Samenvatting
Non-alcoholic steatohepatitis (NASH) is a severe chronic liver disease that
affects about 5% of the population. NASH is characterized by hepatic lipid
accumulation, inflammation and fibrosis and can progress to cirrhosis and
hepatocellular carcinoma. There are currently no drugs available to treat
NASH. Investigation of NASH traditionally relies on animal models, which are often not representative for the human situation. Therefore, the aim of the
doctoral thesis was to develop a human-based in vitro model that can
recapitulate the molecular and cellular mechanisms that drive NASH and can
be used during anti-NASH drug development. To this end, we created a NASH-specific hepatic environment in vitro by exposing human stem cell-derived hepatic cells (hSKP-HPC), primary human hepatocytes (PHH) and human hepatic cell lines (HepG2 and HepaRG) to key NASH-inducing factors. The obtained models mirrored NASH characteristics and could be used to evaluate anti-lipogenic and anti-inflammatory properties of PPAR agonists, a class of anti-NASH drugs that are under clinical evaluation. The hSKP-HPC-derived model most closely mimicked the PHH-mediated drug testing responses, highlighting its possible future position in preclinical drug development.
Furthermore, genetic predisposition of patients to develop NASH could be
evaluated in vitro using hSKP-HPC, paving the way for the investigation of
patient-specific genetic etiologies of NASH. In conclusion, a pragmatic human- and disease-relevant stem cell-derived in vitro NASH model has been developed that can be implemented in drug testing and personalized medicine.
affects about 5% of the population. NASH is characterized by hepatic lipid
accumulation, inflammation and fibrosis and can progress to cirrhosis and
hepatocellular carcinoma. There are currently no drugs available to treat
NASH. Investigation of NASH traditionally relies on animal models, which are often not representative for the human situation. Therefore, the aim of the
doctoral thesis was to develop a human-based in vitro model that can
recapitulate the molecular and cellular mechanisms that drive NASH and can
be used during anti-NASH drug development. To this end, we created a NASH-specific hepatic environment in vitro by exposing human stem cell-derived hepatic cells (hSKP-HPC), primary human hepatocytes (PHH) and human hepatic cell lines (HepG2 and HepaRG) to key NASH-inducing factors. The obtained models mirrored NASH characteristics and could be used to evaluate anti-lipogenic and anti-inflammatory properties of PPAR agonists, a class of anti-NASH drugs that are under clinical evaluation. The hSKP-HPC-derived model most closely mimicked the PHH-mediated drug testing responses, highlighting its possible future position in preclinical drug development.
Furthermore, genetic predisposition of patients to develop NASH could be
evaluated in vitro using hSKP-HPC, paving the way for the investigation of
patient-specific genetic etiologies of NASH. In conclusion, a pragmatic human- and disease-relevant stem cell-derived in vitro NASH model has been developed that can be implemented in drug testing and personalized medicine.
| Originele taal-2 | English |
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| Toekennende instantie |
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| Begeleider(s)/adviseur |
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| Datum van toekenning | 8 jul 2020 |
| Status | Published - 2020 |