Cell Stem Cell
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REFERENCES
Andreetta, F., Bernasconi, P., Baggi, F., Ferro, P.,
Oliva, L., Arnoldi, E., Cornelio, F., Mantegazza,
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Emery, A.E. (2002). Lancet 359, 687–695.
The Niche Revealed
D. Spencer Currle1,2 and Richard J. Gilbertson1,2,*
1Department of Developmental Neurobiology
2Department of Oncology
St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
*Correspondence: richard.gilbertson@stjude.org
DOI 10.1016/j.stem.2008.08.011
A trio of studies in this issue of Cell Stem Cell from Mirzadeh et al., Shen et al., and Tavazoie et al. use three-
dimensional imaging techniques to reveal microanatomical details of the adult neural stem cell niche.
Combined, the results also provide a framework for future functional studies.
Adult NSCs arise from radial glia within
the subventricular zone (SVZ) of the lateral
ventricles (Merkle et al., 2004), one of two
regional concentrations of NSCs in the
brain that include the dentate gyrus sub-
granular zone (Alvarez-Buylla and Lim,
2004). Although the potency of NSCs ren-
ders them an attractive resource in the
hunt for cures of neurodegenerative dis-
eases, the mechanisms that control the
behavior of these cells remain largely
unknown.
Similar to other tissue-specific stem
cells, NSCs are presumed to exist in
specialized microenvironments, or niches,
that regulate their function. Thus, a better
understanding of the architecture of the
ependymal layer and SVZ could yield
important insights into the mechanisms
that regulate NSCs; however, a clear
view of the complex three-dimensional
arrangement of blood vessels, cell pro-
cesses, and extracellular matrix (ECM)
proteins found in this region of the brain
is lost among the thin tissue sections
processed using conventional histologic
approaches. Therefore, three studies in
this issue have used novel whole-mount
imaging techniques to provide the first
234 Cell Stem Cell 3, September 11, 2008 ª2008 Elsevier Inc.
Gargioli, C., Coletta, M., De, G.F., Cannata, S.M.,
and Cossu, G. (2008). Nat. Med. 10.1038/nm.
1852.
Gopinath, S.D., and Rando, T.A. (2008). Aging Cell
7, 590–598.
Hidestrand, M., Richards-Malcolm, S., Gurley,
C.M., Nolen, G., Grimes, B., Waterstrat, A., Zant,
G.V., and Peterson, C.A. (2008). J. Gerontol. A
Biol. Sci. Med. Sci. 63, 566–579.
high-resolution, three-dimensional de-
scriptions of the adult NSC niche.
Tavazoie et al. (2008) and Shen et al.
(2008) focused their studies on the cellular
and molecular interactions surrounding
the SVZ vasculature, since emerging evi-
dence has suggested that blood vessels
are key components of tissue-specific
stem cell niches (Palmer et al., 2000;
Shen et al., 2004; Yoshida et al., 2007).
Using glial fibrillary acidic protein-green
fluorescence protein (GFAP-GFP) trans-
genic reporter mice, they demonstrate
that the SVZ vasculature includes an ex-
tensive, superficial network of planar in-
terconnected blood vessels that spans
the entire SVZ, just beneath the ependy-
mal layer. Their studies demonstrate that
GFAP+/LeX+ BrDU-retaining NSCs inter-
act closely with these vessels, an intimate
relationship that Shen and colleagues
report Type A neuroblasts retain as they
migrate from the SVZ to the olfactory bulb.
A noteworthy insight provided by these
studies and those of Mirzadeh et al.
(2008) is the demonstration that adult
NSCs, similar to their radial glial fore-
bears, are highly polarized, contacting
the ventricle through a short apical pro-
Minasi, M.G., Riminucci, M., De, A.L., Borello, U.,
Berarducci, B., Innocenzi, A., Caprioli, A., Sira-
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cess and a blood vessel through a long
basal process. Indeed, Mirzadeh et al.
(2008) show that these basal processes
contribute to the gliotubes that seem to
guide migrating neuroblasts, much as ra-
dial glial fibers guide neuroblasts up to the
developing cortical plate. Although adult
NSCs have been shown to arise from ra-
dial glia (Merkle et al., 2004), and neuro-
genic radial glia have been identified in
the adult songbird brain, the data con-
tained in this issue of Cell Stem Cell sug-
gest that mammalian radial glia progeni-
tors establish critical structure-function
relationships within the niche that are
inherited by adult NSCs.
A close interaction between SVZ NSCs
and blood vessels might be expected in
light of similar cell-cell interactions in the
hippocampus (Palmer et al., 2000); how-
ever, data from Tavazoie et al. provide
the first evidence that these sites of
neurovascular interaction have functional
significance in vivo. They show that
NSC-vessel contacts in the SVZ are un-
usually permeable and frequently devoid
of astrocytic endfeet or a pericyte sheath
(features of the blood-brain barrier that
minimize access of neural cells to
Cell Stem Cell

Previews

circulating molecules through- much to maintaining CSF

out the rest of the brain). Prior flow; however, recent evi-
studies have shown that dence that cilia can coordinate
NSCs are regulated by endo- cell signaling raises the excit-
thelial-derived factors (Shen ing possibility that E2 cells
et al., 2004); thus, the new ul- function as transducers of cell
trastructural data from Tava- signals between the ventricle
zoie et al. (2008) might reveal and the SVZ. In contrast to
how NSCs gain access to E1 and E2 cells, the third cell
these factors. The potential type observed in this location,
significance of these neuro- Nestin+/CD24 NSCs, were
vascular interactions is sup- often Prominin1+ and remark-
ported further by evidence ably numerous (over 6200 in
that these locations can act the lateral wall of the lateral
as staging posts for regenera- ventricle of one mouse). These
tion of the SVZ niche following NSCs were restricted to the
chemical ablation of transient lateral and anterior medial
amplifying cells and neuro- walls of the lateral ventricle,
blasts (Tavazoie et al., 2008). coinciding with the neurogenic
In addition to the vascula- niche. Within these neurogenic
ture, ECM proteins are be- ‘‘hotspots’’ NSCs are shown to
lieved to provide both a physi- be arranged in a striking ‘‘pin-
cal framework and instructive wheel’’ formation, in which
signals within stem cell niches. the apical surface of one or
With this in mind, Shen and more NSCs is surrounded by
colleagues looked in the SVZ packed E1 cells (Figure 1). Im-
to see if NSCs express the portantly, it is highly likely that
laminin receptor a6b1 integrin the CD133+/CD24 NSCs with
(VLA6), since laminin was Figure 1. Depicting Neural Stem Cells in Their Niche apical processes are the stem
found to be abundant and Cartoon illustrating the remarkable ‘‘pinwheel’’ arrangement of neural stem cells misidentified in other
cells (blue) and ependymal type 1 (E1) and E2 cells in the wall of the lateral
localized around blood ves- ventricle in work revealed by Mirzadeh et al. (2008). Artwork by Kenneth studies as ependymal cells
sels. They observed VLA6 ex- Xavier Probst. with stem cell properties (Cos-
pression in vessel-associated kun et al., 2008).
cells as well as neurosphere Together, the data provided
cultures of LeX+ cells, and that preincuba- only rarely contact the ventricle through in the three articles in this issue im-
tion of SVZ neurospheres with an integrin an apical process (Doetsch et al., 1999), prove our understanding of NSC niche
neutralizing antibody inhibited the binding while others suggest that the ependymal architecture and establish a vital founda-
of NSCs to endothelial cells in culture. cells are capable of re-entering the cell tion for future functional studies that may
Further, infusion of an integrin neutraliz- cycle as multipotent progenitors in re- ultimately uncover the mechanisms that
ing antibody directly into the lateral ven- sponse to injury (Coskun et al., 2008). underlie NSC regulation in vivo.
tricle of adult mice released SVZ cells To peak beneath the carpet of cilia that
from the vasculature and increased cell obscures the ventricle wall, Mirzadeh
proliferation. Integrin-laminin interactions et al. used g-tubulin and b-catenin anti-
have been reported to act as stem cell bodies to label the basal bodies and REFERENCES
‘‘anchors’’ in other organisms, including cell membranes, respectively, of cells in
Alvarez-Buylla, A., and Lim, D.A. (2004). Neuron
invertebrates (Tanentzapf et al., 2007); the ependymal layer. In doing so, they 41, 683–686.
thus, the data from Shen and colleagues identified two different non-NSC cell
extend the concept that these proteins types that contact the adult lateral ventri- Coskun, V., Wu, H., Blanchi, B., Tsao, S., Kim, K.,
Zhao, J., Biancotti, J.C., Hutnick, L., Krueger,
are critical regulators in niche microenvi- cle: ependymal cells with multiple basal R.C., Jr., Fan, G., et al. (2008). Proc. Natl. Acad.
ronments. bodies and multiple long cilia (termed Sci. USA 105, 1026–1031.
Complementing these studies, Mirza- E1 cells) and a previously unknown cell
Doetsch, F., Caille, I., Lim, D.A., Garcia-Verdugo,
deh et al., provide an exquisite picture (termed E2) with complex basal bodies J.M., and Alvarez-Buylla, A. (1999). Cell 97, 703–
of the cellular architecture within the and two long cilia. These two cell types 716.
ependymal layer and SVZ of the lateral were located within all regions of the
Mirzadeh, Z., Merkle, F.T., Soriano-Navarro, M.,
ventricle. The positioning and identity of ventricle and showed no evidence of Garcia-Verdugo, J.M., and Alvarez-Buylla, A.
NSCs relative to the ependymal layer proliferation. The discovery of E2 cells (2008). Cell Stem Cell 3, this issue, 265–278.
have been the subject of much contro- is particularly noteworthy. The relative in-
Merkle, F.T., Tramontin, A.D., Garcia-Verdugo,
versy. Some studies suggest that adult frequency of these biciliated cells sug- J.M., and Alvarez-Buylla, A. (2004). Proc. Natl.
NSCs are located within the SVZ and gests that they are unlikely to contribute Acad. Sci. USA 101, 17528–17532.

Cell Stem Cell 3, September 11, 2008 ª2008 Elsevier Inc. 235
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(2000). J. Comp. Neurol. 425, 479–494.
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K., and Temple, S. (2004). Science 304, 1338–
1340.
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Chuang, S.-M., Goderie, S.K., Roysam, B., and
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Tavazoie, M., Van der Veken, L., Silva-Vargas, V.,
Louissaint, M., Colonna, L., Zaidi, B., Garcia-Ver-
Previews
dugo, J.M., and Doetsch, F. (2008). Cell Stem
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Tanentzapf, G., Devenport, D., Godt, D., and
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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, UK
2Singapore 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.sg
DOI 10.1016/j.stem.2008.08.007

Two recent studies report the generation of induced pluripotent stem cells from patients presenting with a
total of eleven different diseases (Park et al., 2008; Dimos et al., 2008). Future differentiation studies using these
lines 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
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
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
that many genetic diseases are of 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.

236 Cell Stem Cell 3, September 11, 2008 ª2008 Elsevier Inc.