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priate expression of the differentiated
phenotype
• Optimisation of the culture conditions
to differentiate adult bone
marrow stem cells into functional
hepatocytes
• Development of more complex
cell co-culture models to combine
absorption and metabolism
in intestine and liver.
2. Identification of drug transport and
metabolism pathways in the available
hepatic and intestinal in vitro models:
• Modulation of their expression by
culture conditions
• Development of high-throughput
methodologies for their study.
3. Determination of cellular and molecular
targets as endpoints of drug exposure
in intestine and liver with respect
to:
• Effects on cell proliferation (e.g.,
cell cycle control, apoptosis/necrosis)
• Effects on differentiated functions
(e.g., protein secretion, cell
junctions, expression of genes
involved in transport and metabolism).
4. In silico approaches to modelling the
liver and the intestine:
• Development of mechanismbased
pharmacokinetic models
• Exploration of the predictive utility
of new in vitro models
• Identification of areas requiring
refinement for future in vitro
models.
5. Determination of the transfer potential
of the developed in vitro models
for their utilisation within the industrial
setting, that derives from the
close collaboration within the project
of research academic institutions and
SMEs.
Experimental Design &
Results Achieved
Partners working with cellular models
have mainly dealt with objectives 1 and
2, trying to characterise and optimise the
cellular models already available or under
development in the areas of hepatocytes
and enterocytes. The activities performed
and the results achieved are described
below.
Hepatic Cell Models
Different models and approaches were
explored for the hepatic differentiation,
since the major problem with hepatocytes
in vitro is the rapid loss of their specialised
functions.
The first approach (by partners INSERM,
BPI, Novomass, and Advancell) has been
the extensive characterisation and optimisation
of the HepaRG cell line. HepaRG,
a human liver cell line of tumour origin,
has been extensively characterised for the
expression of bio-transformation activities
such as several major CYPs, antioxidant
activities and efflux transport activities
(BSEP and MRP2). Differentiated HepaRG
PROGRESS REPORTS FROM EU-FUNDED PROJECTS
Progress Report 2011 & AXLR8-2 Workshop Report
95