Stem Cell-Based Toxicity Screening
- PDF / 122,398 Bytes
- 5 Pages / 612.283 x 793.701 pts Page_size
- 79 Downloads / 166 Views
LEADING ARTICLE
ยช 2012 Adis Data Information BV. All rights reserved.
Stem Cell-Based Toxicity Screening Recent Advances in Hepatocyte Generation Sebastian Greenhough and David C. Hay MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
Abstract
Preclinical cell-based toxicity screening is an essential stage in the drug development process. Current technology is based on immortalized cell lines, rodent cells and primary human hepatocytes, all of which suffer from shortcomings. Cell lines and rodent cells have limited relevance to human physiology, while primary human cells remain a scarce and variable resource. These systems are inadequate, as evidenced by the high levels of compound attrition in the clinical trial and postmarketing stages of development, producing safety risks and high financial costs. Hepatotoxicity and drug-induced liver injury account for a substantial proportion of compound failures, highlighting the need for accurate and predictive liver toxicity models. Pluripotent stem cell-derived hepatocyte-like cells offer a means of creating physiologically relevant drug screening assays that could serve as an additional method of detecting toxicity in the lead optimization phase of drug development. The scalability and definition of pluripotent cell culture systems are constantly improving, bringing a potentially inexhaustible cell resource closer to industrial translation. Meanwhile, increased understanding of pluripotency, differentiation and reprogramming, combined with optimization of tissue culture environments, will allow the ongoing issues of hepatocyte lifespan and immature function to be addressed. In future, extensive validation of stem cell-derived hepatocyte-like cells against existing drug screening methods will be required if they are to be established as a standard tool for investigating drug toxicity.
1. Introduction Toxicity screening is an essential part of the drug development process[1] and attrition of compounds in the clinical stages accounts for considerable safety concerns and a great deal of financial expense.[2] Currently existing preclinical screening models suffer from several shortcomings, and a number of safety issues have been encountered in the clinic to date.[3] Immortalized human cells are used extensively as a first pass screen and have the advantages of being scalable, reproducible and low cost. They do, however, suffer from drawbacks including an incomplete functional profile and an abnormal karyotype.[4] Primary rodent cells possess greater function, but are problematic in that the metabolism of many drugs is species specific.[5] Neither population achieves the level of function or displays the gene expression associated exhibited by freshly isolated human hepatocytes,[6] which are widely regarded as the gold standard for safety testing. These cells are, however, scarce, variable and difficult to maintain in culture.[7]
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) represent a potentially inexhaustible,
Data Loading...
