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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.

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