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3 Development of New In Vitro Stem Cell-Based Cell Models for Toxicology

3 Development of New In Vitro Stem Cell-Based Cell Models for Toxicology

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G.N. Stacey et al.

2009). As pluripotent stem cells develop into multipotent lineages they lose the

expression of critical pluripotent genes such as Nanog and Oct4 (or POU5F1 in

humans). The loss of the expression of these genes is often used to demonstrate successful progression to multipotent lineages. The intermediate mesoderm expresses

factors such as Pax2, Osr1 and Lhx1, which may or may not be lost as differentiation continues to metanephric mesenchyme and ureteric bud lineages (Xia et al.

2013; Takasato et al. 2014). Different protocols have been used to generate reasonably pure populations of intermediate mesoderm, including sequential addition of

BMP4/FGF2, retinoic acid/activin A/BMP2 (Lam et al. 2014) or by activation of

Wnt signaling with the small molecule agonist CHIR99021 (CHIR) to create

brachyury and Mixl1 positive mesendoderm cells (Araoka et al. 2014; Narayanan

et al. 2013). Several different mixes of developmental growth factors have been

used to differentiate the intermediate mesoderm further into metanephric mesenchyme and ureteric bud cells and even to podocyte and proximal-like phenotypes

(Song et al. 2012; Silva et al. 2009). A list of commonly used markers for each of

the developmental stages and also markers and characteristics of the mature phenotypes, which are present in vivo and maintained in primary culture and some cell

lines are given in Table 11.5.

While there has been great success in the derivation of target renal cells from

pluripotent stem cells, there is still a great deal of work that needs to be done. For

example, most of the protocols developed to-date give mixed populations of cells,

in different differentiation states. Traditional strategies for in vitro toxicity studies

rely on relatively pure cultures of the target cell types. However, probably more

troublesome is the lack of temporal phenotypic stability of the derived cells, which

would be problematic for reproducibility and interpretation of chemical exposures.

However, the field is in its infancy and it is hoped that many of these challenges will

be overcome in the near future. Table 11.5 gives examples of some to the key markers which may be useful in the development and control of stem cell-derived models

of kidney tissue.


General Acceptability Criteria of Stem Cell-Derived

In Vitro Toxicology Assays

In order that in vitro toxicity methods based on stem cells-derived cell or tissue

model (test system) can be considered reliable and relevant with global applicability, they must be reliable and robust showing technical reproducibility between different experimental runs, operators, laboratories and source of equipment and

reagents. A key component in assuring such reliability and standardisation of data

outputs is the use of suitable positive and negative controls. The generation of clear

and unambiguous data, and a clear defined concept on how to use the results in the

context of hazard and risk assessment contexts are of high importance. For new in

vitro toxicity methods based on stem cells as a test system, enough historical data


Ensuring the Quality of Stem Cell-Derived In Vitro Models…


should be generated in the development phase to define specific acceptance criteria

for all elements of the in vitro method and a defined level of expected performance

of the method or the specific measurements of interest.

In order to define such stem-cell based phenotypic criteria the stem cells must

have a specific functionality, which can be measured, whilst for stem cell-based

molecular features a very well defined characteristics need to be identified to establish specific acceptance criteria. Acceptance criteria related to the biological function of stem cell-derived models are used to qualify the stem cells for use in a

specific in vitro toxicity method and have been based largely on marker phenotype

as described in Sect. 3 above. These can help to assure consistent performance of

the stem cell-derived cell model based on monitoring activities carried out at specific points in preparation and use of the stem cell derived culture. However, the

association between marker phenotype and predictability of toxicity with different

compounds clearly requires validation and control of appropriate functional features of the cellular model. Exemplars of these are also discussed above in Sect. 3.

Such acceptance criteria may need to be specific to the stem cell line used or its

genotype and also the intended application of the assay. However, for in vitro methods where different stem cell models may need to be used for the same application

(e.g. read-out, multiple genotypes tested against the same compound), it is important to define performance standards that the different methods should comply with

to enable the stem cell user community to compare results from different stem cellbased in vitro methods.

Regulatory acceptance and validation of new in vitro assays can be a timeconsuming process and given the variety of new alternative in vitro methods now

becoming available, a system of capturing early stage protocols and qualification

data is now being developed in a collaboration between the ToxBank consortium

and the Joint Research Centre in Ispra (Stacey et al. 2014b). Developing in vitro

methods to achieve regulatory acceptance usually follows a series of steps:

(1) method development (e.g. carried out in academic, industrial or regulatory


(2) method optimisation (e.g. carried out by the original developer, new users of a

particular method, or by validation bodies)

(3) method validation (with or without the involvement of validation bodies)

(4) method acceptance (e.g. facilitated by the involvement of the Organisation of

Economic Cooperation and Development, OECD, through the development of

test guidelines)

Acceptance and performance criteria, covering all aspects of the test system and

test method should be developed and optimised as early as possible to expedite the

overall validation process. Validation is a pivotal step towards the regulatory acceptance and the international recognition of in vitro methods for a range of scientific

purposes by a variety of end-users, as described in internationally accepted guidance (OECD 2005), and throughout this book.



G.N. Stacey et al.

Establishment of Control Materials

The process of regulatory acceptance must include evaluation of the performance of

novel in vitro toxicity methods and their comparison with established in vitro and in

vivo toxicological methods. However, it is also important to control the essential

components of the in vitro method including the exposure and purity of the test

chemicals (test items), the in vitro biological models (test systems including any

stem cell based test system), the analytical techniques used and the experimental

design. Endpoint controls are increasingly PCR-based and it is likely that there will

be a role for DNA or RNA-based reference materials to provide quantitative controls for assuring suitability of cultures for use in toxicology assays.

Control compounds (positive controls) whose mode of action and in vitro

response is well characterised are clearly important to demonstrate consistent functionality of cell-based models and a number have been established in the ToxBank

project and by EURL ECVAM at the European Commission Joint Research Centre.

Such reference materials will be vital for international standardisation in development of these assays and reference materials for analytical techniques will probably

be an important influence in standardisation of stem cell–based toxicological assays

in the long term. However, such control materials are highly specific to the cell type

and induced mechanism of toxicity. Another useful approach for developers of in

vitro stem cell or tissue-based methods for specific toxicological applications is to

consult lists of commercially available chemicals that can be used to assess the performance of their new developed methods. A range of sets of test compounds being

established for different purposes can be found at http://chelist.jrc.ec.europa.eu/.

Control materials will clearly also be important for the control of safety testing

for viral contaminants and numerous international reference materials for virus

detection in certain products have already been established. For more information

see http://nibsc.org/.


Conclusions and Future Perspectives

Future toxicological applications in routine testing using stem cell or tissue test

systems will be dependent on the ability to deliver consistency in their molecular

and phenotypic functions. Another critical factor in their successful uptake in

industry will be the availability of cell preparations which can be used directly in in

vitro methods. This may involve more efficient differentiation protocols and also

new cryopreservation methods for differentiated cells and progenitor cultures.

Careful attention to good cell culture practice in coordination with attention to regulatory and industry requirements will be critical. This will probably require the

qualification of initial cultures (prior to differentiation), using new phenotypic and/

or epigenetic screens to establish batch to batch consistency and maintenance of



Ensuring the Quality of Stem Cell-Derived In Vitro Models…


Complex systems comprising multiple cell types that generate more sophisticated and predictive data sets could be extremely valuable and are just beginning to

be developed. Approaches have also been developed within the SEURAT-1 programme using 3D culture to establish stable systems to study repeat dose and

chronic drug effects and increased comparability with in vivo function.

The recent successes in direct differentiation to certain cell types outlined in

this chapter provide future potential in vitro models with more efficient differentiation but these are still at a very early stage of research development. Major

challenges remain regarding our ability to achieve sufficient numbers of cells

reproducibly for large scale assays and our ability to assure that the responses of

culture models produced by artificial cell differentiation replicate those of cells

created via natural pathways of cellular development and differentiation. However,

new strategies and developments including bead-based combinatorial differentiation (Tarunina et al. 2014; Efthymiou et al. 2014) are providing promising potential solutions.

The importance of technological developments and systems biology approaches

for stem cell models of the future will also require progress in the following areas:

• stem cell “omics” technologies and more readily accessible bioinformatics


• stem cell culture automation as well as high-throughput techniques to promote

reproducibility and capacity for industry use

• development of stem cell cultures in systems biological approaches to generate

information regarding toxicological pathways or the mode of action of test items

of various kinds.

• establishment of the potential toxicological applications using iPSC and the

donor concept (e.g. DILI project)

• use of stem cell-based in vitro methods for integrated testing strategies

• validated stem cell-based mechanistic tools targeting key events in adverse outcome pathway, especially specific for human cells.

• the adverse outcome pathways (AOPs) concept that has been designed to be used

for human risk assessment. Therefore to be useful for regulatory purposes it has

to demonstrated that the key events described in the AOP are relevant to human

cells, and vice versa. For this reason the critical molecular mechanisms of toxicity that are unique for human cells have to be studied using human models

derived from hPSCs since the available human cells originated from cancer tissue do not represent the physiological, normal human situation and have very

limited application

• role of stem cell-based toxicological methods for future regulatory applications

(mixtures, grouping of substances) in combination with profiling methods such

as omics etc.

• enhancing communication on progress in development of qualified stem cell

based assays


G.N. Stacey et al.

It is hoped that stem cell and tissue-based in vitro models will increasingly help

to elucidate critical toxicological questions and hopefully more elusive chronic

toxic effects. Going forward, it will be important to continue identifying gaps and

opportunities regarding the role of stem cell and tissue-based in vitro toxicological

methods in assuring complementarity with other in vitro methods by exploiting the

unique features of stem cells (especially of human origin) as a toxicological test

systems. Much progress has been made in the development of stem cell-based neural cell models. However, key challenges remain for the development of accurate in

vitro human cell-based models of in vivo tissue types including, muscle (especially

cardiac tissue), liver and kidney. We have highlighted some advances in these areas

but further work is required to provide accurate models of adult human tissue which

can be generated reliably and efficiently for use in the setting of routine industrial

scale screening.


Appendix 1: Ethics Criteria for Cell Lines Selection

(hiPSCs and hESCs)

In order to establish that all cell lines were obtained from tissue that has been ethically sourced the researchers must be able to provide evidence for the following:

• That fully informed consent was obtained and recorded for the donor tissue

• That consent permits the intended uses of the hPSC lines derived from the

donor’s tissue

• That the donor’s identity was anonymised

• A validated copy of the original consent form (with donor details redacted) is

available and/or a statement is available from a person authorised by the owner

or derivation centre on the ethical provenance of the cell line including a contact

that would facilitate confirmation of the original consent without breaking donor


• There should be a clear statement on any constraints applied by the donor on the

use of derivatives from their cells/tissues.

• Cell lines are registered within the hESCreg database

• Copies of blank consent form (or an English translation) and any information

provided to the donor are available.

• Evidence from the donation process that the donor was aware that:

• Derived lines may be exploited commercially but that donors would not receive

personal financial benefit.

• The donors decision to donate tissue would not influence their personal treatment

an there would be no feedback on data from the cell line derived from their tissue. Derived hPSCs could be used for a wide range of purposes in different laboratories and may be tested for genetic characteristics, microbiological

contamination and other features of the cells.


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