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HARVARD
MEDICAL
SCHOOL
Matthias
Nahrendorf MGH Center for Systems Biologyhttp://csb.mgh.harvard.edu/investigator/matthias_nahrendorf
New Frontiers in
Atherosclerotic Disease
and Myocardial Infarction:
From local inflammation to
systemic stem and
progenitor cell reaction
Monocytes/macrophages in
atherosclerosis
Swirski & Nahrendorf, Science 2013;339:161-6
Monocytes/macrophages in
myocardial infarction
Swirski & Nahrendorf, Science 2013;339:161-6
Blood
monocytosis
Recruitment
Ly-6Chi
E
F
LV
dilation
Infarct
expansion
Protease
activity
Inflammatory
cyto/chemokine
s
Collagen
synthesis
Resolution of
inflammation
Atherosclerosi
s
Heart
FailureIm
pair
ed
in
farc
t he
alin
g a
fte
r pla
qu
e r
uptu
re
(e.g. MPO, TNF-α)
(e.g. MMPs,
cathepsins)
(e.g. reduced TGF-β)
Circulation 2010; 121:2437
Long-term
hematopoieti
c stem cell
Short-term
hematopoieti
c stem cell
Common
myeloid
progenitor
Granulocyte
Macrophage
progenitor
MacrophageMonocyte
Macrophage
dendritic cell
progenitor
Proliferation
Life span
Differentiation
Self renewal
Percentage quiescent cells
Bone marrow Blood
Spleen
Destinatio
n tissue
0
6
12
18****
MI
0.0
0.2
0.4
No MI MI
**
MINo MI
Long-term
hematopoieti
c stem cell
Short-term
hematopoieti
c stem cell
Common
myeloid
progenitor
Granulocyte
Macrophage
progenitor
MacrophageMonocyte
Macrophage
dendritic cell
progenitor
Bone marrow Blood
Spleen
Destinatio
n tissue
18F-FLT PETFACS Bone Marrow
Dutta P., Cell Stem Cell. 2015;16 (5):477-487
1 day before
Nestin
HSC
Osteoblast
Blood
3 days later
Bone marrow
Courties G et al., Circ Res 2015
Swirski & Nahrendorf, Science 2013
Dutta et al., Nature 2012
Rischpler et al., Circ Imaging 2016
18F-FDG PET/MRI in patients
18F-FDG PET in patients with acute MI
Tawakol et al., iJACC 2015
Sp
lee
nM
arr
ow
Infarct
correlation with carotid
Kim et al., Circ Cardiovasc Imaging 2014;7:454-460 Wollenweber et al., Circ Cardiovasc Imaging 2014;7:811-8
18F-FDG PET in patients with acute MI
Danger signals: IL-1β
Sager H. et al,
Circulation 2015
200
5
0
IL-1
β m
RN
A
10
******** *****
750
0
1500
Infa
rct IL
-1β
(pg/m
l)
no MI 24h 72h
MI
no MI 24h 72h
MI
Blo
od
IL-1
β (
pg/m
l)
125
0
250*****
no MI 24h 72h
MI
Marr
o
wIL
-1β
(pg/m
l)
100
0
200**
no MI 24h 72h
MI
3 days
3 days
14d
14d
FACS
MI
FACS
WT
WT
WT
WT
WT
WT
WT
WT
steady state
non-infarcted
parabiont
Sca-1
CD150
CD150
24
12
0
200
5
0
IL-1
β m
RN
A
10
******** *****
750
0
1500
Infa
rct IL
-1β
(pg/m
l)
3 days
3 days
3 days
14d
14d
14d
FACS
MI
WT FACS
MI
FACS
WT
WT
WT
WT
WT
WT
WT
WT
WT
steady state
non-infarcted
parabiont
non-infarcted
IL1R1-/- parabiont
no MI 24h 72h
MI
no MI 24h 72h
MI
Blo
od
IL-1
β (
pg/m
l)
125
0
250*****
no MI 24h 72h
MI
Marr
o
wIL
-1β
(pg/m
l)
100
0
200**
no MI 24h 72h
MI
Sca-1
CD150
CD150
IL1
R1
-/-
IL1
R1
-/-
24
12
0
Danger signals: IL-1β
Ly6C
CD11b
MI + Ctrl IgG MI + anti IL-1β
30
15
0
*5
10
0
*5
0
10
*
6
0
12
Anti IL-1β therapy: Infarct
Sager H. et al,
Circulation 2015
MI + anti IL-1βMI + Ctrl IgG
100
0
200
20
0
40
15
0
30
*
*
Anti IL-1β therapy
Sager H. et al,
Circulation 2015
14dflow
cytometry
21d
MI
14dflow
cytometry
21d
10
0
20
Ly6c
hig
hm
onocyte
s
/ml blo
od (
x10
4)
*
*
Non-circulating danger signals?
Sager H. et al, Science
Translational Med 2016
14dflow
cytometry
21d
MI
14dflow
cytometry
21d
10
0
20
Ly6c
hig
hm
onocyte
s
/ml blo
od (
x10
4)
*
*
5
0
ma
cro
ph
ag
es
/ao
rta
(x1
04)
2.5F4
/80Ly6C
56
9
55
9
*** *
**
tota
l p
laq
ue
siz
e
(mm
2)
0.3
0
0.6* *
Non-circulating danger signals!
Sager H. et al, Science
Translational Med 2016
*
no MI MI (2d)
0
7.5
15
no
rad
ren
alin
e p
er
ao
rtic
arc
h (
ng
/ml)
MI + 6OHDAMI
VCAM-1 E-SelectinICAM-2
0
1
2
M
A
M
A
PP
L L
tyrosine hydroxylase *
1 1.2 1.4 1.5
ICAM-1
ICAM-2
VCAM-1
E-Selectin
P-Selectin
1.1 1.3
*
*
*
Vascular sympathetic innervation ↑
Sager H. et al, Science
Translational Med 2016
Dan Anderson
James Dahlman
Endothelial
RNAi
Sager H. et al, Science
Translational Med 2016
0
1
0
1
0
1
0
1
0
1
VCAM-1
Co
un
t
ICAM-1 E-Selectin P-SelectinICAM-2
siCAM5siCtrlisotype control
0.5 0.5 0.5 0.5 0.5
ICAM-1 ICAM-2 E-SelectinVCAM-1 P-Selectin
Icam1 Icam2 SeleVcam1 Selp0
1
0
1
0
1
0
1
0
1
0.50.50.5 0.5 0.5
*
**
*
*
*
**
* *
Sager H. et al, Science
Translational Med 2016
GF
P
CD11b
GF
P+
ce
lls/a
ort
a
12.5
0
250.055 0.009
siCAM5siCtrl
*
ne
utr
op
hils
/ao
rta
(x1
03)
11
22
0
3
0
6 4
2
0
********
*********
*******
ma
cro
ph
ag
es/
ao
rta
(1
04)
Ly6
ch
igh
mo
no
cyte
s/a
ort
a
(10
3)
MI & siCtrl MI & siCAM5no MI athero
Recruitment ↓
Sager H. et al, Science
Translational Med 2016
siCAM5siCtrl
FMT/CT
30
0
60
pla
que s
ize
(mm
2)
0.6
0.3
0
******
*
necro
tic c
ore
(mm
2 x
10
-2)
3
0
6****
LV
-EF
(%
) 30
15
0
2.5
0
5
Ly6
ch
igh
monocyte
s
/mg
infa
rct
(x10
3)
*
*
*
MI & siCtrl
MI & siCAM5
no MI athero
Sager H. et al, Science
Translational Med 2016
Factors / Pathways ?
HSPC
Supply of inflammatory
leukocytes
Stress Lack of exerciseDiet Sleep deprivation Atherosclerosis
Nahrendorf & Swirski,
Circ Res 2015
CX
CL12 m
RN
A.05
0.1
*
nora
dre
nalin
e
(ng/m
l)
10
20*
TH
+are
a (
%)
5
10*
Tyrosine hydroxylase
HS
C (
10
3)
/ fe
mur
1
2 *
Brd
U+
HS
C (
%)
10
20
*
CD150
CD150
Control
HSC
Stress
proliferating HSC
Chronic psychosocial stress
activates bone marrow stem cells
Heidt / Sager et al.,
Nature Med. 2014;20(7):754-758
Chronic psychosocial stress
causes leukocytosis in mice
*
30
15
1
.5
**
4
2
*
Heidt / Sager et al.,
Nature Med. 2014;20(7):754-758
Chronic psychosocial stress
kindles inflammation in plaque
20
10
*
CD11b
Control Stress
32
16
% C
D1
1b
+
are
a
*
8
16
Ne
utr
op
hils
(10
4)
/ a
ort
a
2
1
Ly6
ch
igh
mo
no
cyte
s
(10
4)
/ a
ort
a
2
4
Ma
cro
ph
ag
es
(10
4)
/ a
ort
a
CD11b
**
Control Stress
*
Heidt / Sager et al.,
Nature Med. 2014;20(7):754-758
Amygdala
PET signal
Bone marrow PET signal r = 0.44
Spleen PET signal r = 0.5
Aortic PET signal r = 0.49
Fat PET signal r = 0.02
CVD risk OR 1.6
Tawakol et al., Lancet, in press.
Acknowledgements
Gabriel Courties
Timo Heidt
Hendrik Sager
Fanny Herisson
Kristy Stengel
Kevin King
Yoshiko Iwamoto
Kamila Naxerova
Yuan Sun
Benoit Tricot
Greg Wojtkiewicz
Fil Swirski
Partha Dutta
Mike Moskowitz
Marcelo Di Carli
Claudio Vinegoni
Scott Hiebert
David Scadden
Peter Libby
Ralph Weissleder
HARVARD
MEDICAL SCHOOL
Funding from NHLBI, AHA,
DFG, MGH Research
Scholarcsb.mgh.harvard.edu/nahrendorf