DOI: 10.1161/CIRCULATIONAHA.112.151696
A Quick Fix? Short-Term CXCR4 Inhibition Redistributes Pro-Angiogenic
Bone Marrow Cells to Ischemic Myocardium in an eNOS-Dependent Fashion
Running title: Limbourg; Single-shot CXCR4 inhibitor in myocardial ischemia
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Florian P. Limbourg, MD
ermany
Dept of Nephrology and Hypertension, Hannover Medical School, Hannover, G
Germany
Address
Add
Ad
dr forr Correspondence:
dress
C rr
Co
rresp
ponden
en
ncee:
Flor
oria
iann P.
P. Limbourg,
Lim
mbo
b ur
urg,
g, M
D
Florian
MD
Professor, V
ascu
as
cula
cu
laar Me
M
d ci
di
cine
ne an
nd Transplantation
Tran
Tr
nsp
spla
lant
la
ntat
nt
atio
at
ionn Re
io
Rese
ear
arch
ch
Vascular
Medicine
and
Research
Department of Nephrology and Hypertension and Excellence Cluster Rebirth
Hannover Medical School
30625 Hannover, Germany
Tel: 49-511-5329589
Fax: 49-511-5329783
E-mail: [email protected]
Journal Subject Codes: [129] Angiogenesis; [151] Ischemic biology - basic studies
Key words: bone marrow mononuclear cells; Editorials; myocardial infarction
1
DOI: 10.1161/CIRCULATIONAHA.112.151696
Autologous cell therapy with bone marrow (BM)-derived pro-angiogenic cells is a promising
new treatment modality to enhance ischemic recovery after myocardial infarction. However, the
introduction into the clinical mainstream is hampered by technical challenges with cell
procurement, handling, selection, expansion and application. In this issue of Circulation, Jujo et
al. show that mobilization of endogenous cells by a clinically approved drug inhibiting the
CXCR4 receptor improves myocardial recovery after infarction in a mouse model of
ischemia/reperfusion (IR).1
The key finding of this study is that a single dose of the highly specific and short-acting
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
CXCR4 antagonist AMD3100 (AMD), a bicyclam also known as plerixafor, reduces early
infarct
nfarct size and adverse cardiac remodelling when administered immediately at tthe
he ttime
he
im
me of
reperfusion
eperfusion after coronary ligation. Interestingly, experiments in BM chimeric mice revealed that
the
he pr
prot
protective
otec
ot
eccti
tive
ve eff
effect
fffec
ectt of AMD treatment required
d eendothelial
ndothelial NO ssynthase
y th
yn
has
asee (eNOS) expression in
BM,, but not in
BM
n pperipheral
errip
phe
h raal ti
tiss
tissues,
ssuues,
ss
ues, ssince
incce m
in
mice
icee rreconstituted
eco
onsstitu
uted wi
with
th eeNOS-deficient
NOSNOSS-deefi
fici
cieent
ci
ent (K
(KO)
O) bbone
onee
on
marrow
while
eNOS
KO
with
wildtype
ma
arr
r ow ddid
id
d not
not benefit
ben
nef
efiit ffrom
rom
ro
m AM
AMD
D trea
ttreatment,
reaatm
men
ent, w
hilee eN
NOS K
O mice
mice rreconstituted
ecoonst
onsttit
itut
u ed
ut
dw
ithh wild
w
ild
dty
type
p
pe
bone marrow
w sh
show
showed
ow
wed
e a rreduction
ed
duc
ucti
t on iin
n in
infa
infarct
farc
fa
rctt si
rc
size
ze aand
n ffibrosis.
nd
ibro
ib
rosi
ro
sis.
si
s.. A
AMD
MD ttreatment
reat
re
atme
at
ment
me
n iincreased
nt
ncre
nc
reas
re
ased
as
e baseline
and ischemic levels of circulating CXCR4+ and Sca-1+/Flk1+ mononuclear cells (MNC)
compared to control injection, and enhanced recruitment of Tie2-GFP BM-derived cells to the
ischemic myocardium, while levels of Tie2-GFP cells decreased in BM. AMD treatment also
increased BM eNOS expression, possibly by directly increasing eNOS promoter activity,
upregulated BM matrix metalloproteinase (MMP)-9, and enhanced processing of soluble kit
ligand (sKitL), a key hematopoietic growth factor pathway regulated by NO. Notably, although
AMD was administered just once after induction of ischemia, the biological effects on cell
mobilization and growth factor pathway regulation were sustained over several days and required
2
DOI: 10.1161/CIRCULATIONAHA.112.151696
eNOS expression in BM cells.
The CXCR4 chemokine receptor mediates retention and mobilization of BM-derived
cells in cellular milieus expressing its cognate chemokine ligand SDF-1 (CXCL12), thereby
coordinating distribution of cells during development and homeostasis.2 CXCR4 is the only
identified receptor for SDF-1 and the interaction of SDF-1 with CXCR4 appears to be unique
and non-promiscuous, with the exeption of the chemokine MIF, which also binds CXCR4.
CXCR4 is abundantly expressed in the hematopoietic system. It is expressed in mature
leukocytes, such as neutrophils, monocytes and T cells,3 but also in BM progenitor and
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
hematopoietic stem cell populations, some of which have pro-angiogenic effects.4, 5 In addition,
CXCR4 is also expressed in resident tissues, particularly endothelial and stroma
stromal
al ce
cells
ell
llss in B
BM,
M,
M,
which also constitutively express and secrete the cognate ligand SDF-1. A unique function of
BM
M endothelial
end
ndot
othe
ot
heli
he
lial and
and
nd stromal cells is that they enrich
enr
nrric
i h SDF-1 in thee BM
BM microenvironment
micr
mi
c oenvironment by
CXCR4-dependent
translocation
SDF-1
across
barrier,
which
CXCR4-depend
CXC
nd
den
entt tr
tra
ansl
sloc
sl
ocaatio
oc
atio
ionn of ffunctional
unctionnal
nal SD
DF-1 ac
acro
rosss tthe
he bblood-BM
lood
lo
odd-B
BM ba
barr
rrie
ieer,
r w
h ch iiss
hi
mediated
me
edi
diat
ated
at
ed by
by transcytosis
tran
tr
an
nsccyt
y osis
osiss and
andd regulates
reg
gul
ulat
a ess arrest
at
arr
rres
estt and
es
and
n adhesion
addheesio
ionn off transplanted
io
traansspl
plan
an
nteed hematopoietic
hem
he
mato
mato
opo
poieeticc
cells.
progenitor cel
ellls
ls..6 During
Dur
u in
i g tissue
tiiss
ssue
u injury
ue
inj
njur
uryy or ischemia,
ur
isc
sche
hemi
he
m a, such
mi
such
h as
as myocardial
myoc
my
ocar
oc
ardi
d al infarction
di
inf
nfar
arct
ar
ctio
ionn or limb
io
lim
imb
ischemia, SDF-1 expression shifts to non-hematopoietic sites in ischemic organs, where the
amplitude of hypoxia directly correlates with SDF-1 expression, and is released into the
circulation while SDF-1 levels in BM decrease.7, 8 In addition to injured tissues, platelets are a
major source of SDF-1, which express and release SDF following cytokine-induced activation,
which is a major determinant in ischemic cell recruitment and neovascularization.4
Is the timing of AMD treatment important?
SDF-1 interaction with CXCR4 mediates retention of cells at sites of production or storage, but
also retention in ischemic tissues, where it retains cells in a perivascular location.4, 9 Thus,
3
DOI: 10.1161/CIRCULATIONAHA.112.151696
redistribution of CXCR4+ cell populations from BM to ischemic tissues by CXCR4 antagonism
is dependent on spatial and temporal SDF-1 gradients and requires precise timing. This was
demonstrated by a recent report from this group showing that a single dose of AMD preserved
cardiac function in a permanent ligation model, while continuous administration worsened
cardiac function.10 The detrimental effects of long-term AMD administration were also reported
previously in peripheral ischemia models, in which the loss of ischemic cell retention by chronic
AMD treatment lead to impaired angiogenesis and ischemic recovery.4, 9 Jujo et al. now show
that in the IR mouse model, induction of SDF-1 mRNA in ischemic regions of the heart is
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
delayed until day 3 after IR. The short half-life of AMD seems to be advantageous in this setting.
Unless the half-life of the compound, which is cleared mainly by renal excrection,
excrectio
on, iiss
ignificantly altered by myocardial dysfunction, it is likely that the effects of AMD, when
significantly
ad
dmi
mini
nist
ni
ster
st
erred in a sin
ssingle
ingle dose at time of reperfus
sio
ionn, are limited too thee fi
fir
rs 24 hours, thus
rst
administered
reperfusion,
first
eleeas
a ing cellss from
from
m the
the bone
bon
onee marrow
marrrow
marr
w without
withouut
ut interfering
inteerfferin
in
ng with
with
th
h delayed
delaayed
ayed
d ischemic
issch
chem
emic
em
ic retention.
ret
e enti
enti
tionn.
releasing
Ho
ow can
can a short-acting
shor
sh
orrtt-ac
a tiingg drug
ac
dru
ug antagonizing
anta
an
tago
ta
goni
nizi
ni
zin
zi
ng CXCR4
C CR
CX
CR44 develop
deve
de
velo
ve
op sustained
sust
sust
stai
a ned
ai
d effects
efffe
fect
c s on
ct
How
hematopoieti
tiic gr
grow
owth
ow
th
h ffactor
accto
torr si
sign
g al
gn
a in
ng an
and
d ce
elll m
o illiz
ob
izat
atio
at
ion
io
n in
i the
the BM?
BM?
hematopoietic
growth
signaling
cell
mobilization
While SDF-1 expression in ischemic tissues is essential for cell retention, elevation of SDF-1 in
response to stress also induces mobilization of BM cells over a period of several days. This
seemingly contradictory action of SDF-1 involves paracrine signaling mediated by hematopoietic
growth factor shedding in the BM microenvironment. SDF-1 induces the activation of MMP-9,
expressed in stromal and hematopoietic cells, and the shedding of sKitL, a stem-cell active
chemokine. This induces translocation and mobilization of early BM progenitors from the
quiescent to the permissive proliferative vascular niche, from which cells are launched into the
circulation.11 This pathway is regulated by eNOS at several levels: CXCR4 signaling is eNOS-
4
DOI: 10.1161/CIRCULATIONAHA.112.151696
dependent, and upregulation of MMP-9 and release of sKitL are impaired in eNOS KO mice.12, 13
Interestingly, a single dose of AMD injected under steady-state conditions has been shown to
increase circulating levels of SDF-1 and mobilize hematopoietic progenitors through CXCR4dependent active secretion of SDF-1 by BM stromal cells.14 Although SDF-1 levels in plasma or
BM were not measured in the current study by Jujo and colleagues, it is possible that AMD
treatment in the setting of ischemia results in early and prolonged release of significant amounts
of SDF-1 in BM, thereby initiating a molecular cascade leading to sKitL shedding. This would
induce stem cell mobilization, but also further boost SDF-1 levels, since sKitL induces SDF-1
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
release from platelets.4 Although the cell type mediating these effects of AMD remains
unknown, the study by Jujo et al. demonstrates that BM-derived eNOS is a neces
necessary
esssa
sary
r
intermediate.
ntermediate. Interestingly, a subpopulation of reticular BM stromal cells distinct from
en
endothelial
ndo
doth
thel
th
elia
el
iall cells
ia
ceellss or osteoblasts
osteoblasts has recently been
n id
ide
identified
entified to be tthe
h m
he
main
ainn source of BM SDF-1
ai
expression
ex
xpr
pres
e sion byy elegant
elleg
egan
nt transgenic
trran
ansg
sgen
sg
enic
en
ic reporter
rep
epor
orrte
ter studies.
stud
udies.5 The
ud
Thee qquestion
uest
ue
stio
i n wh
io
whet
whether
ethe
h r SD
SDF-1
DFF-11 medi
m
mediates
edi
diat
ates
ess tthe
h
he
ef
effects
ffe
fect
ctts of A
AMD
M ttreatment
MD
reeat
atm
ment
ment
n is of ssome
omee im
om
importance,
mpo
port
rtan
rt
nce
c , si
since
incce it m
may
ay
y hhave
a e cl
av
cclinical
inical iimplications.
ini
mpli
mp
liica
cattion
onns.
Which cell types
typ
ypes
e contribute
es
con
o tr
trib
i ut
utee to
om
myocardial
yoca
yo
ard
rdia
iall re
ia
repa
repair?
pair
pa
ir??
ir
Jujo et al. postulate that the effects of AMD treatment are mediated by progenitor cells, including
endothelial progenitors, based on the description of the mobilization of Sca-1+/Flk-1+ cells and
myocardial recruitment of BM-derived Tie2-GFP+ cells. However, the data are not unequivocal.
For example, Sca-1 is expressed by BM EC, and circulating EC are detected in many vascular
disease settings.5, 15 Furthermore, contrary to the statement of Jujo and colleagues, Tie2
expression is not a feature specific to EC, but also found in different lineages of the
hematopoietic system including monocytes/macrophages.4, 16 Of note, CXCR4-mediated
mobilization and ischemic recruitment required for neovascularization has been shown to
5
DOI: 10.1161/CIRCULATIONAHA.112.151696
involve VEGFR1+/CXCR4+ and CD11b+/CX3CR1+/CXCR4+ cells consistent with monocytes,
which are mobilized into peripheral blood after a single dose of AMD in humans.4, 9, 17
Unfortunately, CXCR4+ leukocyte subsets were not studied by Jujo et al..
What are the clinical implications?
Short term AMD treatment as adjunct therapy for acute myocardial revascularization might
simplify the concept of cell therapy by circumventing the problems of cell procurment, selection
and administration, instead introducing a concept of mobilization of endogenous cell populations
supporting myocardial recovery. However, a key issue will be the timing of the AMD
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
administration relative to the duration of ischemia and the expression of SDF-1 in ischemic
issues, since inhibiting recruitment of circulating cells to ischemic sites could bee ddetrimental.
e riime
et
ment
ntal
nt
al.. At
al
tissues,
the
he same time, patients with chronic ischemia would not be expected to benefit from this kind of
reaatm
tmeent
ent,
t, since
sin
ince appropriate
appropriate
pp
mo
ostly absent in thi
is situ
uat
atiion.
io 18
treatment,
homing cues are mostly
this
situation.
The effects
efffe
fecctss off short-term
sho
hort
rt-t
rt
-ter
-t
erm
er
m AMD
AMD treatment
treattment in thee acute
acutee setting
acu
setttinng might
se
might
ght be further
furrth
ther
e eenhanced
er
nhhan
ance
ced
ce
by another
ano
noth
t er class
th
cla
lass
ss off drugs
drug
dr
ugss interfering
ug
inte
in
teerffer
erin
ingg with
in
with
h SDF-1
SDF
DF-1
-1 inactivation,
inacttiv
vat
atio
ion,
io
n, e.
e. g.
g. dipeptidylpeptidase
d pept
di
pept
ptid
idyl
ylpe
yl
pept
pe
ptid
pt
idaasee IV
id
V ((DPP
DPP
DP
P
IV)
V) inhibitors,
inhibitors
rs,, or
o gliptins.
gli
lipt
ptin
pt
in
ns. DPP
DPP
P IV
IV cleaves
clea
cl
eaave
vess and
and inactivates
inac
in
acti
ac
tiiva
vate
tess SDF-1
te
SDFSD
F 1 and
Fan
nd ph
phar
pharmacological
arma
ar
m co
ma
colo
logi
lo
gica
gi
c l inhibition
ca
n
of DPP IV improves cell recruitment and myocardial recovery after infarction.19
However, if the effects of single-administration AMD are mediated by amplifying the
release of SDF-1 from BM or platelets then the use of heparin-based anticoagulation in the acute
setting could counteract the efficacy of AMD treatment, since heparin binds SDF-1 as well as
CXCR4 and inhibits CXCR4 signaling.20 In addition, the use of effective anti-platelet therapy
might further decrease AMD efficacy by decreasing the availability of SDF-1 from platelets. One
last question remains: Considering that the AMD effects require eNOS, can this treatment work
in patients with cardiovascular disease, who have impaired NO bioavailability?
6
DOI: 10.1161/CIRCULATIONAHA.112.151696
Funding Sources: FPL is supported by funding from the Deutsche Forschungsgemeinschaft, the
Cluster of Excellence REBIRTH, the German Federal Ministry of Education and Research, and
the German-Israeli-Foundation.
Conflict of Interest Disclosures: None.
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16
6. Pucci
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Ven
nneeri MA,
MA, Biziato
Bizzia
i to
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D, Nonis
No A,
A, Moi
oi D,, Sica
Sic
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Di Serio
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isti
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ggene
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n tu
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re sshared
haareed by
by ttumor-infiltrating
umoor-inf
um
nfil
nf
iltr
il
traatin
tr
ingg ti
in
ttie2-expressing
e2-e
e2
- xpre
-e
xpress
sssin
ng mo
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8
A Quick Fix? Short-Term CXCR4 Inhibition Redistributes Pro-Angiogenic Bone Marrow Cells
to Ischemic Myocardium in an eNOS-Dependent Fashion
Florian P. Limbourg
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