[ Pobierz całość w formacie PDF ]
Cell Stem Cell
In This Issue
Review Focus: Therapeutic Discovery
MERKLE AND EGGAN, PAGE 656, ENGLE AND PUPPALA, PAGE 669, YU ET AL., PAGE 678, AND
GARBERN AND LEE, PAGE 689
This issue features a series of Perspectives on therapeutic discovery with stem
cells. Two of the articles broadly discuss the challenges and considerations for
incorporating human pluripotent stem cells into disease modeling and drug
discovery efforts, respectively, and the other two focus more specifically on
therapeutic translation of stem cell technologies for treating either neurological
or cardiac disease. Read the editorial by Deborah Sweet in this issue to find out
more about other activities
Cell Stem Cell
has planned to cover this important
topic.
A Positive Role for ROS in SSC Self-Renewal
MORIMOTO ET AL., PAGE 774
Knockout of
the NADPH oxidase1 revealed an indispensable role for
physiological
levels of reactive oxygen species in spermatogonial stem cell
self-renewal.
ROS and NF-
k
B Drive Colorectal Cancer Initiation
MYANT ET AL., PAGE 761
This study demonstrates Rac1-mediated ROS production and NF-
k
B activation is required for Lgr5 stem cell expansion and
colorectal cancer initiation following loss of the
Apc
gene. Preview by Pelicci.
Stem-Cell-Based Drug Screen IDs a Potential Therapeutic for ALS
YANG ET AL., PAGE 713
Kenpaullone was identified as a strong hit in an ESC-derived motor neuron survival screen. This compound acts as a dual
kinase inhibitor and is effective on various mouse and human ALS motor neuron lines. Preview by Lee.
2-in-1: a Shared Disease Mechanism for Disparate Phenotypes
Revealed by hPSCs
TULPULE ET AL., PAGE 727
hESC/iPSC models of Shwachman-Diamond syndrome reveal elevated protease activity as a common underlying
mechanism for dysfunction in pancreatic and hematopoietic lineages.
KDR Is a Functional Receptor Instructing Liver Development
GOLDMAN ET AL., PAGE 748
The receptor KDR (VEGFR2), normally associated with mesoderm derivatives, identifies an endoderm-derived hepatic
progenitor in hESCs that is also present in fetal mouse and human liver.
3D Organization of Pluripotency
APOSTOLOU ET AL., PAGE 699
The
Nanog
promoter interacts with the rest of the genome in an unexpectedly complex pluripotency-specific chromatin
interaction network that depends on Mediator and cohesins.
Bone Matrix Contributions to the HSC Niche
ASADA ET AL., PAGE 737
Bone-embedded osteocytes respond rapidly to G-CSF and regu-
late hematopoietic stem/progenitor cell mobilization.
Adenoviral Delivery of Neurogenesis
Stimulators Slows HD Progression
BENRAISS ET AL., PAGE 787
Expression of BDNF and noggin using adenoviral vectors induces
neurogenesis that slows motor deterioration and extends life
span in a mouse model of Huntington’s disease.
Cell Stem Cell
12
, June 6, 2013
ª
2013 Elsevier Inc.
xvii
Cell Stem Cell
Editorial
The Stem Cell Experience
This year, we are delighted to welcome the stem cell community
to the annual ISSCR meeting in our ‘‘home town’’ of Boston. The
ISSCR last chose Boston as a venue for its meeting 9 years ago,
when the society and the meeting were considerably smaller, so
we are very excited to see the meeting back here now that it has
grown into such an impressive and multifaceted event. In the
registration bag this year, instead of a copy of our June issue,
meeting attendees will find a variation on the popular ‘‘Best
Of’’ reprint collection series focusing on
Cell Stem Cell
articles
published in 2012. This collection will also be available in an
extended version as an online digital edition, so even if you are
not coming to Boston for the meeting this year, you will be
able to browse and enjoy the full collection at your leisure.
For the review feature in our June issue, we have chosen to
focus on the application of stem cells to therapeutic discovery
through a series of Perspectives from leaders in the field in the
areas of disease modeling and application. In one of these
articles, Florian Merkle and Kevin Eggan discuss disease
modeling using human iPSCs, and in a second, Dinesh Puppala
and Sandra Engle cover the integration of human pluripotent
stem cells into drug discovery programs. The third article, from
Fred Gage and colleagues, covers the application of iPSCs to
devising treatments for neurological disease, while the fourth,
from Jessica Garbern and Richard Lee, looks at cardiac regener-
ation. Together, these articles give a timely update on some of the
key areas of development for the stem cell field. They also form a
prelude for other events scheduled for later this year, particularly
a Cell Symposium on ‘‘Using Stem Cells to Model and Treat Hu-
man Disease,’’ being held in Los Angeles in November. Between
now and the Symposium, there will be two focused webinars on
related topics, so look out for news about these soon as well. To
complement this review feature, for our cover we have chosen a
painting entitled ‘‘Popred’’ by the artist Sarah Ezekiel, who is con-
nected to the theme of the issue through MND/ALS, one of the
diseases that forms a focus of discovery efforts.
This year also sees some important developments for
Cell Stem
Cell
and the ISSCR. One of the most significant is that we are
excited to welcome a new journal into the stem cell fold:
Stem
Cell Reports
, which launches in June and at the ISSCR meeting.
You will find a copy of the inaugural issue of this journal in your
registrationbagalongwith the
Cell StemCell
‘‘Best Of’’ collection.
Stem Cell Reports
is a new journal owned and run by the ISSCR
and published by Cell Press, and it has a distinguished editorial
team led by Christine Mummery. With its open-access model
and focus on concise papers,
StemCell Reports
will be a valuable
complement to
Cell Stem Cell
for the publication of important
studies in the stem cell field. The scope, focus, and emphasis of
Cell Stem Cell
will not change: it will continue to be owned and
run by Cell Press and affiliated with the ISSCR. However, the
ISSCR pages and articles that previously appeared in
Cell Stem
Cell
have now instead moved to
Stem Cell Reports
, along with
oversight by the ISSCR Scientific Director, Heather Rooke.
At
Cell Stem Cell
, earlier this year we were very happy to add a
newmember to our in-house editorial team, Jonathan Saxe, who
joined us from a postdoctoral position in Haifan Lin’s group at
Yale University. This month, we have also made some changes
to the organization and membership of our advisory editorial
board. In keeping with our updated relationship with the ISSCR,
the
Cell Stem Cell
ISSCR advisory board members (Arnold
Kriegstein, Haifan Lin, Toshio Suda, and Leonard Zon) have
transferred over to become part of the main
Cell Stem Cell
edito-
rial board. They are joined on the board by 16 additional new
members, all of whom we are delighted to welcome to our
team: Iannis Aifantis, Caroline Alexander, Hans Clevers, Hongkui
Deng, Elaine Dzierzak, Richard Gilbertson, Konrad Hochedlin-
ger, Craig Jordan, Hanna Mikkola, Huck Hui Ng, Stuart Orkin,
Emmanuelle Passegu ´ , Kathrin Plath, Yoshiki Sasai, Deepak Sri-
vastava, and Mervin Yoder. At the same time, we are bidding a
fond farewell to Thomas Laux, Angela McNab, and Shinichi Nish-
ikawa, and we thank them for all of their efforts and contributions
over the past 6 years. Several of our new editorial board mem-
bers have contributed to a Voices article in this issue, in which
they prepared a short piece about a 2012
Cell Stem Cell
paper
that they particularly enjoyed. I hope you in turn will enjoy reading
these diverse perspectives on a broad range of studies, and that
doing so will perhaps encourage you to go back and revisit some
of the papers with a fresh eye. The topics covered in these high-
lights range from chromatin regulation in ESCs (
Brookes et al.,
2012
) through morphogenesis (
Nakano et al., 2012
) and lineage
contribution (
van Amerongen et al., 2012
) to the ways in which
stem cell regulation contributes to hematopoietic disease and
cancer (
Ceccaldi et al., 2012
;
Magee et al., 2012
;
Kalaitzidis
et al., 2012
). This Voices article is also included in the ‘‘Best
Of’’ collection as a complement to the selection of articles based
on downloads, and all of the papers featured in the selections are
included in the extended online edition.
If you are coming to Boston for the 2013 ISSCR meeting, we
hope you will have time to visit our booth in the exhibit hall
(#627). You will be able to pick up a free copy of this June issue,
an extra ‘‘Best Of’’ if you’d like one, plus many of the other jour-
nals in the Cell Press family, including
Cell Reports
, our broad
scope open-access journal launched last year. You could also
learn about our other planned activities, including the conference
and webinars mentioned above, and meet editors from
Cell
Stem Cell
and other Cell Press journals to get an inside look at
the publishing process. We will have information about the
new Cell Press full text and Snapshot iPad apps, and you will
have a chance to try them out at the booth. At
Cell Stem Cell
,
we have continued to expand our social media presence, and
before and during the meeting we will post news and information
via Twitter (@CellStemCell or
https://twitter.com/cellstemcell
)
and Facebook (
https://www.facebook.com/cellstemcell
). Don’t
forget to enter the Cell Press ‘‘Boston Experience’’ competition
by sending us a photo of yourself at a Boston landmark (and
yes, the convention center does count!) via social media or email
for your chance to win an iPad Mini or a scarf featuring ‘‘Popred,’’
the painting that graces the cover of this issue and, if you are
fortunate enough to win, could soon be gracing you.
In closing, and unfortunately on a more somber note, I
would like to take this opportunity to pay tribute to Dr. Christa
Cell Stem Cell
12
, June 6, 2013
ª
2013 Elsevier Inc.
631
Cell Stem Cell
Editorial
Muller-Sieburg, who sadly passed away earlier this year. Dr.
Muller-Sieburg made many pioneering contributions to studies
of HSCs, and particularly, as Connie Eaves and colleagues out-
lined in their Perspective article last year (
Copley et al., 2012
), to
initial investigations of HSC heterogeneity that formed a founda-
tion for current and future analyses. Her influence will no doubt
be evident in HSC work presented at this year’s ISSCR meeting.
I am sure I speak for the entire
Cell Stem Cell
team when I say
that we look forward to sharing all of our stem cell experiences
with you, at this meeting and beyond. As always, we welcome
your feedback and input about the journal and the field overall.
Ceccaldi, R., Parmar, K., Mouly, E., Delord, M., Kim, J.M., Regairaz, M., Pla,
M., Vasquez, N., Zhang, Q.S., Pondarre, C., et al. (2012). Cell Stem Cell
11
,
36–49.
Copley, M.R., Beer, P.A., and Eaves, C.J. (2012). Cell Stem Cell
10
, 690–697.
Kalaitzidis, D., Sykes, S.M., Wang, Z., Punt, N., Tang, Y., Ragu, C., Sinha, A.U.,
Lane, S.W., Souza, A.L., Clish, C.B., et al. (2012). Cell Stem Cell
11
, 429–439.
Magee, J.A., Ikenoue, T., Nakada, D., Lee, J.Y., Guan, K.L., and Morrison, S.J.
(2012). Cell Stem Cell
11
, 415–428.
Nakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K.,
Saito, K., Yonemura, S., Eiraku, M., and Sasai, Y. (2012). Cell Stem Cell
10
,
771–785.
van Amerongen, R., Bowman, A.N., and Nusse, R. (2012). Cell Stem Cell
11
,
387–400.
REFERENCES
Deborah J. Sweet
Editor,
Cell Stem Cell
http://dx.doi.org/10.1016/j.stem.2013.05.021
Brookes, E., de Santiago, I., Hebenstreit, D., Morris, K.J., Carroll, T., Xie, S.Q.,
Stock, J.K., Heidemann, M., Eick, D., Nozaki, N., et al. (2012). Cell Stem Cell
10
, 157–170.
632
Cell Stem Cell
12
, June 6, 2013
ª
2013 Elsevier Inc.
Cell Stem Cell
Previews
Candidate ALS Therapeutics
Motor toward ‘‘In Vitro Clinical Trials’’
Yong Jun Kim
1
and Gabsang Lee
1
,
*
1
Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore,
MD 21205, USA
*Correspondence:
glee48@jhmi.edu
http://dx.doi.org/10.1016/j.stem.2013.05.009
Conducting drug discovery efforts in patient- and disease-specific cells can maximize their likelihood of
success. In this issue of Cell Stem Cell,
Yang et al. (2013)
demonstrate the power of lineage-specific cell-
based drug screens by identifying a compound that promotes survival of stem-cell-derived ALS mutant
motor neurons.
Amyotrophic lateral sclerosis (ALS), more
commonly known as Lou Gehrig’s dis-
ease, is a notoriously intractable neuro-
degenerative disorder involving specific
loss of motor neurons (MNs). As a result,
patients suffer progressive paralysis and
die due to loss of respiratory function
(
Maragakis, 2010
;
Robberecht and
Philips, 2013
). Causative mutations in
superoxide dismutase-1 (SOD1) are
found in 20% of inherited-ALS patients
(
Robberecht and Philips, 2013
). Currently,
the only FDA-approved drug for treat-
ment of ALS is Riluzole, which has
merely modest effects, extending patient
lifespan by several months. Efforts to
find more effective drugs have yielded
two promising compounds, olesoxime
and dexpramipexole, but the results of
recent clinical trials were not promising
(
Cudkowicz et al., 2011
;
Robberecht and
Philips, 2013
).
One of the major obstacles in study-
ing neurodegenerative diseases is the
difficulty of obtaining relevant cell types
for analysis. In the case of ALS, MNs
are at the root of disease pathophy-
siology. Unfortunately, culturing MNs
is very difficult, and it is almost im-
possible to biopsy sufficient numbers of
MNs from patients for extensive study
(
Maragakis, 2010
). Recent progress in
stem cell biology, especially the develop-
ment of induced pluripotent stem cell
(iPSC) technology, provides immense
opportunities for modeling human dis-
ease and screening potential thera-
peutics, using disease-relevant cell
populations. For instance, after gener-
ating iPSCs from fibroblasts of ALS
patients (
Dimos et al., 2008
), MNs from
these ALS patient-specific iPSCs were
used for validating potential candidate
drugs and identifying their mechanisms
of action (
Egawa et al., 2012
).
In this issue of
Cell Stem Cell
,
Yang
et al. (2013)
provide a conceptually novel
strategy to discover drugs for treatment
of ALS. In their study, the authors diff-
erentiated mouse embryonic stem cells
(ESCs) carrying either wild-type or mutant
human
SOD1
and obtained large number
of MNs. Because other studies found that
trophic factor withdrawal causes signifi-
cant death (around 80%) of MNs carrying
wild-type or human mutant
SOD1
(
Kieran
et al., 2008
), Rubin and colleagues devel-
oped an assay based on this paradigm
and screened approximately 5,000 small
molecules to identify compounds that
prevent cell death of their mouse-ESC-
derived MNs (
Yang et al., 2013
). The use
of MNs bearing human wild-type or
mutant SOD1 resulted in identification of
22 compounds that showed significant
protective effects. Primary hit from this
screen included compounds such as
inhibitors of apoptosis, a matrix meta-
lloprotease (MMP) inhibitor with agonist
activity at cannabinoid receptors, and a
calpain inhibitor. These compounds
have been previously reported to have
effects in ALS mice models, providing
useful validation of their screen.
Among the remaining compounds,
including several kinase inhibitors, the au-
thors focused on Kenpaullone as a ‘‘hit’’
because it strongly increased survival of
both wild-type and
SOD1
mutant MNs.
Although Kenpaullone is a known GSK-3
inhibitor, its capacity to promote MN sur-
vival was significantly greater compared
to other GSK-3 inhibitors tested. The au-
thors then demonstrated that this is due
to Kenpaullone’s ability to inhibit HGK,
which acts as an upstream regulator of
a stress-induced neuronal cell death
signal through a Tak1-MKK4-JNK-c-Jun
pathway. Because CHIR99021 (another
GSK-3 inhibitor tested here) could not
rescue MN death in this experimental
setting, HGK could be considered a new
therapeutic target for further drug discov-
ery. Whether inhibition of HGK alone is
effective in preventing MN death, or
whether it requires concurrent inhibition
of GSK-3, requires additional investiga-
tion. In addition to Kenpaullone’s effect
on cell survival, it preserves morphology
and electrophysiological activity even
after long-term treatment, which suggests
additional corrective benefits to MNs
upon chronic treatment.
The authors then extended their valida-
tion of Kenpaullone to human MNs. They
found that Kenpaullone promotes survival
of human ESC (hESC)-derived MNs, as
well as MNs harboring
SOD1
mutations
from patient-specific iPSCs. More impor-
tantly, Kenpaullone can prevent death of
MNs carrying mutations in
TDP-43
,
another major genetic defect found in
congenital ALS (
Robberecht and Philips,
2013
). Intriguingly, the authors also tested
the effects of olesoxime and dexprami-
pexole. These compounds appeared
promising in mouse studies but did not
fare well in clinical trials (
Cudkowicz
et al., 2011
;
Robberecht and Philips,
2013
). Compellingly, these compounds
were not successful in rescuing death of
MNs carrying human
SOD1
mutations.
This finding is a powerful example of ‘‘pre-
clinical testing in a dish.’’ Such preliminary
screening steps can potentially save a
huge amount of resources and accelerate
Cell Stem Cell
12
, June 6, 2013
ª
2013 Elsevier Inc.
633
[ Pobierz całość w formacie PDF ]