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insideblood
22 JULY 2010 I VOLUME 116, NUMBER 3
● ● ● HEMATOPOIESIS & STEM CELLS
Comment on Winkler et al, page 375
Stem
cells hold their breath
---------------------------------------------------------------------------------------------------------------Gregor B. Adams
UNIVERSITY OF SOUTHERN CALIFORNIA
In this issue of Blood, Winkler and colleagues use blood perfusion to define and
characterize 2 distinct HSC populations in the BM, demonstrating that the most
primitive HSCs reside in a BM niche with negligible perfusion.1
The most primitive hematopoietic stem cells are
located in regions with the lowest blood perfusion,
suggesting that these cells are either located in
regions removed from vascular structures (1), or
alternatively, the stem cells may be located next to
specialized endothelial cells that do not allow the
passive diffusion of various factors (2).
ver the past decade there has been great
interest in in vivo regulatory mechanisms of hematopoietic stem cells (HSCs).
While much has been learned regarding both
the intrinsic and extrinsic determinants of
stem cell function, pinpointing the location of
the cells in the adult bone marrow (BM) has
been elusive. Studies by different groups have
shown that cells of the osteoblast lineage are
key components of the HSC niche, correlating
with previous studies demonstrating that
HSCs are preferentially located at the endosteal surface of bone.2,3 However, the identification of the signaling lymphocyte activation molecule family of receptors as novel
markers of HSCs suggested that the majority
of these stem cells were actually positioned
O
blood 2 2 J U L Y 2 0 1 0 I V O L U M E 1 1 6 , N U M B E R 3
adjacent to cells of the endothelial lineage, thus
implicating the vascular niche.4 The relevance
of each niche, and its specific role in regulating
HSC number and function has since been extensively discussed in the literature with no
conclusive evidence for differing roles of these
niches.5 Complicating matters further was a
recent report suggesting that in some cases,
the endosteal and vascular HSC niches may in
fact be indistinct, and that HSCs are actually
located adjacent to both osteoblastic and endothelial cells.6
In this article, Winkler and colleagues1
used the properties of blood perfusion to define these potentially distinct niches. Specifically, the authors used the diffusion of the
Hoechst 33342 (Ho) DNA dye after intravenous injection to identify the location of the
HSCs relative to the perfusion of the dye in
vivo. This technique had been previously used
by Parmar and colleagues7 where they recognized that primitive HSCs reside in regions of
the BM that are the least perfused by the Ho
dye and have the lowest levels of oxygenation,
suggesting that hypoxia may play a key role in
the maintenance of stem cell function in the
BM. Winkler and colleagues made an important advance using this technique to show that
the HSCs could actually by subdivided into
2 distinct subpopulations dependent upon Ho
uptake. The authors found that the cells resident in those areas least perfused by the Ho
dye (Honeg) had the greatest degree of stem cell
activity compared with those phenotypically
defined HSCs resident in areas that were per-
fused to a slightly higher degree (Homed cells).
The authors made 2 other interesting observations. First, during granulocyte colonystimulating factor–induced mobilization,
HSCs were found to be localized in regions
with increased blood perfusion. These results
suggested that the HSCs migrated from their
hypoxic microenvironment to a location more
accessible to vascular perfusion, possibly a
perivascular location, where the cells then
enter into the circulation. Second, as expected,
immunophenotypically identified endothelial
cells were located near the areas of highest
blood perfusion, whereas osteoblastic cells
were located in regions of negligible perfusion.
However, interestingly, cells identified
as mesenchymal stromal cells
(CD45⫺Lin⫺CD31⫺Sca-1⫹CD51⫹) were
actually located in areas of highest blood perfusion, again presumably perivascularly.
While not conclusively pinpointing the
location of the most primitive HSCs in the
adult BM, this article markedly narrows down
the search. Their data confirm previous reports that used a more controversial method of
identifying HSCs to suggest that the hematopoietic cells with the slowest turnover, potentially primitive HSCs, are located in a hypoxic
zone, removed from capillary structures.8 The
question of the relative role of the endosteal
niche versus the vascular niche remains open.
The most primitive stem cells may in fact not
be present next to vascular structures. However, endothelial cells may control perfusion
(particularly oxygen) to regulate HSC function, or the HSCs may be located next to vessels where the blood flow is so low that diffusion is very poor (see figure). This would
suggest that there may be specialized vascular
structures that comprise the vascular niche.
Conflict-of-interest disclosure: The author
declares no competing financial interests. ■
REFERENCES
1. Winkler IG, Barbier V, Wadley R, Zannettino ACW,
Williams S, Lévesque J-P. Positioning of bone marrow
hematopoietic and stromal cells relative to blood flow in
307
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood. 2010;116(3):
375-385.
5. Kiel MJ, Morrison SJ. Uncertainty in the niches that
maintain haematopoietic stem cells. Nat Rev Immunol.
2008;8(4):290-301.
2. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature.
2003;425(6960):841-846.
6. Lo Celso C, Fleming HE, Wu JW, et al. Live-animal
tracking of individual haematopoietic stem/progenitor cells
in their niche. Nature. 2009;457(7225):92-96.
3. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425(6960):836-841.
7. Parmar K, Mauch P, Vergilio J-A, Sackstein R, Down
JD. Distribution of hematopoietic stem cells in the bone
marrow according to regional hypoxia. Proc Natl Acad Sci
U S A. 2007;104(13):5431-5436.
4. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst
C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial
niches for stem cells. Cell. 2005;121(7):1109-1121.
8. Kubota Y, Takubo K, Suda T. Bone marrow long labelretaining cells reside in the sinusoidal hypoxic niche. Biochem Biophys Res Commun. 2008;366(2):335-339.
● ● ● LYMPHOID NEOPLASIA
Comment on Kikuchi et al, page 406
Proteasome and HDAC: who’s zooming
who?
---------------------------------------------------------------------------------------------------------------David McConkey
M. D. ANDERSON CANCER CENTER
Proteasome and HDAC inhibitors interact strongly to promote cell death in multiple myeloma and other human cancer cells. This study challenges current assumptions about the mechanisms underlying these interactions.
roteasome inhibitors (PIs) are the most
active therapies for multiple myeloma
(MM), but they do not produce cures, and
there is currently an aggressive effort to identify PI-based combinations that produce
greater clinical activity.1 Among the candidates identified in preclinical studies, combinations of PIs and histone deacetylase inhibitors (HDACis) appear to be among the most
P
potent, producing synergistic cytotoxicity in
preclinical MM models2,3 and in a variety of
other human solid and hematologic cancer cell
lines and xenografts.4 These studies prompted
the initiation of 2 phase 1 clinical trials to
evaluate the effects of combination therapy
with bortezomib plus vorinostat (also known
as SAHA, a pan HDACi) in refractory MM.
Although the results should be treated as pre-
liminary until phase 2 data are available, overall response rates in both trials were about
50%,1 suggesting that there will be benefit
from combining PIs and HDACis in patients.
Bortezomib appears to have greater singleagent activity than HDACis,1 supporting the
notion that HDACis work by enhancing bortezomib’s cytotoxic activity, and not vice versa.
As “targeted” agents, PIs and HDACis are
“dirty” drugs that no doubt work by many
different mechanisms.4 Early studies suggested that PIs might kill MM and other cancer cells by blocking the inflammation- and
cell survival–associated transcription factor,
NF␬B,4 but more recent data have challenged
this notion.5 Rather, there is greater consensus
for the idea that PIs induce MM cell death by
promoting proteotoxic protein build-up and
aggregation, mimicking certain neurodegenerative diseases.4 MM cells display a uniquely
high protein synthetic load and possess very
well-developed endoplasmic reticular-Golgi
networks, which may explain why PIs display
such uniquely high antitumor activity in the
disease.
Histone deacetylases can be grouped into
3 major subfamilies (type I, type II, and sirtuins) based on structural and functional homologies.6 The most familiar are the type I
HDACs (HDACs 1-3), which regulate chromatin structure by promoting histone deacetylation and chromatin compaction, although
type I HDACs can also alter the acetylation of
nonhistone proteins. Less is known about the
Two mechanistic explanations for PI-HDACi synergy. (A) HDAC inhibitors promote PI-induced proteotoxic stress. By blocking the proteasome, PIs promote the
accumulation of damaged and misfolded proteins that are prone to aggregation, and it is this protein aggregation that serves as the primary cytotoxic stress, causing
downstream reactive oxygen species (ROS) accumulation, JNK activation, and ER caspase (4 and 12) activation. HDACis promote this proteotoxic stress by blocking
HDAC6, which is required for “aggresome” formation and the transfer of protein aggregates to lysosomes via autophagy. (B) Proteasome inhibitors promote type I HDAC
inhibition. In this model, inhibition of type I HDACs serves as the primary cytotoxic stimulus, perhaps by promoting expression of “death genes” such as TNF-related
apoptosis-inducing ligand (TRAIL) and Bim, a BH3-only member of the BCL-2 family. PIs synergize with HDAC inhibitors by promoting caspase-8 activation, cleavage and
inactivation of Sp-1, and subsequent down-regulation of type I HDAC expression. Importantly, other studies have demonstrated that PIs promote TRAIL- and
Bim-dependent apoptosis, so they may also interact with the HDACi pathway downstream of their effects on Sp-1.
308
22 JULY 2010 I VOLUME 116, NUMBER 3
blood
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2010 116: 307-308
doi:10.1182/blood-2010-05-281238
Stem cells hold their breath
Gregor B. Adams
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