A Functional Role of Matrix Metalloproteinase-8 in Stem/Progenitor Cell Migration and Their Recruitment into Atherosclerotic Lesions
Rationale: Accumulating evidence indicates that stem/progenitor cells 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 stem/progenitor cell migration and their recruitment into atheromas.
Methods and Results: We found that stem/progenitor cells in atheromas expressed MMP8 and that MMP8 knockout significantly reduced stem/progenitor cell numbers in atherosclerotic lesions in 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 stem/progenitor cells 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 MMP8 deficiency inhibited the ability of stem/progenitor cells to migrate from the arterial lumen and from the adventitia, into atherosclerotic lesions. In vitro assays indicated that MMP8 facilitated stem/progenitor cell migration across endothelial cells and through Matrigel or collagen I. We also found that MMP8 cleaved a-disintegrin-and-metalloproteinase-domain-10 (ADAM10) and that MMP8 deficiency reduced mature ADAM10 on stem/progenitor cells. Knockdown of MMP8 or incubation with the ADAM10 inhibitor GI254023X decreased E-cadherin shedding on stem/progenitor cells. The decrease in migratory ability of stem/progenitor cells with MMP8 knockdown was reduced by incubation of such cells with culture supernatant from stem/progenitor cells without MMP8 knockdown, and this compensatory effect was abolished by an antibody against soluble E-cadherin.
Conclusions: MMP8 plays an important role in stem/progenitor cell migration and their recruitment into atherosclerotic lesions.
- Received May 17, 2012.
- Accepted October 15, 2012.
- Copyright © 2012, American Heart Association