexTerm>energy metabolism<P
rimary>Energy metabolism</Primary></IndexTerm>. The transcriptomics approach of
van Dartel et al. revealed dynamic changes in energy metabolism during early ESC
differentiation in response to embryotoxic compounds. The test showed activatio
n of glycolysis, truncated activation of the tricarboxylic acid (TCA) cycle, act
ivation of lipid synthesis, and activation of glutaminolysis (van Dartel et al.
<CitationRef CitationID="CR143">2014</CitationRef>).</Para>
<Para ID="Par42">As outlined previously, the use of human cells has important ad
vantages compared to murine cells. <IndexTerm>Species-specific differences<Prima
ry>Species-specific differences</Primary></IndexTerm> in embryonic development b
etween man and mouse have been reported including DNA methylation, DNA repair, a
nd the expression of genes involved in drug metabolism (Krtolica et al. <Citatio
nRef CitationID="CR81">2009</CitationRef>). Accordingly, an EST using hESCs woul
d significantly enhance the validity as such species-specificity problems would
be alleviated (Wobus and Löser <CitationRef CitationID="CR152">2011</Cita
tionRef>). A recent study, adapting the EST to human cells, using hiPSCs and hum
an dermal fibroblasts has successfully detected the teratogenic effects of thali
domide, which is not detected in the validated mouse EST (Aikawa et al. <Citatio
nRef CitationID="CR5">2014</CitationRef>). Additional proof-of-concept studies w
ith the goal to determine the suitability of hESCs for toxicology tests have bee
n performed. Adler and coworkers carried out studies evaluating the effects of a
ll-trans retinoic acid and 13-cis retinoic acid on human ESCs, human ES-derived
progenitors, and human foreskin fibroblasts, thereby detecting a toxic effect of
13-cis retinoic acid, which was not detected in previous mouse EST analyses (Ad
ler et al. <CitationRef CitationID="CR2">2008a</CitationRef>). Moreover, in a se
cond study, they established a <IndexTerm>human EST<Primary>Human EST</Primary><
/IndexTerm> yielding results very similar to the mouse EST (Adler et al. <Citati
onRef CitationID="CR3">2008b</CitationRef>). They proposed to use additional mar
kers of undifferentiated ESCs as well as markers of neural plate morphogenesis a
nd early cardiogenesis to expand the amount of molecular endpoints for evaluatio
n of embryotoxicity.</Para>
<Para ID="Par43">As of today, the validation process of the EST is an ongoing pr
oject, and the test is continuously being improved by addition of new endpoints
and adjustments for high-throughput screening and the future use of hESCs or hiP
SCs. Although studies of an EST with human cells are very promising, still many
issues need to be addressed. These include insufficient sensitivity and specific
ity of the test. Importantly, test systems with hESCs or hiPSCs are plagued by p
oor reproducibility due to the inherent difficulties in culturing and differenti

ating human PSCs in a standardized manner. hPSCs are best passaged by cut-and-pa
ste or as small clumps rendering standardization difficult. Attempts at <IndexTe
rm>standardization<Primary>Standardization</Primary></IndexTerm> were made durin
g the EU consortium project <IndexTerm>ESNATS<Primary>ESNATS</Primary></IndexTer
m> (Embryonic Stem Cell-based Novel Alternative Testing Strategies) where a new
toxicity testing platform based on human ESCs was developed. Five test systems w
ere developed to an adequate level for entering possible pre-validation procedur
es (Rovida et al. <CitationRef CitationID="CR117">2014</CitationRef>; Leist et a
l. <CitationRef CitationID="CR85">2013</CitationRef>; Krug et al. <CitationRef C
itationID="CR82">2013</CitationRef>).</Para>
<Heading>Brief EST Protocol</Heading>
<Para ID="Par44">The EST evaluates occurrence of beating <IndexTerm>foci<Primary
>Foci, EST protocol</Primary></IndexTerm> after 10 days of differentiation in th
e presence of a test compound. For this, mESCs are first differentiated as singl
e cells and seeded in hanging drops to aggregate and form EBs (“hanging d
rop” culture according to Wobus et al. <CitationRef CitationID="CR153">19
91</CitationRef>). After 3 days, the hanging drops are washed off and transferre
d to suspension culture for 2 more days before being plated as 1 EB/well
into 24-well plates. After 5 additional days, the plates are inspected visually
under the microscope and scored for beating foci, indicative of successful diffe
rentiation to <IndexTerm>cardiac myoblasts<Primary>Cardiac myoblasts</Primary></
IndexTerm>. In parallel, cytotoxicity of the test compound to 3T3 fibroblasts (a
s “adult” tissue) and undifferentiated hESCs is measured with the
<IndexTerm>MTT assay<Primary>MTT assay</Primary></IndexTerm>. On the basis of th
e three endpoints, a biostatistical prediction model is generated that assigns t
he tested substance to an embryotoxicity category (strong, weak, or non-embryoto
xic).
<OrderedList>
<Heading>Endpoints of the Test</Heading><ListItem><ItemNumber>1.</ItemNumber> <I
temContent>
<Para ID="Par45">Inhibition of ESC differentiation into cardiac myoblasts, measu
red by light microscopy</Para>
</ItemContent></ListItem><ListItem><ItemNumber>2.</ItemNumber> <ItemContent>
<Para ID="Par46">Inhibition of ESC and 3T3 proliferation</Para>
</ItemContent></ListItem><ListItem><ItemNumber>3.</ItemNumber> <ItemContent>
<Para ID="Par47">Inhibiton of ESC and 3T3 cell viability determined by the MTT a
ssay</Para>
</ItemContent></ListItem>
</OrderedList>
<UnorderedList Mark="None">
<Heading>Endpoint Values</Heading><ItemContent>
<Para ID="Par48">IC<Subscript>50</Subscript>: 50 % inhibition of growth a
nd viability of the cells</Para>
</ItemContent><ItemContent>
<Para ID="Par49">ID<Subscript>50</Subscript>: 50 % inhibition of differen
tiation of ESCs into cardiac myoblasts</Para>
</ItemContent>
</UnorderedList></Para>
<Para ID="Par50"><Emphasis Type="Italic">This protocol is a short extract of the
official ECVAM DB-ALM Protocol number 113. For more information and the SOP, we
refer to the EURL ECVAM online database</Emphasis> (<ExternalRef>
<RefSource>http://ecvam-dbalm.jrc.ec.europa.eu/</RefSource>
<RefTarget TargetType="URL" Address="http://ecvam-dbalm.jrc.ec.europa.eu/"/>
</ExternalRef>) <Emphasis Type="Italic">as well as</Emphasis> Seiler and Spielma
nn (<CitationRef CitationID="CR126">2011</CitationRef>)<Emphasis Type="Italic">.
</Emphasis></Para>
</Section2>
</Section1>
</Body>
<BodyRef FileRef="43401_0_En_114-1_Chapter_OnlinePDF.pdf" TargetType="OnlinePDF"
PDFType="Typeset" OutputMedium="Online"/>
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