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)