Functional role of matrix metalloproteinase-8 in stem/progenitor cell migration and their recruitment into atherosclerotic lesions.
BACKGROUND
Accumulating evidence indicates that stem/progenitor cells (SPCs) represent an important source of cells in atheromas and contribute to lesion formation and progression.


OBJECTIVE
We investigated whether matrix metalloproteinase-8 (MMP8) played a role in SPC migration and their recruitment into atheromas.


RESULTS
We found that SPCs in atheromas expressed MMP8 and that MMP8 knockout significantly reduced SPC numbers in atherosclerotic lesions in apolipoprotein E (ApoE)-deficient mice fed a Western diet. Further in vivo experiments showed that ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(-/-) mice had fewer SPCs in atheromas and smaller lesions than ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(+/+) mice. Ex vivo experiments showed that MMP8 deficiency inhibited the ability of SPCs to migrate from the arterial lumen and the adventitia into atherosclerotic lesions. In vitro assays indicated that MMP8 facilitated SPC migration across endothelial cells and through Matrigel or collagen I. We also found that MMP8 cleaved a-disintegrin-and-metalloproteinase-domain-10 and that MMP8 deficiency reduced mature a-disintegrin-and-metalloproteinase-domain-10 on SPCs. Knockdown of MMP8 or incubation with the a-disintegrin-and-metalloproteinase-domain-10 inhibitor GI254023X decreased E-cadherin shedding on SPCs. The decrease in migratory ability of SPCs with MMP8 knockdown was reduced by incubation of such cells with culture supernatant from SPCs without MMP8 knockdown, and this compensatory effect was abolished by an antibody against soluble E-cadherin.


CONCLUSIONS
MMP8 plays an important role in SPC migration and their recruitment into atherosclerotic lesions.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK. q.xiao@qmul.ac.uk
Qingzhong
Q
Xiao
Feng
F
Zhang
Luyang
L
Lin
Changcun
C
Fang
Guanmei
G
Wen
Tsung-Neng
TN
Tsai
Xiangyuan
X
Pu
David
D
Sims
Zhongyi
Z
Zhang
Xiaoke
X
Yin
Binia
B
Thomaszewski
Boris
B
Schmidt
Manuel
M
Mayr
Ken
K
Suzuki
Qingbo
Q
Xu
Shu
S
Ye
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic; D011480:Protease Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
C555398:3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide; D000950:Antigens, Ly; D001057:Apolipoproteins E; D015415:Biomarkers; D015820:Cadherins; D024042:Collagen Type I; D004151:Dipeptides; D006877:Hydroxamic Acids; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D011480:Protease Inhibitors; D049452:Green Fluorescent Proteins; D051722:ADAM Proteins; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8