Stem Cell Models for Drug Discovery and Toxicology Studies

Abstract

Human stem cells and their derivatives could provide virtually unlimited sources of tissue for a wide range of toxicity models that could complement conventional animal models with more relevant, humanized versions. Human embryonic stem cells (hESCs) have already been proven valuable for drug/toxicity screens and mechanistic studies including analysis of disease pathway and developmental toxicity. Human-induced pluripotent stem cells (iPSCs), which are generated by reprogramming somatic cells back to become hESC-like cells, allow assays to be designed where the contribution of an individual's genetic background or environmental exposure history to toxicity response can be determined. Comprehensive profiling of hESC/iPSCs via genomics, proteomics, transcriptomics, and metabolomics could be used to elucidate pathway perturbations that underlie toxicity and disease, enabling the development of predictive assays for toxicity. While technological hurdles still exist for widespread use and implementation, incorporation of human stem cell based assays into drug discovery and toxicity testing offers the potential for safer, more customized medicines and more accurate risk assessment for environmental toxicants, as well as reduced costs and decreased use of animal models. We examine limitations and deficiencies of current toxicology approaches and how human stem cell based in vitro assays may overcome them. We describe how human stem cells are used for predictive toxicology. We also identify technological limitations that prevent stem cells from being integrated into standard practice, as well as new tools and technologies that may overcome them. We discuss research priorities that are most useful for transforming cell-based toxicology models into reality, and research areas in which stem cell technology could make substantial contributions to the development and implementation of stem cell based models for toxicity testing. Increased use of human in vitro models of toxicity could reduce the use of animals in safety and risk assessment studies and offers the potential to dramatically enhance our understanding of the molecular basis of toxicity, leading to improved human models and assays for predicting biological response to drugs and environmental hazards.

Assessment of Bisphenol A (BPA) neurotoxicity in vitro with mouse embryonic stem cells

“…Moreover, ESCs can virtually differentiate specifically into any type of cells of an adult organism. Those cells can then be used for cell function toxicity assays as any other derived primary cell type (Wobus and Loser, 2011;Liu et al, 2013;Mori and Hara, 2013).…”

Embriyonik Kök Hücreler ve İndüklenmiş Pluripotent Kök Hücreler

“…Bu nedenle hayvan deneyleri öncesinde İPK hücre çalışmaları, hedefin daha doğru seçilmesi ve hayvan deneylerindeki gereksiz tekrarların önlenmesini sağlayabilir. Geliştirilen hasta ve hastalık spesifik İPK hücreler yeni ilaç test ve çalışmalarını hem kolaylaştırmakta, hem de farmakolojik ve toksikolojik çalışmaları hızlandırmaktadır (42).…”

Mesenchymal Stem Cells: An Innovative Approach in Pharmacokinetics

“…This disease-in-adish model is useful to understand molecular mechanisms of diseases and cellular responses to various therapeutic and toxic agents. Hence, in vitro culture of human ES (hES) cells is a suitable system to study etiology and prognosis of many degenerative diseases and a valuable tool for drug or toxicity screening and mechanistic studies including analysis of disease pathway and developmental toxicity [22]. Developmental toxicity is often associated with birth defects, low birth weight, and biological dysfunction.…”