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Cell Stem Cell
Previews
Induced Pluripotent Stem Cells and Human Disease
Alan Colman1,2,*1Wolfson Centre for Age-Related Disease, King’s College London, Hodgkin Building, Guy’s Campus, London SE1 1UL, UK2Singapore Stem Cell Consortium, Institute of Medical Biology, 8A Biomedical Grove, #06-06 Immunos, Singapore 138648,Republic of Singapore*Correspondence: alan.colman@imb.a-star.edu.sgDOI 10.1016/j.stem.2008.08.007
Two recent studies report the generation of induced pluripotent stem cells from patients presenting with atotal of eleven different diseases (Park et al., 2008; Dimos et al., 2008). Future differentiation studies using theselines may offer insight on specific disease pathophysiology and aid the design of protective drug therapies.
The advent of human embryonic stem cell
(hESC) technology has fostered great
optimism that if their extensive, though
unpredictable, in vitro differentiation
properties could be harnessed appropri-
ately, these pluripotent cells could
provide powerful models of human devel-
opment and disease, as well as material
for cell replacement therapies. Although
this vision has been partially delivered
with the provision of disease-specific
hESC lines from afflicted embryos identi-
fied in preimplantation diagnostic screen-
ing programs (Pickering et al., 2005), only
common, monogenic conditions can be
captured in this way. Somatic cell nuclear
transfer using adult cell donors offers
a more comprehensive route to patient-
specific hESC. However technical, logisti-
cal, and ethical difficulties have, to date,
presented insuperable difficulties. The
landmark discovery by Takahashi and Ya-
manaka (reviewed in Yamanaka, 2007)
that induced pluripotent stem cells
(iPSCs), which share very similar proper-
ties with hESCs, could be prepared from
mouse skin fibroblasts, has already been
reproduced for a variety of human cell
types taken from healthy donors. In the
last month, two papers have been pub-
lished describing the generation of iPSC
lines from individual patients harboring
236 Cell Stem Cell 3, September 11, 2008 ª2
a variety of both simple and complex
genetic diseases.
Daley and colleagues (Park et al., 2008)
report the production of human iPSC lines
for ten diseases, ranging from simple Men-
delian traits, like adenosine deaminase de-
ficiency and Gaucher disease type III, to
complex conditions, like Parkinson’s dis-
ease and Type 1 diabetes. In addition,
they generated a line from a female carrier
of Lesch-Nyhan syndrome with its charac-
teristic mutation in one of the two alleles of
the X-linked hypoxanthine-guanine phos-
phoribosyltransferase (hprt) gene. By
analogy to the classic work using mouse
hprt+/� ESCs, these human cells should
prove extremely valuable in refining strate-
gies for studies of homologous recom-
bination as well as X chromosome acti-
vation/inactivation. These various lines
were made by the now standard proce-
dure of infecting dermal fibroblasts or, in
one case, bone marrow mesenchymal
cells, with disabled retroviruses express-
ing the reprogramming factors OCT4,
SOX2, KLF4, and c-MYC. The resulting
iPSC lines displayed a variety of pluripo-
tent stem cell markers (including NANOG,
SSEA-3, and -4), and all of those tested
could differentiate in vitro (embryoid bod-
ies) and in vivo (teratoma formation in
immunodeficient murine hosts) into cell
008 Elsevier Inc.
lineages characteristic of all three embry-
onic germ layers (ectoderm, mesoderm,
and endoderm).
Eggan and colleagues (Dimos et al.,
2008) used similar methods to produce
iPSC lines from skin cells from an 82-
year-old female patient diagnosed with
a familial form of amylotrophic lateral scle-
rosis (ALS; also known as Lou Gehrig’s
disease). This lesion, which in this case
was caused by a mutation in the superox-
ide dismutase gene, leads to motor neu-
ron loss in the spinal cord and motor
cortex with resulting paralysis and death.
By converting the iPSCs into motor neu-
rons and glial cell types, they established
that reprogramming and in vitro differenti-
ation are not necessarily thwarted by do-
nor age. This is an important benefit given
thatmanygenetic diseases areof sporadic
occurrence, with no family history, and be-
come only evident with advancing years.
Park et al. conclude their paper by sig-
naling their intent to provide these lines
as a resource to the biomedical research
community. This is an eminently laudable
declaration, and one hopes that the in-
ventory of disease-specific lines will be
expanded rapidly in the near future. How-
ever, before the full potential of these iPSC
lines can be realized, a number of uncom-
fortable issues have to be addressed.
Cell Stem Cell
Previews
First, iPSC generation involves retroviral
integration and, as both the new papers
attest, residual expression from some of
the added genes. While the impact of
this exogenous expression on cell poten-
tiality remains unclear, the presence of in-
tegrated retroviral sequences precludes
the use of these cells for donor patient
cell therapy, even if the genetic lesion
were repaired. However, new methods in-
volving the transient exposure of somatic
cells to reprogramming genes (or their
products) or small molecule effectors
are under development (discussed in
Tada, 2008). Second, it is not clear that
iPSCs can display all the properties of
ESCs: in mice where more stringent tests
can be applied, murine iPSCs, unlike
ESCs, have not yet formed live young in
tetraploid aggregation assays. Third, ex-
perience in differentiating ESC, the gold
standard, has itself been checkered. It is
not clear whether any somatic cell line-
ages made in vitro are perfect replicas
of the adult cell types. For example, dif-
ferentiation of mouse ESC into adult he-
mopoietic stem cells has fallen far short
of requirements even with additional ge-
netic manipulation (see Murry and Keller,
2008). hESC-derived cells with adult beta
cell-like properties have not been made
in culture, while hESC-derived cardiomyo-
cytes display mostly embryonic pheno-
types. It may be that if perfect adult identity
is required, the best cellular targets could
be cell types that emerge very early in em-
bryonic development and do not generally
undergo division during postnatal life,
such as retinal pigmented epithelial cells.
Transplantation, of course, provides the
most stringent test of actual or latent cell
functionality, but in many situations, an in-
formative outcome can be compromised
by poor engraftment resulting from inade-
quate ‘‘preconditioning’’ in culture, or the
disappearance of regional developmental
cues in adult host tissues. Although im-
provements in heart function have been
claimed after mouse or human ESC-de-
rived cardiomyocytes transplantation into
infarcted mouse hearts, these are likely
short term gains unrelated to structural in-
tegration of donor cardiomyocytes (Van
Laake et al., 2007).
Despite these present shortcomings,
cell perfection may not be required to per-
mit important benefits accruing from the
use of disease-specific iPSCs in drug
discovery and screening. For example,
experiments using coculture of mESC-
derived motor neurons with primary (Na-
gai et al., 2007) or ESC-derived astrocytes
(Di Giorgio et al., 2007) have corroborated
earlier mouse chimera findings implicat-
ing astrocyte involvement, and in particu-
lar, their secretion of toxic factors, in the
degeneration of motor neurons in a mouse
model of ALS. The new availability of
these cell types from human ALS-specific
iPSCs could presage the development of
drugs that either prevent the production
of toxic factors by astrocytes or, alterna-
tively, prevent motor neuron degradation
in their presence.
In summary, the reports by Park and
Dimos and their colleagues represent the
Cell Stem Cell 3, S
first salvo of what should be a rich harvest
of iPSC lines covering a host of simple
and complex genetic diseases. Assuming
present technological hurdles can be
overcome and equivalence with conven-
tional ESs is established, they should sup-
plant ESCs for many applications since
only iPSCs are made from living donors
with detailed medical histories attesting
to the impact of the disease on particular
individuals.
REFERENCES
Di Giorgio, F.P., Carrasco, M.A., Siao, M.C., Mani-atis, T., and Eggan, K. (2007). Nat. Neurosci. 10,608–614.
Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisen-thal, L.M., Mitsumoto, H., Chung, W., Croft, G.F.,Saphier, G., Leibel, R., Goland, R., et al. (2008).Science 29, 1218–1221.
Murry, C.E., and Keller, G. (2008). Cell 132,661–680.
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Van Laake, L.W., Passier, R., Monshouwer-Kloots,J., Verkleij, A.J., Lips, P.J., Freund, C., den Ouden,K., Ward-van Oostwaard, D., Korving, J., Tertoo-len, L.G., et al. (2007). Stem Cell Res. 1, 9–24.
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