Cellular models for disease exploring and drug screening

Protein & Cell, Apr 2010

The biopharmaceutical industry has been greatly promoted by the application of drug and disease models, including both animal and cellular models. In particular, the emergence of induced pluripotent stem cells (iPSC) makes it possible to create a large number of disease-specific cells in vitro. This review introduces the most widely applied models and their specialties.

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Cellular models for disease exploring and drug screening

Protein Cell Cellular models for disease exploring and drug screening Zhi-kun Li 0 1 Qi Zhou 1 0 Graduate School, Chinese Academy of Sciences , Beijing 100049 , China 1 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101 , China The biopharmaceutical industry has been greatly promoted by the application of drug and disease models, including both animal and cellular models. In particular, the emergence of induced pluripotent stem cells (iPSC) makes it possible to create a large number of diseasespecific cells in vitro. This review introduces the most widely applied models and their specialties. cellular models; disease models; induced pluripotential stem cells; neural diseases INTRODUCTION It has been a long history since people declared war on disease. The manuscript Shen Nong Ben Cao Jing in ancient China represents the permanent aspiration of humans: to understand and cure diseases. Due to the prosperity of life science in the last two centuries, an increasing number of diseases have been conquered, such as variola and tuberculosis, and drug and disease models played an indispensable role in the process. It is worth mentioning that some recently emerged techniques have breathed new life into this old field. THE ANIMAL MODELS OF DRUGS AND DISEASES Since etiological pioneers vaccinated mice with the serum derived from smallpox patients in the 19th century, animal models have been playing a vital role in the field of biomedical study. Vertebrate models, including rodents or livestock, are extensively used in disease and drug research. With the development of model construction techniques, a growing number of diseases can be simulated and investigated with animals. However, the limitation of the animal model reveals itself when further study is required. The comparison of the mouse and the human genome has revealed that more than 80% of mouse genes have bidirectional homologues in the human genome (Waterston et al., 2002) , indicating the rationality of using the mouse as a human disease model. Nevertheless, the 20% of differences has hindered the usage of the mouse model, which does not accurately recapitulate the human disease phenotype. For example, the mutated HPRT1 gene leads to Lesch-Nyhan syndrome that is tied to neurological abnormalities; however, the mice model with the homologous mutation causes excessive uric acid and renal calculus (Stout and Caskey, 1988) . In addition, some mutations of disease homologous genes result in non-visual phenotype change in the mouse model (Cartwright, 2009) . Other laboratory animals, such as rats or non-human primates, are thought to be better alternatives, but the limitation still exists. Because the genetic differences between human and animal may cause diverse phenotypes, a number of diseases cannot be properly simulated with animals. The application is also hindered by the heterogeneity and complexity of animal models. The phenotype changes or the therapeutic effects in animal models are not always authentic representations of human physiological conditions. For example, a large number of neurological diseases can be simulated in rodents, but only few of them can precisely represent the human syndrome at molecular or anatomical level (Jakel et al., 2004) . In addition, the construction and utilization of animal models may lead to ethical disputations. ADULT DERIVED CELL MODELS OF DRUGS AND DISEASES Somatic cell models Cellular models can partially complement the disadvantages of animal models. Traditionally, primary cells can be used in pathological study, drug screening or toxicity tests at cellular or molecular level (Jakel et al., 2004; Sundstrom et al., 2005) . The utilization of human cells makes it possible to understand diseases in a genuine human source medium rather than non-human origin substitutes. Nevertheless, the model is far from perfect. Some primary cells are characterized by a low proliferative capacity associated with a rapid decline of differentiation ability during subculturing, which thereby limits their use (Darimont, 2003). Furthermore, there are abundant diseases caused by the physiological abnormality of cardiac muscle, cerebra or spinal cord, but samples from those spots are hard to take. A practicable alternative to model these diseases is to transfer pathogenic mutated genes into available cell lineages. The disease- related events, such as cell senescence or cell cycle changes, can be mimicked (Brown et al., 1997; Bunz et al., 1998) . Using this rationale, cell lines expressing G-protein coupled receptors (GPCR) can be used for drug screening (Zeh et al., 2003). However, the relatively low efficiency has hampered the application of these models (Zeh et al., 2003; Schneider et al., 2007) . Another limitation of the cellular model comes from its superiority: as an in vitro model, it is not influenced by intracorporal factors such as circulatory s (...truncated)


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Zhi-kun Li, Qi Zhou. Cellular models for disease exploring and drug screening, Protein & Cell, 2010, pp. 355-362, Volume 1, Issue 4, DOI: 10.1007/s13238-010-0027-9