Present state and future perspectives of using pluripotent stem cells in toxicology research

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed

Towards the Maturation and Characterization of Smooth Muscle Cells Derived from Human Embryonic Stem Cells

In this study we demonstrate that CD34+ cells derived from human embryonic stem cells (hESCs) have higher smooth muscle cell (SMC) potential than CD34− cells. We report that from all inductive signals tested, retinoic acid (RA) and platelet derived growth factor (PDGFBB) are the most effective agents in guiding the differentiation of CD34+ cells into smooth muscle progenitor cells (SMPCs) characterized by the expression of SMC genes and proteins, secretion of SMC-related cytokines, contraction in response to depolarization agents and vasoactive peptides and expression of SMC-related genes in a 3D environment. These cells are also characterized by a low organization of the contractile proteins and the contractility response is mediated by Ca2+, which involves the activation of Rho A/Rho kinase- and Ca2+/calmodulin (CaM)/myosin light chain kinase (MLCK)-dependent pathways. We further show that SMPCs obtained from the differentiation of CD34+ cells with RA, but not with PDGFBB, can be maturated in medium supplemented with endothelin-1 showing at the end individualized contractile filaments. Overall the hESC-derived SMCs presented in this work might be an unlimited source of SMCs for tissue engineering and regenerative medicine.Marie Curie-Reintegration GrantMIT-Portugal programCrioestaminalAssociação Viver a CiênciaFundação para a Ciência e a Tecnologia (PTDC/SA-BEB/098468/2008 and PTDC/CTM/099659/2008 to L.F.; SFRH/BD/40077/2007 to H.V.