TINJAUAN PUSTAKA
The Importance of Induced Pluripotent
Stem Cell Research in Medical Science
Agustina Kadaristiana
MD, Research Assistant, PT. Admiral Jaya Medika, Jakarta, Indonesia
ABSTRACT
The degenerative diseases that are currently incurable, such as heart disease, stroke, and diabetes, became the global leading causes of
death in 2010 and 2011. This fact urges scientists to find alternative treatment for those conditions. In 2006, Takahashi and Yamanaka
succeeded in generating an alternative source of stem cells called induced pluripotent stem cell (iPSC). This groundbreaking work
holds the promise of new ways to repair cell damage and improve treatment of currently untreatable conditions without raising ethical
debates. Many scientists still question whether iPSC is completely interchangeable with ESC in terms of pluripotency and cell mortality.
Indeed, iPSC clones and ESC clones have overlapping degrees of variation. It can be concluded that different cell lines will be best suited for
different applications. This essay will describe the development stem cell research, comparison between IPSC and ESC, the promise of IPSC
technology and current challenges in the applications of iPSCs.
Keywords: Induced pluripotent stem cell, medical science, stem cell, untreatable disease
ABSTRAK
Penyakit degeneratif yang saat ini belum dapat disembuhkan, seperti penyakit jantung, stroke, dan diabetes, menjadi penyebab kematian
utama di dunia pada tahun 2010 dan 2011. Fakta ini mendorong peneliti untuk mencari terapi yang bersifat kuratif. Tahun 2006,
Takahashi dan Yamanaka berhasil menemukan sumber alternatif sel punca bernama sel punca pluripoten yang diinduksi/Induced
Pluripotent Stem Cell (iPSC). Penemuan besar ini memberi harapan dalam memperbaiki sel rusak dan meningkatkan kualitas terapi
penyakit yang belum bisa disembuhkan tanpa menimbulkan perdebatan etika. Masih dipertanyakan apakah pluripoten dan kematian
sel klon sel iPS sama dengan sel punca embrionik (Embrionic Stem Cells/ESC). Ternyata, terdapat variasi tumpang tindih antara klon iPSC dan
ESC. Dapat disimpulkan bahwa sel yang berasal dari alur berbeda, cocok untuk penggunaan yang berbeda. Makalah ini bertujuan
untuk memaparkan perkembangan penelitian sel punca, perbandingan antara sel iPSC dan ESC, keunggulan teknologi iPSC sekaligus
tantangan dalam aplikasinya. Agustina Kadaristiana. Manfaat Penelitian Induced Pluripotent Stem Cell Research untuk Dunia
Kedokteran.
Kata kunci: Dunia kedokteran, induced pluripotent stem cell, penyakit yang tidak dapat diobati, sel punca
Introduction
World Health Organization indicates that
non-communicable diseases, such as heart
disease, stroke, and diabetes, became the
global leading causes of death in 2010
and 2011. However, until recently, those
conditions are still incurable. The use of
stem cells, hold the promise of new ways to
repair cell damage and improve treatments.1
Stem cells are defined as the cells that have
the capacity to self-renew (i.e. generate
perfect copies of themselves upon division)
and undergo lineage differentiation (i.e.
specialized cell types that perform specific
function in the body).2,3 Depending on the
capacity to generate specialized cells, stem
Alamat korespondensi
cells are classified into tissue (or adult) stem
cells and pluripotent stem cells. Tissue (or
adult) stem cells are in the body to maintain
the organ or tissue in which they reside.
Under normal conditions, each type of
this kind of cell only generates the organ
or tissue systems to which it belongs
(unipotency), except for the mesenchymal
stem cell, which can generate bone, cartilage,
and muscle (multipotency).4
In contrast, pluripotent stem cells have the
potential to generate any type of cell found
in the body. Pluripotent stem cells are
generated in the laboratory and have not
been identified in the adult body. There are
three types of pluripotent stem cell, namely
embryonic stem (ES) cells, epiblast stem cells,
and induced pluripotent stem cells (iPSCs).
Embryonic stem (ES) cells are derived from
early-stage, pre-implantation embryos, and
were the first type of pluripotent stem cells
to be discovered.5 Epiblast stem cells are a
type of pluripotent mouse stem cell derived
from a slightly later stage of embryonic
development than mouse ES cells; they
more closely resemble the human embryonic
stem.6,7
Induced pluripotent stem (iPSCs) are the
stem cells that generated from adult cell
by using a reprogramming technique. This
groundbreaking work was awarded the
Nobel Prize in Physiology or Medicine in
email: kadaristiana@gmail.com
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2012. Following this invention, researchers are
rapidly adopting iPS cells for study, although
there is ongoing discussion in the field about
whether they are identical with ES cells.5,8
The Benefit of Stem Cell Research
There are many ways in which human stem
cells can be used both in research and
clinically.5 In terms of research, studies of
human embryonic stem cells could yield
information about the complex events that
occur during human development. Stem cell
study may also provide knowledge about
the biology of cell and therefore has the
potential to improve and accelerate drug
screening, drug discovery, and pre-clinical
toxicological assessment of new drugs.9
As far as medical benefits are concerned,
human stem cells have a high potential to be
applied to cell-based therapy. The purpose
of cell-based therapy is to replace missing
or damaged cells and (in the future) to
generate artificial organs for transplantation.
Therefore, stem cell therapy is also known
as regenerative therapy.10 Stem cells, directed
to differentiate into specific cell types,
offer the possibility of a renewable source
of replacement cells and tissues to treat
previously incurable conditions, including
Alzheimer’s disease, spinal cord injury, stroke,
burns, heart disease, diabetes, osteoarthritis
and rheumatoid arthritis.9 The subsequent
Figure 1. Stem cells and their types5
812
advances, including the derivation of hES
cell lines, the human iPS cell technology,
and progress in making specific specialized
cells from stem cells in the laboratory, have
suggested that stem cell therapies may be
more broadly applied to aid a wide range of
disorders.10
Development of Stem Cell Research
Tissue stem cells have been used therapeutically for many years in the context of
Haematopoietic Stem Cell Transplantation
(HSCT), in order to treat many types of
blood cancer. In addition, stem cell-based
skin grafting11,12 and treatment for corneal
damage13 have also been conducted. In
HSCT, stem cells are harvested from patient
or donor and are transplanted back into the
patient to restore damaged cells. However,
the need for transplantable tissues and
organs far outweighs the available supply.5
In 1998, Dr. James Thomson was able to
derive the first human embryonic stem
cells. This invention is expected to solve the
limited supply of donated organs and tissues.
Moreover, studying ES cells seems to offer
limitless possibilities because its property
makes ESC able to generate every human
cell type.14 Narsinh, et al, (2011) argue that
the opportunity to model disease, discover
disease mechanisms and, ultimately, use cell
therapy for previously untreatable conditions
is particularly alluring.15 On the contrary, the
derivation of human ES cells has sparked
controversy because their derivation involved
the destruction of a human embryo. There
were heated debates regarding the moral
status of the embryo.16 Some countries take
a tight but permissive approach to research
involving the use of human embryos to
generate ES cell lines.5 Others have placed
some restrictions on research in this area,
either through direct legislation, patentability
or by limiting the uses of research.5,17
Another obstacle in hESCs research is logistic
problem. The limited supply of donor human
embryos makes this research application
somewhat challenging.15 In particular,
Narsinh, et al, (2011) also argue the products
derived from hESCs for transplantation
purposes would face rejection by the
transplant recipient’s immune system or
necessitate lifelong therapy with toxic
immunosuppressive medication.15 All of
these reasons explain the relatively low
compound annual growth rate (CAGR) of
hESCs global publications (Table 1 & Figure
2).5
Despite the hindrances to the study of
human ES cells over the past decade, great
strides were being made in understanding
the pathway that regulate the maintenance
and pluripotency of ES cells. In 2006,
Takahashi and Yamanaka announced the
successful alternative sources of personalized
patient-specific stem cells called induced
pluripotent stem cells (IPSCs).8 The iPS cells
are derived from adult mouse fibroblast
through the reprogramming of only four
genes: OCT4 (also known as POU5F1),
SOX2, Kruppel-like factor 4(KLF4), and
c-MYC.8 In 2007, this finding was replicated
in human cells.18,19 This groundbreaking work
was awarded the Nobel Prize in Physiology
or Medicine in 2012. On the same day,
James Thomson’s group also reported the
generation of human iPSC using a different
combination of factors.19 The process of
making IPSC does not require the destruction
of human embryos, thereby circumventing
the ethical debate surrounding hESC
derivation. In addition, this technology allows
the creation of patient-specific IPSC, which is
theoretically secure against immune system.9
To date, researchers have rapidly adopted
the iPS cells for study. As a consequence, the
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Table 1. CAGR for stem cells overall, ES cells (all organisms),
hES cells, and iPS cells (all organism) from 2008 to 2012.
Source: Scopus
Table 2. Number of ESC and iPSC clones analyzed in published studies.20
Conclusion about the
Relationship between
ESCs and iPSCs
It is difficult to distinguish
between them
There are notable differences
growth rate of iPSC publication soared up to
level off at 77,0% in only four years (Table 1).
On the top of that, the total global studies of
iPSCs exceeded hESCs study, in 2011-20125
(Figure 2).
Comparison between ESCs and iPSCs
Despite this heady progress, there are
heated debates between scientists regarding
the similarity between iPSCs and ESCs.
Researchers still question whether iPS cells
are different from ESCs, and if so, whether
any differences that do exist are functionally
relevant. Moreover, they also raise questions
about the capability of iPS as a suitable
alternative for research and therapy.15,20
According to Yamanaka (2012), during
the first few years of his studies IPSC was
remarkably similar to ESC.20 Narsinh, et al,
(2011) have expressed a similar view that
the iPSCs maintain the key feature of ESCs,
including the morphology, the ability to
propagate in culture indefinitely and the
Clone Numbers
First Author
Year
ESC
iPSC
68
A.M. Newman
2010
23
M.G. Guenther
2010
36
54
C. Bock
2011
20
12
M.Chin
2009
3
5
C.M. Marchetto
2009
2
2
J. Deng
2009
3
4
Z. Ghosh
2010
6
4
A. Doi
2011
3
9
Y. Ohi
2011
3
9
K. Kim
2011
6
12
R. Lister
2011
2
5
capacity to generate cells.15 Starting in
2009, however, scientists started reporting
differences between iPS and ESCs. For
instance, a reduced and more variable
yield of neural and cardiovascular progeny
has been observed in iPSCs. In addition,
iPSC derived early blood progenitor and
endothelial cells appear to undergo
premature senescence. Some researchers
have concluded that iPSCs have an
intrinsically lower differentiation capacity
than ESCs, whereas other research groups
believe that the cell of origin might have a
specific effect on the differentiation capacity
of the derived iPSCs.15, 20
(generally fewer than 10) for each group,
whereas those that found the similarity of
iPSCs to ESCs analyzed many more clones
from multiple laboratories.20
These studies showed that iPSC clones and
ESC clones have overlapping degrees of
variation (Figure 3).20 It should be noted that
variations among ESC clones have been
well documented.21,22 Although it is possible
that iPSCs clones show greater variation,
and that some clones differ from ESCs in
their gene expression, DNA methylation;
of differentiation ability, it appears that at
least some iPSC clones are indistinguishable
from ESC clones.23 In light of such variability,
To answer these questions, Yamanaka (2012)
compared iPSCs and ESCs clones and has
observed a clear tendency. He found that
studies which report differences between
those cells are comparatively small in number
Figure 3. Overlapping Variations Present in iPSC and ESC
Clones
Measurement of a range of properties of iPSCs and ESCs,
including gene expression, DNA methylation propensity,
and (for mouse cells) complementation activity in embryos
has led to the realization that the properties of both ESC and
iPSC lines vary. However, as analysis of significant numbers
of clones from multiple laboratories has accumulated, it has
become clear that there is considerable overlap in terms of
the properties of ESC and iPSC lines and, at a general level,
Figure 2. Global publication count in stem cell research from 1996-20125
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these two cell types are difficult to distin-guish.
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Table 3. Disease modeled with iPS cells9
it seems likely that different cell lines will be
best suited for different applications.20
The Promise of Induced Pluripotent
Stem Cells (iPSCs) in Research and
Therapy
Since human iPSC technology as the
alternative resources for generating stem
cells was first introduced in 2007, this
814
invention has been a major breakthrough in
biomedical science. The iPSC technology is
highly promising because it allows scientists
to generate an unlimited population of
stem cells that can be differentiated into
the desired cell types for studying disease
mechanisms, screening, and developing
drugs or for developing regenerative therapy
in an ethical acceptable way.
Patient-derived iPSCs have been shown to
be useful for modeling diseases (Table 3) and
screening drug candidate libraries starting
with the seminal studies by the groups led
by George Daley24 and Kevin Eggan.25 In
2009, Lee and colleagues harnessed iPS cells
to demonstrate disease modeling and drug
screening for familial dysautonomia, a rare
genetic disorder of the peripheral nervous
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system. This initial report demonstrated
how iPS cells can facilitate the discovery of
therapeutic compounds and described
how these cells provided a platform for
modeling different severity of familial
dysautonomia and for generating a
predictive test to determine differences in
the clinical manifestations of the disorder.26
Up until now, there have been more than 100
reports of modeling diseases that have been
published using patient-derived iPSCs with
specific disease.20
treatment of Parkinson’s disease,29 platelet
deficiency,30 spinal cord injury,31,32 and macular degeneration.33 To date, researchers
from RIKEN have been conducting the first
clinical trial of iPSCs in human since 2013. This
study, led by Masayo Takahashi, is aiming
to treat age-related macular degeneration,
the most common cause of visual impairment
in the elderly, using the reprogrammed
stem cells.34 In the future, it might become
possible to apply this strategy to treat a
broader range of diseases.20
The iPSC technology is contributing to
the study of regenerative medicine (i.e.
cell-based therapies to replace missing
or damaged cells, and generate artificial
organs for transplantation). The iPSCs are
favorable because it is possible to use
self-cell donor which suppress the risks of
rejection and infection.9 One of the most
striking applications of iPSCs was reported
by Nakauchi and colleagues, who was
able to generate a rat pancreas in a mouse
using iPSCs.27 In another landmark study
from Jaenisch’s research group, Werning and
colleagues derived dopaminergic neurons
from iPS cells that when implanted into the
brain became functionally integrated and
improved the condition of a rat model of
Parkinson’s disease. The successful implantation and functional recovery in this model
is evidence of the therapeutic value of
pluripotent stem cells for cell-replacement
therapy in the brain – one of the most
promising areas for the future of iPS cells
application. After the seminal work in mice
by Rudolf Jaenisch’s laboratory,28 scientists are
now making progress toward using iPSCs in
regenerative medicine, for example for the
Challenges in iPSCs Application
Induced pluripotent stem cells technology
may bring hope in curing currently untreatable diseases. In the future, this technology
will contribute to personalized, predictive,
preemptive,35,36 and precision medicine.37
However, there are several challenges for
the field to actualize its potential. Firstly,
scientists are still struggling to understand
the proper production of the iPSCs
population and ensure that the populations
do not contain other potentially harmful
cell types. For cells generated from human
pluripotent stem cells, contamination of the
transplant with even a small number of cells
can promote tumor formation. Therefore, it
is essential to determine the safest protocol
regarding iPSCs transplantation before it is
proposed as clinical treatment.5
In terms of accessibility, Inoue (2014) argues
that the use of autologous iPSCs from every
individual would likely result in high medical
costs.38 In addition, it was found that the
process of generating iPSCs using current
methods also takes a long time (more
than three months).39,40 These reasons,
therefore, will limit the accessibility of
iPSCs technology particularly for patients
who need prompt treatment. As a
consequence, iPSCs banking will probably
have to be considered in order to ensure
the patients receive the cells with a good
immunological match, thus minimizing the
use of immunosuppressant drugs.41
Conclusion
This essay has examined the prospect of
using induced pluripotent stem cell as an
alternative source in stem cell supply. The
importance of IPSC technology and its
comparison with embryonic stem cells has
also been discussed. Although the routine
application of iPSCs is still far from being
achieved, the IPSCs technology is promising
for medical sciences. The iPSC technology
provides the opportunity for generating
an unlimited population of stem cells that
can be differentiated into the desired cell
type for studying disease mechanisms, for
screening and developing drugs or for celltransplantation based medicine. However,
understanding the proper iPS-specialized
cells production still remains a hurdle and
the limitations to access iPSCs technology
due to financial and logistical problems have
to be considered by scientists. Therefore, it
is important to encourage researchers to
determine the safest as well as the most
effective and efficient procedure to bring
iPSCs technology to medical application. To
achieve this goal, it is necessary to improve
research collaboration and government
support. The invention of IPSCs is likely to
provide solutions in regenerative medicine
and enrich the knowledge of medical
science.
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