New Frontiers in Atherosclerotic Disease and Myocardial Infarction: From local inflammation to systemic stem and progenitor cell reaction
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1 New Frontiers in Atherosclerotic Disease and Myocardial Infarction: From local inflammation to systemic stem and progenitor cell reaction Matthias Nahrendorf MGH Center for Systems Biology HARVARD MEDICAL
2 Monocytes/macrophages in atherosclerosis Swirski & Nahrendorf, Science 213;339:161-6
3 Monocytes/macrophages in myocardial infarction Swirski & Nahrendorf, Science 213;339:161-6
4 Impaired infarct healing after plaque rupture Atherosclerosi s Blood monocytosis Recruitment Ly-6C hi Inflammatory cyto/chemokine s (e.g. MPO, TNF-α) Protease activity (e.g. MMPs, cathepsins) Resolution of inflammation (e.g. reduced TGF-β) Collagen synthesis Infarct expansion LV dilation E F Heart Failure Circulation 21; 121:2437
5 Bone marrow Blood Spleen Destinatio n tissue Long-term hematopoieti c stem cell Short-term hematopoieti c stem cell Common myeloid progenitor Granulocyte Macrophage progenitor Macrophage dendritic cell progenitor Monocyte Macrophage Differentiation Proliferation Percentage quiescent cells Life span Self renewal
6 Bone marrow Blood Spleen Destinatio n tissue Long-term hematopoieti c stem cell Short-term hematopoieti c stem cell Common myeloid progenitor Granulocyte Macrophage progenitor Macrophage dendritic cell progenitor Monocyte Macrophage 18 No FACS Bone Marrow. 18 F-FLT PET No Dutta P., Cell Stem Cell. 215;16 (5):
7 Bone marrow 1 day before 3 days later Nestin Blood HSC Osteoblast Courties G et al., Circ Res 215
8 Dutta et al., Nature 212 Swirski & Nahrendorf, Science 213
9 18 F-FDG PET/MRI in patients Rischpler et al., Circ Imaging 216
10 18 F-FDG PET in patients with acute Tawakol et al., ijacc 215
11 Marrow Spleen 18 F-FDG PET in patients with acute correlation with carotid Infarct Kim et al., Circ Cardiovasc Imaging 214;7: Wollenweber et al., Circ Cardiovasc Imaging 214;7:811-8
12 IL-1β mrna Infarct IL-1β (pg/ml) Blood IL-1β (pg/ml) Marro w IL-1β (pg/ml) Danger signals: IL-1β no 24h 72h no 24h 72h no 24h 72h no 24h 72h steady state non-infarcted parabiont 14d 3 days FACS 24 Sca-1 14d 3 days FACS 12 CD15 CD15 Sager H. et al, Circulation 215
13 IL-1β mrna Infarct IL-1β (pg/ml) Blood IL-1β (pg/ml) Marro w IL-1β (pg/ml) Danger signals: IL-1β no 24h 72h no 24h 72h no 24h 72h no 24h 72h steady state non-infarcted parabiont non-infarcted IL1R1 -/- parabiont 14d 3 days FACS 24 Sca-1 14d 3 days FACS 12 CD15 IL1R1 -/- 14d IL1R1 -/- 3 days FACS CD15
14 Anti IL-1β therapy: Infarct + Ctrl IgG + anti IL-1β CD11b Ly6C Sager H. et al, Circulation 215
15 Anti IL-1β therapy + Ctrl IgG + anti IL-1β Sager H. et al, Circulation 215
16 Ly6c high monocytes /ml blood (x1 4 ) Non-circulating danger signals? 14d 21d flow cytometry 14d 21d flow cytometry 2 1 Sager H. et al, Science Translational Med 216
17 Ly6c high monocytes /ml blood (x1 4 ) total plaque size (mm 2 ) F4/8 macrophages /aorta (x1 4 ) Non-circulating danger signals! 14d 21d flow cytometry d 21d flow cytometry Ly6C Sager H. et al, Science Translational Med 216
18 noradrenaline per aortic arch (ng/ml) Vascular sympathetic innervation no (2d) tyrosine hydroxylase L L P P M M A A + 6OHDA ICAM-1 ICAM-2 VCAM-1 E-Selectin ICAM-2 VCAM-1 E-Selectin P-Selectin Sager H. et al, Science Translational Med 216
19 Endothelial RNAi Dan Anderson James Dahlman Sager H. et al, Science Translational Med 216
20 Count isotype control sictrl sicam 5 ICAM-1 ICAM-2 VCAM-1 E-Selectin P-Selectin ICAM-1 ICAM-2 VCAM-1 E-Selectin P-Selectin Icam1 Icam2 Vcam1 Sele Selp Sager H. et al, Science Translational Med 216
21 neutrophils/aorta (x1 3 ) macrophages/ aorta (1 4 ) (1 3 ) GFP GFP + cells/aorta Recruitment sictrl.55.9 sicam CD11b Ly6c high monocytes/aorta no athero & sictrl & sicam 5 Sager H. et al, Science Translational Med 216
22 LV-EF (%) Ly6c high monocytes /mg infarct (x1 3 ) necrotic core (mm 2 x 1-2 ) plaque size (mm 2 ) sictrl sicam FMT/CT.3 no athero & sictrl & sicam Sager H. et al, Science Translational Med 216
23 Stress Diet Sleep deprivation Lack of exercise Atherosclerosis Factors / Pathways? HSPC Supply of inflammatory leukocytes Nahrendorf & Swirski, Circ Res 215
24 BrdU + HSC (%) noradrenaline (ng/ml) TH + area (%) CXCL12 mrna HSC (1 3 ) / femur Chronic psychosocial stress activates bone marrow stem cells Control Stress HSC Tyrosine hydroxylase 2 CD15 proliferating HSC 1 CD15 Heidt / Sager et al., Nature Med. 214;2(7):
25 Chronic psychosocial stress causes leukocytosis in mice Heidt / Sager et al., Nature Med. 214;2(7):
26 Chronic psychosocial stress Neutrophils (1 4 ) / aorta Ly6c high monocytes (1 4 ) / aorta Macrophages (1 4 ) / aorta kindles inflammation in plaque Control Stress Control Stress 2 1 CD11b CD11b % CD11b + area Heidt / Sager et al., Nature Med. 214;2(7):
27 Amygdala PET signal Bone marrow PET signal r =.44 Spleen PET signal r =.5 Aortic PET signal r =.49 Fat PET signal r =.2 CVD risk OR 1.6 Tawakol et al., Lancet, in press.
28 Acknowledgements Fil Swirski Partha Dutta Mike Moskowitz Marcelo Di Carli Claudio Vinegoni Scott Hiebert David Scadden Peter Libby Ralph Weissleder Gabriel Courties Timo Heidt Hendrik Sager Fanny Herisson Kristy Stengel Kevin King Yoshiko Iwamoto Kamila Naxerova Yuan Sun Benoit Tricot Greg Wojtkiewicz csb.mgh.harvard.edu/nahrendorf Funding from NHLBI, AHA, DFG, MGH Research Scholar HARVARD MEDICAL SCHOOL
HARVARD MEDICAL SCHOOL
The Role of the Various Monocyte Types in Atherothrombotic Disease Protective vs. Detrimental Effects and Therapeutic Implications Matthias Nahrendorf MGH Center for Systems Biology http://csb.mgh.harvard.edu/investigator/matthias_nahrendorf
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