Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jan 27, 2018; 10(1): 22-33
Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.22
Bioengineered humanized livers as better three-dimensional drug testing model system
Sandeep Kumar Vishwakarma, Avinash Bardia, Chandrakala Lakkireddy, Raju Nagarapu, Md Aejaz Habeeb, Aleem Ahmed Khan
Sandeep Kumar Vishwakarma, Avinash Bardia, Chandrakala Lakkireddy, Raju Nagarapu, Md Aejaz Habeeb, Aleem Ahmed Khan, Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
Author contributions: Vishwakarma SK, Bardia A and Khan AA conceptualized and designed the study; Vishwakarma SK, Bardia A, Lakkireddy C and Nagarapu R performed the experiment and arranged data; Vishwakarma SK performed statistical analysis and graphical representation of results; Vishwakarma SK, Bardia A and Khan AA wrote the manuscript; Lakkireddy C and Nagarapu R formatted the manuscript; Habeeb MA and Khan AA provided required infrastructure and reagents to conduct the experiments.
Institutional review board statement: The study design was approved by the Institutional Review Board of Deccan College of Medical Sciences, Hyderabad.
Institutional animal care and use committee statement: The animal study was approved by the Institutional Animal Ethics Committee of Deccan College of Medical Sciences, Hyderabad.
Conflict-of-interest statement All authors have declared no conflict of interest towards the publication of this study.
Data sharing statement: The data reported in the present manuscript can be shared after taking permission from the corresponding author of the study.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Aleem Ahmed Khan, PhD, Research Scientist, Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India. aleem_a_khan@rediffmail.com
Telephone: +91-40-24342954
Received: September 26, 2017
Peer-review started: October 7, 2017
First decision: November 23, 2017
Revised: November 28, 2017
Accepted: December 28, 2017
Article in press: December 29, 2017
Published online: January 27, 2018
Processing time: 111 Days and 21.8 Hours
Abstract
AIM

To develop appropriate humanized three-dimensional ex-vivo model system for drug testing.

METHODS

Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses.

RESULTS

The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs.

CONCLUSION

The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.

Keywords: Acellularization; Repopulation; Drug testing; Humanized liver; Bioengineering

Core tip: Liver is the central organ for absorption, distribution, metabolism, excretion and toxicity (ADMET) of pharmacological drugs and molecules. Available in vitro and in vivo preclinical models deals with several limitations including xenogeneic barrier, lack of natural humanized liver architecture and functional responses. Bioengineered humanized livers developed in present study can overcome on such limitations. This humanized liver model system provides better platform which could be used more efficiently to screen the ADMET of several pipeline drugs and other pharmacological molecules. This approach could reduce the time and cost of the total drug screening experiments as compared to the animal models. It provides enhanced dose response relationship by using drug concentrations relative to human exposure. Ease of ex-vivo access of cellular and molecular responses in humanized liver model system during pharmacological screening also offers high-throughput studies to determine the cellular response networks and toxicity pathways.