REVIEW

Korean J Intern Med 2014;29:547-557

http://dx.doi.org/10.3904/kjim.2014.29.5.547

Recent technological updates and clinical

applications of induced pluripotent stem cells
Sebastian Diecke1,2,3,*, Seung Min Jung4,*, Jaecheol Lee1,2,3, and Ji Hyeon Ju4

1
Division of Cardiology, Induced pluripotent stem cells (iPSCs) were first described in 2006 and have
Department of Medicine,
2 since emerged as a promising cell source for clinical applications. The rapid pro-
Institute for Stem Cell Biology
and Regenerative Medicine, and gression in iPSC technology is still ongoing and directed toward increasing the
3
Stanford Cardiovascular Institute, efficacy of iPSC production and reducing the immunogenic and tumorigenic po-
Stanford University School of
Medicine, Stanford, CA, USA; tential of these cells. Enormous efforts have been made to apply iPSC-based tech-
4
Division of Rheumatology, nology in the clinic, for drug screening approaches and cell replacement therapy.
Department of Internal Medicine, Moreover, disease modeling using patient-specific iPSCs continues to expand
Seoul St. Mary’s Hospital, College
of Medicine, The Catholic Uni­ our knowledge regarding the pathophysiology and prospective treatment of rare
versity of Korea, Seoul, Korea disorders. Furthermore, autologous stem cell therapy with patient-specific iPSCs
shows great propensity for the minimization of immune reactions and the pro-
Received : July 21, 2014 vision of a limitless supply of cells for transplantation. In this review, we discuss
Accepted: July 22, 2014
the recent updates in iPSC technology and the use of iPSCs in disease modeling
Correspondence to and regenerative medicine.
Ji Hyeon Ju, M.D.
Division of Rheumatology, Keywords: Induced pluripotent stem cells; Reprogramming technique; Gene ed-
Department of Internal
Medicine, Seoul St. Mary’s
iting; Disease model; Regenerative medicine
Hospital, College of Medicine,
The Catholic Uni­versity of
Korea, 222 Banpo-daero, Seo-
cho-gu, Seoul 137-701, Korea
Tel: +82-2-2258-6893
Fax: +82-2-3476-2274
E-mail: [email protected]

*These authors contributed

equally to this work.

INTRODUCTION derived from the inner cell mass of preimplantation

embryos and demonstrate excellent pluripotency, but
Stem cells are pluripotent cells with the capacity for their use is confounded by ethical issues regarding the
self-renewal and differentiation into various types of destruction of the blastocyst [4]. MSCs are obtained
adult cells [1]. Ever since their discovery in 1960, stem from adult adipose tissue, blood, bone marrow, and
cells have formed the hub of countless explorations of cord blood and are thus free from ethical concerns,
disease, regeneration, and indeed, “the secret of life” but their use is still limited by low cell numbers and
itself [2,3]. Stem cells are roughly categorized as embry- diminished pluripotency. However, the more recently
onic stem cells (ESCs), mesenchymal stem cells (MSCs), introduced iPSCs show enormous promise for disease
and induced pluripotent stem cells (iPSCs). ESCs are modeling and regenerative medicine because their

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 The Korean Journal of Internal Medicine Vol. 29, No. 5, September 2014

pluripotency is similar to that of ESCs, while their uti- in question, followed by large-scale drug screening and
lization is without ethical controversy [5]. new drug development for disease management.
Mouse iPSCs were first introduced by Takahashi and In this review, we recapitulate the recent progress
Yamanaka [6] in 2006 by generating mouse pluripotent made in the area of iPSC technology. In the first part of
stem cells from dermal fibroblasts via transduction the review, we summarize recent techniques for iPSC
with four reprogramming factors, octamer-binding generation (i.e., viral and episomal vector-mediated
transcription factor 4 (Oct4), Kruppel-like factor 4 reprogramming, as well as microRNA [mRNA]- and
(Klf4), sex determining region Y-box 2 (Sox2), and c-Myc protein-mediated induction of pluripotency). We also
(i.e., the canonical Oct4, Sox2, Klf4, and c-Myc [OSKM] discuss gene editing to correct genetic defects in iPSCs
quartet). The discovery of iPSCs dramatically altered and to produce resultantly sound stem cells. In the
the previous dogma of cellular differentiation as a second part of the review, we deliberate upon assorted
unidirectional, nonrevertible developmental process, clinical applications of iPSCs, from the standpoint of
resulting in a paradigm shift in the field of develop- recent feasibility and future possibilities.
mental biology. Furthermore, the work of Takahashi
and Yamanaka [6] provided the foundation for an en-
tirely new field of research in cell reprogramming and PART 1. RECENT UPDATES IN iPSC GENERATION
translational medicine. The newly generated mouse
iPSCs were nearly indistinguishable from ESCs, in that In 2006, Takahashi and Yamanaka [6] demonstrated
iPSCs and ESCs can both proliferate indefinitely under that terminally-differentiated somatic cells can be re-
controlled culture conditions and then differentiate in verted into a cell type having enhanced developmental
vivo and in vitro into all cell types, making iPSCs and potential by overexpressing transcription factors that
ESCs alike an attractive cell source for translational regulate the maintenance of ESC pluripotency. OSKM
and regenerative medicine applications. However, were identified as the most important reprogramming
ethical concerns, limited availability, and possible im- factors for the induction of pluripotency following a
munogenicity are the main disadvantages of ESCs over screening of 24 genes which were virally overexpressed
iPSCs. in mouse embryonic fibroblasts [6]. These four factors
Generation of human iPSCs followed the production synergistically activate the molecular circuitry of plu-
of mouse iPSCs, and like mouse iPSCs, the human ripotency, which converts the differentiated somatic
equivalent escapes the ethical conundrum of blastocyst cell into an undifferentiated pluripotent cell [8].
destruction. In addition, self-derived autologous hu- In 2007, Takahashi et al. [9] and Yu et al. [10] suc-
man iPSCs now enable the ready attainment of human cessfully reproduced their groundbreaking work with
leukocyte antigen (HLA)-full matched stem cells with- mouse f ibroblasts in human f ibroblasts. This was
out the effort of searching the human HLA bank data- accomplished by using either the same combination
base. Acquisition of an immunologically tolerant stem of factors (OSKM), or human Oct4 and Sox2 together
cell source will undoubtedly facilitate the future utili- with Nanog and LIN28. Subsequent studies revealed
zation of iPSCs in the field of human regenerative med- that reprogramming efficiency could be significant-
icine. Furthermore, patient-specific iPSCs may open ly increased by using polycistronic reprogramming
a new field of personalized medicine, represented by constructs, chromatin-modifying chemicals, and
novel “patient in a dish” and “patient in a tube” explo- mRNAs, as well as through activation or inhibition
rations [2,7]. Indeed, disease modeling with patient-de- of various signaling pathways involved in the regula-
rived iPSCs has been successfully used to clarify the tion of cell proliferation [11-14]. Moreover, Bayart and
pathophysiology of several rare and/or incurable dis- Cohen-Haguenauer [15] showed that individual re-
eases, including retinal degeneration, spinal muscular programming factors could be exchanged or entirely
atrophy, and Alzheimer’s disease. The next step will removed from the reprogramming cocktail without
be to employ these iPSC-based disease platforms for a losing the capacity to induce pluripotency in somatic
thorough molecular analysis of the disease phenotype cells.

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Dieck S, et al. Recent updates of iPSC

Conventional reprogramming techniques depend on virus, and replicates in the cytoplasm of infected cells
the stable integration of transgenes but introduce the without DNA intermediates or stable integration into
concurrent risk of insertional mutagenesis [16]. Several the target cell genome [23]. Sendai virus-mediated
nonintegrating reprogramming techniques have thus reprogramming is perhaps the most efficient integra-
been developed to circumvent the risk of spontaneous tion-free method of iPSC production currently avail-
tumor formation and to improve the quality of the gen- able and was previously used to effectively reprogram
erated iPSCs. Some of these techniques are grounded fibroblasts and PBMCs [23,24].
on the almost complete removal of the integrated viral However, besides being an expensive method, the
DNA or alternatively, on the use of nonintegrating vi- major drawback of using the Sendai virus is the per-
ruses [17,18]. Furthermore, the launch of virus-indepen- sistence of residual viral material. The latter requires
dent reprogramming methods based on DNA, protein, an extended period of tissue culture (10 to 20 passages)
or mRNA expression is expected to further improve to establish virus-free iPSC lines for further down-
iPSC quality [19-21]. stream analysis and differentiation experiments [14].
The following sections summarize the recent advanc- To overcome this limitation, specific mutations have
es in reprogramming technology for the derivation of been introduced into key viral proteins to develop
iPSCs (including patient-specific iPSCs), as well as gene temperature-sensitive Sendai viral particles, allowing
editing techniques for the generation of modified iP- for faster and more efficient removal of viral material
SCs. from the host cell cytoplasm via a temperature shift [25].
Nonetheless, working with Sendai viral particles still
requires stringent biosafety containment measures
Generation of clinically feasible iPSCs: an overview and a separate tissue culture room, further increasing
For the purposes of clinical application of human iP- the costs of the procedure.
SCs, it is important to choose the correct donor cell
type and the best reprogramming method. The perfect DNA-based episomal reprogramming
donor cell should be easy to obtain, ideally from the As an alternative to the viral-mediated induction of
patient him or herself, and to reprogram. Therefore, pluripotency, several DNA-based reprogramming
fibroblasts, keratinocytes, and peripheral blood mon- methods have been developed by using either non-rep-
onuclear cells (PBMCs) are all preferred cell types as licating [20,26-28] or replicating episomal vectors [29].
the initiation point for the induction of pluripotency. These techniques are attractive because they reduce
Recent efforts to establish large-scale iPSC biobanks the biosafety concerns involved in the production
have concentrated their efforts on PBMCs because they and transduction of viral particles. However, the re-
can be readily attained via phlebotomy and are robustly programming eff iciency of non-replicating vectors
reprogrammable [22]. is rather low, requiring multiple transfections of the
Safety is the major issue surrounding cell generation target cells [20,26,27]. A possible explanation for this
for translational applications. Therefore, non-inte- phenomenon is provided by the low transfection effi-
grative reprogramming methods are favored over in- ciency of large polycistronic reprogramming plasmids
tegrative methods, limiting the possibility of internal in addition to the transgene silencing mechanism of
mutagenesis and consequent tumor formation. Below, plasmid-based vectors in mammalian cells [30]. To
we describe the most frequently used nonintegrative overcome these obstacles, Jia and colleagues [20] devel-
reprogramming techniques and discuss their compar- oped minicircle vectors as a shuttle system for the re-
ative advantages and drawbacks. programming factors. Minicircles consist of a special
episomal vector devoid of any bacterial plasmid and
Reprogramming using the Sendai virus are therefore smaller in size than standard plasmids.
Most iPSC laboratories use F-deficient Sendai virus These properties substantially enhance the transfec-
particles to induce pluripotency in somatic cells. The tion efficiency and expression rate of minicircles [31].
Sendai virus is a negative-sense, single-stranded RNA However, the reprogramming efficiency of minicircles

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 The Korean Journal of Internal Medicine Vol. 29, No. 5, September 2014

remains quite low, and the production and purification mRNA transfections [36]. The B18R protein signifi-
methodology associated with this vector system is rela- cantly enhances cell survival after the series of trans-
tively complex and fairly time-consuming [32]. fections by blocking the interferon alpha signaling
Accordingly, we developed a novel single plasmid pathway [37]. Another limitation of mRNA-mediated
reprogramming system termed the codon-optimized reprogramming for clinical approaches is the require-
4-in-1 minicircle (CoMiP), which carries codon-opti- ment of a feeder cell layer and feeder cell-derived con-
mized sequences of the canonical OKSM reprogram- ditioned media, both of which can increase the risk of
ming quartet and a short hairpin RNA against the transmitting undetected human pathogens to the host
p53 tumor suppressor [26]. Similar to minicircles, the [38]. The recent optimization of established mRNA re-
CoMiP vector system overcomes the transgene silenc- programming factors has addressed some of the afore-
ing observed with regular plasmids and provides at mentioned caveats, allowing the production of foot-
least 2- to 10-fold higher levels of transgene expression print-free iPSCs from human fibroblasts without the
[33]. Furthermore, the CoMiP vector is a highly efficient, use of feeder cells or other possibly xeno-contaminated
integration-free, cost-effective agent and is applicable reagents [39]. Furthermore, Yoshioka and colleagues
to a wide variety of cell types, including fibroblasts and [40] successfully generated “clean” iPSCs from newborn
PBMCs. or adult human fibroblasts by a single transfection
Another compelling methodology for the derivation of a synthetic, self-replicative RNA. However, further
of human iPSCs involves the binding of Epstein-Barr validation of this approach is necessary to establish its
virus-encoded nuclear antigen-1 (EBNA-1) to a cis-act- vigor and reproducibility.
ing viral DNA element, oriP. The EBNA-1/oriP associ- Delivery of reprogramming factors to cells as trans-
ation permits the persistence of plasmids in actively membrane permeable fusion proteins is another
dividing human cells as multicopy episomes that means of inducing pluripotency that prevents possible
attach to chromosomes during mitosis [34,35]. After alteration of the target cell genome [41,42]. Despite the
multiple cell divisions, oriP/EBNA-based vectors are promise of this strategy, the protein-mediated repro-
progressively lost from the targeted host cells. Never- gramming approach is hampered by slow kinetics,
theless, these vector systems significantly increase the inefficiency, low reproducibility, and high cost [16].
reprogramming efficiency through the prolonged ex- Recently, an exciting alternative approach was intro-
pression of transgenes within the transfected cell [35]. duced that exclusively uses small-molecule compounds
However, DNA-based reprogramming methods could to reprogram mouse somatic cells [43]. However, the
potentially lead to the integration of foreign DNA into efficiency of this technique is also quite low, and the
the host genome and therefore require accurate down- study must be reproduced by using human rather than
stream screening methods to confirm the derivation of mouse somatic cells to achieve broader clinical interest.
integration-free pluripotent cells [16,27]. Methodologies for the generation of clinically feasi-
ble iPSCs are still under development. The successful
Induction of pluripotency via mRNA or protein advance of integration-free techniques for the in-
expression duction of pluripotency, as well as xeno-free culture
The continuous, transient transfection of modified conditions both during and after the reprogramming
mRNAs into parental cells is an elegant approach for process, would be pivotal for future translational appli-
the induction of pluripotency that guarantees deri- cations.
vation of integration-free iPSCs [21,36]. Because this
method is independent of a DNA intermediate, it cir- Targeted editing of the iPSC genome
cumvents prospective integrations and thus, time-con- Traditionally, human ESCs were modified by using la-
suming screening experiments. However, modified borious and inefficient transfection protocols, homol-
mRNA transfection still requires pre-treatment of ogous recombination, and clonal expansion [44]. Re-
target cells with the expensive interferon alpha an- cently, tremendous progress has been made in terms of
tagonist, B18R, and a laborious series (up to 14 days) of stem cell transfection, cultivation, and genome editing.

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Dieck S, et al. Recent updates of iPSC

Defined culture conditions together with small-mol- ease of assembly. However, which of the three methods
ecule reagents and advanced stem cell transfection has the highest cutting efficiency without additional
protocols provided the initial foundation for the devel- off- target effects remains to be determined [48,49].
opment of new editing procedures for pluripotent stem Genome engineering strongly depends on cellular
cells. Currently, three main technologies are used to responses to DNA damage. For example, induction of
target and correct a wide variety of mutations in iPSCs: double-strand DNA breaks triggers either error-prone,
the zinc finger nuclease (ZFN) system, the transcrip- nonhomologous end joining or homology-directed
tion activator-like effector nuclease (TALEN) system, repair at specific genomic locations, leading to small
and the clustered regularly interspaced short palindro- insertions/deletions at the target site or introduction
mic repeats (CRISPR) system. Gene editing with ZFNs of a homologous donor DNA template, respectively [49].
and TALENs utilize programmable, sequence-specific Based on these repair mechanisms, it is possible to de-
DNA-binding domains linked to a nonspecific DNA rive heterozygous/homozygous knockout cell lines or
cleavage domain, Fok1, to form a functional dimeric to precisely introduce/correct specific gene mutations.
nuclease [45,46]. On the other hand, the CRISPR system The precise correction or introduction of a particular
takes advantage of the RNA-guided Cas9 nuclease to mutation in the same genetic background allows a
generate directed double-stranded DNA breaks [47]. more accurate way of disease modeling. Using these so
Although ZFNs were initially used for genome edit- called isogenic cell lines are the foundation to elucidate
ing experiments, the TALEN and CRISPR systems are the underlying molecular mechanism of a certain dis-
now preferable due to their relatively low expense and ease.

Induced pluripotent
stem cells
PI
T R A-

DA

-6
0 O CT4
1

Sendai viral
tion
ntia
Plasmids ere
Diff
n y
sio tenc
mRNA po
f p er
n o onv
i

Drug screening
lur

Genome editing
c

Reprogramming
indu Cell

CRISPR:
ctio

Gene disruption
TALEN:

Transgene insertion
ZINC finger: Cardiomyocytes
(Mesoderm)
Gene correction
Stem cell therapy

Keratinocytes Motoneurons
(Ectoderm)
Dif Cardiovascular
fere
Fibroblasts ntia
tion
Peripheral blood
mononuclear cells Metabolic
Neurodegenerative
Genome edited
Somatic cell induced pluripotent Disease modeling
isolation stem cells

Figure 1. Generation of patient-specific induced pluripotent stem cells (iPSCs) and clinical applications thereof. Somatic cells
isolated from a patient are reprogrammed into iPSCs by transduction with the four reprogramming factors, octamer-binding
transcription factor 4 (Oct4), sex determining region Y-box 2, Kruppel-like factor 4, and c-Myc. Genetic defects in iPSCs can
be corrected via gene editing with zinc finger nucleases (ZFNs), activator-like effector nucleases (TALENs), and the clustered
regularly interspaced short palindromic repeats (CRISPR) system. Next, iPSCs with or without edited modifications are
differentiated into various target cells for disease modeling, drug screening, and stem cell therapy. DAPI, 4',6-diamidino-2-
phenylindole.

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 The Korean Journal of Internal Medicine Vol. 29, No. 5, September 2014

In summary, recent advances in integration-free re- entiation of the patient-specific iPSCs into disease-spe-
programming technology and genome engineering, cific cell types [52-60]. This approach is favored because
combined with the enormous differentiation capacity risk and harm to the patient are minimal compared
of pluripotent cells, renders iPSCs an ideal tool for with other cell transfer therapies; furthermore, a vast
translational research (Fig. 1). number of target cells can be consistently generated
from patient-specific iPSCs with infinite expansion
capacity. If relevant expanded iPSCs and target cells
PART 2. CLINICAL APPLICATIONS OF iPSCS were to be globally distributed to researchers and drug
development teams, the performance of standardized
Recent advances in stem cell technology are likely to and directed research in a specific disease area might
greatly expedite the clinical use of iPSCs in applica- become possible. This feat would increase not only the
tions for human patients. These cells are an attractive safety and feasibility of cell source but also the accuracy
candidate for research because they can assume the of disease simulation.
individual characteristics of multiple cell types, in- Many reports have documented discrepancies be-
cluding disease-relevant cells. Although ESCs share tween mouse disease models and actual human disease
the proliferative capacity and multipotency of iPSCs, [61,62]. Investigations of iPSCs generated from cells and
their use in pathophysiological research is limited due tissues directly harvested from patients would likely
to their inability to take on a disease-selective pheno- minimize the fallacies originating from such discrep-
type. By contrast, patient-derived iPSCs retain specific ancies. Researchers would then be able to simulate the
genetic and epigenetic memories of the individual conditions caused by aberrant genes of patient-specific
from which they originated, enabling the simulation of iPSCs in a dish or in a tube. On the other hand, the
the patient’s own disease. Currently, disease modeling expense incurred by the generation of certain genetic
of several disorders has been realized by using dis- mutations in cell lines or animal models can be an
ease-relevant cells differentiated from patient-specific economical roadblock to large-scale drug development
iPSCs. This extraordinary achievement has resulted in and disease modeling [2,63]. From this point of view,
the pioneering of a new field of research for the deduc- the generation of patient-specific iPSCs often costs less
tion of pathogenic disease mechanisms, as well as for than the generation of animal disease models or genet-
preclinical drug screening. ically engineered animals. Therefore patient-specific
Therapeutic approaches based on iPSC-mediated cell iPSC drug platform might be a good candidate for a
and tissue transplantation are also promising, given preclinical validation tool in terms of economic feasi-
the unlimited proliferative capacity of iPSCs to provide bility and patient safety [64]. If some drugs are success-
sufficient quantities of cells for stem cell therapy. More- ful in such an iPSC platform, drug development may
over, patient-specific iPSCs can hypothetically mini- then proceed to the next stage with more confidence
mize immune reactions and reduce the risk of graft- and less risk. Overall, safety, feasibility, accuracy, and
versus-host rejection. However, several barriers must reasonable cost all favor the research and application of
be overcome before the successful clinical application patient-specific iPSCs for disease modeling and drug
of iPSCs. In this part of the review, we discuss the feasi- screening.
bility and concerns of iPSCs in association with disease Nevertheless, disease modeling with iPSCs has sever-
modeling, drug screening, and regenerative medicine. al limitations and concerns, including lack of homoge-
neity in many iPSC cell lines. In vitro disease modeling
Disease modeling and drug screening is affected by cellular artifacts and culture conditions.
Nowadays, disease simulation is a mainstream of iPSC Thus, if environmental factors readily affect iPSC
applications in research laboratories and in clinics properties and differentiation into target cells, repro-
[2,50,51]. Disease modeling with iPSCs recapitulates ducibility of disease modeling with patient-specific iP-
a pathologic condition in vitro by reprogramming a SCs becomes a formidable issue. Although target cells
patient’s somatic cells into iPSCs, followed by rediffer- are differentiated from stable iPSCs, the former exist in

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Dieck S, et al. Recent updates of iPSC

a spectrum, from immature cells to mature and func- transplantation [71], possibly eliminating the need for
tional cells. Therefore, target cell diversity is indisput- lifelong immunosuppressive drugs. Self-renewal and
ably a barrier to the simulation of disease in a dish [4,65]. everlasting proliferation are another merit of iPSCs in
Second, the complexity of disease pathophysiology regenerative medicine. As noted above, the proliferative
may not be revealed by any single cells derived from capacity of iPSCs is equivalent to that of ESCs; hence,
patient-specific iPSCs, because cell-to-cell interactions iPSCs represent a limitless source of cells for cell re-
also play important roles in intractable diseases. There- placement therapy. Moreover, the pluripotency of iPSCs
fore, simulation of a complex disease requires a more enables the formation of a functional organ structure
complicated and elaborate system rather than that beyond what is capable with a mixture of cells and cel-
afforded by isolated cells and cellular components [66]. lular components [72]. However, the development of
For this reason, the initial stages of iPSC application new biomaterials and appropriate scaffolds will be nec-
to disease modeling have concentrated on straightfor- essary to fully support the clinical application of iPSCs
ward genetic disorders, given that the pathologically in human medicine.
autonomous iPSC cells generated in a monogenic dis- Nonetheless, iPSC-based cell therapy is hampered
ease represent the main phenotype of the that condi- by substantial obstacles. In particular, the clinical use
tion [67]. of these cells requires ongoing and strict guidelines to
Third, disease modeling faces challenges if the minimize harmful outcomes to patients while maxi-
disease pathogenesis itself is inf luenced by the en- mizing patient safety. Although technical progress con-
vironment. Host susceptibility and environmental tinues, there remains a tremendous gap between iPSC
factors critically interact in the progression of chronic generation for research purposes and for therapeutic
degenerative and metabolic conditions. Accordingly, purposes.
efforts have been made to lessen the gap between dis- Good manufacturing practice (GMP) and standard
ease simulation and reality. For instance, environmen- operating procedures (SOP) are important terms that
tally-induced senescence can be mimicked in disease are frequently encountered in the clinical application
modeling by the addition of specific molecules to the of stem cells. GMP and SOP principles necessarily esca-
culture system, such as progerin, which reportedly in- late the expense of iPSC generation and manipulation.
duces premature aging in stem cells [68]. This type of Thus, the balance between cost and safety remains an
strategy will be advantageous for accurate simulations issue. However, despite this caveat, iPSC therapy seems
of chronic human degenerative diseases. imperative for certain conditions. For example, neuro-
degenerative and cardiac diseases have limited treat-
Regenerative medicine ment options other than regenerative therapy because
Stem cells show great promise for the minimization neurons and cardiomyocytes are not renewable. Stem
of immune rejection in regenerative medicine, as suc- cell strategies, including the use of iPSCs, are encour-
cessfully demonstrated by attempts to alleviate signs aging for the replacement of lost nerve or cardiac tissue
and symptoms in disease-relevant animal models. For and other non-renewable tissues or organs. On a prac-
example, Parkinson’s disease model rats were effective- tical note, the first clinical trial of iPSCs was recently
ly treated by cell replacement therapy with terminal- approved for the treatment of age-related macular de-
ly-differentiated neurons derived from reprogrammed generation in Japan [73].
fibroblasts, with little immune rejection [69]. Moreo-
ver, iPSCs corrected through gene editing displayed
the therapeutic potential to cure genetic disorders in PERSPECTIVE
a mouse model of sickle cell anemia, together with re-
duced immunogenicity [70]. In 2012, John B. Gurdon and Shinya Yamanaka were
Regenerative medicine approaches with iPSCs have awarded the Nobel Prize in Medicine for their pioneer-
several clinical merits. Above all, patient-derived iP- ing work on cellular plasticity and cellular differenti-
SCs are immunologically privileged upon autologous ation, only 6 years after Yamanaka initially generated

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 The Korean Journal of Internal Medicine Vol. 29, No. 5, September 2014

iPSCs in 2006 [6]. This accomplishment indirectly Acknowledgments

highlights the intense focus placed on iPSC research This work was supported by Basic Science Research
over the past several years. Vast amounts of research Program through the National Research Foundation
funding and manpower have been invested in iPSC of Korea (NRF) funded by the Ministry of Science, ICT
technology to widen the opportunity for new clinical & Future Planning (2013R1A1A1076125) and Grant for
applications and hasten the realization of stem cell “the Center for Evaluating Next-Generation Stem Cell-
therapy. based Therapeutics” supported by National Institute of
In the near future, we anticipate that patient-specific Food and Drug Safety Evaluation, part of the Ministry
iPSCs will prove increasingly useful for in vitro disease of Drug and Food Safety (14172 CENST 974), and a grant
modeling. Diseases with an unclear pathogenic mech- from German research foundation (DFG) DI1877/1-1.
anism are an obvious target for vigorous pathophysio-
logical research with such patient-derived cells. This
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