Influence of Liver Extracellular Matrix in Predicting Drug-Induced Liver Injury: An Alternate Paradigm

Sasikumar, Shyama and Chameettachal, Shibu and Pati, Falguni and et al, . (2022) Influence of Liver Extracellular Matrix in Predicting Drug-Induced Liver Injury: An Alternate Paradigm. ACS Biomaterials Science & Engineering, 8 (2). pp. 834-846. ISSN 2373-9878

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Abstract

In vitro drug-induced liver injury (DILI) models are promising tools for drug development to predict adverse events during clinical usage. However, the currently available DILI models are not specific or not able to predict the injury accurately. This is believed to be mainly because of failure to conserve the hepatocyte phenotype, lack of longevity, and difficulty in maintaining the tissue-specific microenvironment. In this study, we have assessed the potential of decellularized liver extracellular matrix (DLM) in retaining the hepatic cellular phenotype and functionality in the presence of a tissue-specific microenvironment along with its role in influencing the effect of the drug on hepatic cells. We show that DLM helps maintain the phenotype of the hepatic cell line HepG2, a well-known cell line for secretion of human proteins that is easily available. Also, the DLM enhanced the expression of a metabolic marker carbamoyl phosphate synthetase I (CPS1), a regulator of urea cycle, and bile salt export pump (BSEP), a marker of hepatocyte polarity. We further validated the DLM for its influence on the sensitivity of cells toward different classes of drugs. Interestingly, the coculture model, in the presence of endothelial cells and stellate cells, exhibited a higher sensitivity for both acetaminophen and trovafloxacin, a toxic compound that does not show any toxicity on preclinical screening. Thus, our results demonstrate for the first time that a multicellular combination along with DLM can be a potential and reliable DILI model to screen multiple drugs. © 2022 American Chemical Society. All rights reserved.

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IITH Creators:

IITH Creators	ORCiD
Pati, Falguni	http://orcid.org/0000-0002-3588-1800

Item Type:

Article

Additional Information:

The authors would like to acknowledge the Early Career Research award from the Department of Science and Technology, Govt. of India (ECR/2015/000458) and Ramalingaswami Research Fellowship from the Department of Biotechnology, Govt. of India (BT/HRD/35/02/2006). In addition, S.S. would like to thank the Department of Biotechnology, Govt. of India for the DBT-JRF fellowship and the Swinburne University of Technology, Melbourne, Australia, for funding the Swinburne University Postgraduate Research Award (SUPRA).

Uncontrolled Keywords:

decellularization; DILI; extracellular matrix; liver model; toxicity

Subjects:

Others > Biotechnology
Biomedical Engineering
Chemistry

Divisions:

Department of Biomedical Engineering
Department of Biotechnology
Department of Chemistry

Depositing User:

. LibTrainee 2021

Date Deposited:

13 Jul 2022 12:18

Last Modified:

13 Jul 2022 12:18