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