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May 01, 2011 (Vol. 31, No. 9)

Human Stem Cell-Derived In Vitro Model

New Tool Designed to Provide Biological Relevance in Neuro-Related Drug Research

  • A major goal of the pharmaceutical industry has been to reduce late-stage compound attrition. Due to the immense cost associated with the drug development process, the ability to identify insufficient compounds early is absolutely critical. One area given significant focus in hopes of optimizing this process is the development of more relevant in vitro disease models.

    Historically, in vitro models have played an important role in the discovery process, including early-stage disease modeling and candidate identification followed by pharmacokinetic and safety testing. These models have typically consisted of immortalized cell lines or primary cell types but have suffered from biological relevance and scalability/workflow issues. A significant push within the drug discovery field has been the development and validation of a diverse array of more relevant biological systems, including those derived from stem cell culture systems.

    Much excitement arose in the drug discovery community when James Thomson and colleagues reported the derivation and expansion of pluripotent human embryonic stem cells (hESCs), as this cell type could, in theory, provide unlimited self-renewal with the retained ability to give rise to all cell types of the human body.

    More recently, additional advancements by the same group and others were made whereby the addition of a specific set of four exogenous factors (i.e., OCT4, SOX2, NANOG, and LIN28) to human somatic cells resulted in the reprogramming of these cells into a state of pluripotency. These reprogrammed cells could thereafter be propagated continuously as a stem cell population referred to as induced pluripotent stem cells (iPSCs), much akin to hESCs.

    Human iPSCs overcome many of the ethical issues, donor tissue limitations, and funding restrictions associated with hESCs, providing a broader audience with the means to generate pluripotent cell lines more easily and efficiently. This flexible platform opened the door for discovery models focused on specific genetic backgrounds or patient-specific disease models. Since this discovery, numerous groups have generated such human iPSC lines in an attempt to model diseases including: familial dysautonomia, spinal muscular atrophy, Parkinson disease, Huntington disease, Down syndrome, type 1 diabetes mellitus, and others.

    Despite the excitement and promise associated with the use of iPSCs for drug discovery, it should be understood that the expansion of stem cells, their terminal differentiation, and ultimately, the continued culture of mature progeny is a process that poses a significant technical challenge.

    In addition, applying the requisite stringent culture protocols for iPSCs and their differentiated progeny to the scale required for high-throughput drug discovery applications adds an increased level of complexity. To overcome these obstacles, Cellular Dynamics International (CDI; www.cellular?dynamics.com) has focused on harnessing the potential of iPSCs by developing robust, scalable procedures that facilitate the commercialization of highly pure, functional iPSC-derived differentiated cell types.

    These novel cellular models, tested using rigorous phenotypic and functional assays, have been developed to meet the demands of pharmaceutical and academic customers alike. More importantly, the cells produced from this pipeline provide a more relevant human model system while also delivering the consistent product supply and performance required to facilitate large-scale compound screening within the pharmaceutical industry.

    In 2009, CDI launched iCell® Cardiomyocytes, first-of-a-kind purified human cardiomyocytes that not only display the expected single cell cardiac phenotype but also possess the ability to form electrically connected syncytial layers with characteristic electrophysiological and biochemical responses to exogenous agents. Researchers have incorporated the use of these human iPSC-derived cardiac cells into various applications, including cardiotoxic compound screening, identification and investigation of arrhythmogenic compounds, and cardiac hypertrophy studies among others.

    As a result of this success, CDI has extended its human iPSC-derived cell product development to other relevant cell types for drug discovery, including hematopoietic cells, endothelial cells, hepatocytes, and neurons.

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