The potential of engineered human liver co-cultures in phenotypic drug discovery for liver diseases

Date: June 16 2016
Presenter(s): Dr. Salman Khetani

You can download the presentation slides here!

Last HepatoPac Webinar was presented on 16 June, 2016 by Dr. Salman Khetani, Associate Professor, Department of Bioengineering, University of Illinois at Chicago, USA.

Summary: The diverse functions of the liver (i.e. albumin synthesis, glucose and fatty acid metabolism, drug metabolism) can be severely compromised by several diseases. In particular, drug-induced liver injury is a leading cause of drug attrition; hepatitis B virus chronically infects the livers of ~400 million people worldwide; hepatitis C virus chronically infects the livers of ~170 million people; and, the Plasmodium protozoan underlying malaria matures within the liver during its infection of >250 million individuals globally. Furthermore, due to its central role in glucose homeostasis, the liver is often at risk for developing diseases related to over-nutrition, such as non-alcoholic fatty liver disease, which has been linked to fibrosis, cirrhosis, and type 2 diabetes mellitus. Finally, hepatocellular carcinoma is the third leading cause of death from cancer worldwide and the ninth leading cause of cancer deaths in the US alone. Thus, the liver is an important target organ for developing novel drugs to ameliorate or cure the symptoms of the aforementioned diseases, while minimizing adverse effects. Testing drugs and diseases on animals is not a fail-safe paradigm likely due to the significant differences in liver pathways (i.e. drug metabolism enzymes) between animal and human livers. Thus, animal data needs to be supplemented with assays designed using in vitro models of the human liver. However, when cultured in conventional confluent monolayers on adsorbed or gelled extracellular matrix proteins, primary human hepatocytes rapidly lose phenotypic functions and in many cases become unusable for modeling several liver diseases. On the other hand, engineering the microenvironment around hepatocytes using diverse cues such as microarchitecture and co-culture with stromal cells can significantly enhance and augment the longevity of hepatic functions. In this presentation, I will describe the utility of micropatterned co-cultures (MPCCs) of primary hepatocytes and different types of stromal cells for mimicking key aspects of several liver diseases (i.e. hepatitis B/C viral infection, malaria, fatty liver disease, diabetes) towards utility in phenotypic drug discovery applications. Correlation of observed cellular phenotypes with clinical outcomes will be discussed along with validation of the model using drugs with clinical information. Finally, I will describe the continued evolution of MPCCs towards improving the prediction of clinical drug outcomes. In the future, different versions of MPCCs can serve the various needs of the drug development pipeline, ranging from drug discovery to lead optimization.

Dr. Salman Khetani received his BS degrees, summa cum laude, in electrical engineering and biomedical engineering from Marquette University, and MS and PhD degrees in bioengineering from the University of California at San Diego (UCSD). He was a Jacobs fellow and National Science Foundation graduate fellow at UCSD. Dr. Khetani conducted his postdoctoral studies at MIT in the laboratory of Dr. Sangeeta Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology and a world-renowned leader in multi-scale liver tissue engineering and regenerative medicine. Dr. Khetani’s research has been published in peer-reviewed journals such as Drug Metabolism and Disposition, Toxicological Sciences, Nature Biotechnology and the Proceedings of the National Academy of Sciences. In 2007, Dr. Khetani co-founded Hepregen Corporation and led research there as director of research from 2008 to 2011 in order to bring to market bioengineered models of animal and human livers for pharmaceutical drug development. Dr. Khetani then started his academic faculty career in the department of mechanical engineering and school of biomedical engineering at Colorado State University (2011-2015) and recently transitioned as associate professor of bioengineering to University of Illinois at Chicago where he directs the Microfabricated Tissue Models laboratory. He is the recipient of the NSF CAREER award, and his research (past and current) has been funded by DOD, FDA, NIH, NSF, the State of Colorado, and major pharmaceutical companies.