Background Emerging evidence has suggested that adventitia stem/progenitor cells (Ad-SPCs) migrate into intima in response to injury, where they differentiate toward smooth muscle cells (SMCs) and participate in neointima hyperplasia. Matrix metalloproteinase-8 (MMP-8) has potent proteolytic activity on various matrix proteins, and has been shown to be able to cleave many important chemokines/cytokines/growth factors. We have previously identified MMP-8 as a key determinant in atherosclerosis formation and progression, stem cell mobilisation to atherosclerotic plaques, atherosclerotic angiogenesis, angioplasty restenosis as well as macrophage differentiation/polarisation. However, little is known about the functional involvements of macrophage-derived MMP-8 in SMC differentiation from Ad-SPCs and its contribution to neointima hyperplasia.
Purpose In this study, we aimed to investigate the functional roles of macrophage-derived MMP-8 in Ad-SPC differentiation and injury-induced arterial remodelling.
Methods and results By using Ad-SPCs isolated from MMP-8 knockout (MMP_KO) and control wild-type (WT) mice, we observed no significant difference in terms of SMC differentiation induced by TGF-β between WT and MMP-8_KO Ad-SPCs. Further analysis showed that Ad-SPCs expressed a very low level of MMP-8. However, macrophages and Ad-SPCs co-culture studies showed that while WT macrophage could significantly promote MMP-8_KO Ad-SPC differentiation towards SMCs, such differentiation processes was dramatically impaired when the Ad-SPCs were co-cultured with MMP-8_KO macrophages. Moreover, we found that the MMP-8 protein secreted from macrophages was responsible for SMC differentiation from Ad-SPCs. Mechanistically, our data revealed that MMP-8 promoted TGF-β secretion from macrophages and increased its bioactivity, triggering SMC differentiation. Additionally, we showed that macrophages-derived MMP-8 activated Notch1 Signalling through increasing the cleavage of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in Ad-SPCs, and the activated Notch1 signalling promoted SMC differentiation from Ad-SPCs. We further demonstrated that the binding site for CBF1, Suppressor of Hairless, and Lag-1 (CSL) within SMC gene promoters is responsible for Notch1 mediated SMC differentiation from Ad-SPCs. Finally, by using a well-established arterial remodelling model and macrophage transplantation we demonstrated that macrophage-derived MMP-8 increased neointima SMC hyperplasia by promoting Ad-SPC differentiation towards SMCs in response to vascular injury.
Conclusions We have identified macrophage-derived MMP-8 as a critical regulator in SMC differentiation from Ad-SPCs and neointima SMC hyperplasia in response to injury. Our data provide new insight into the roles of MMP-8 in Ad-SPC differentiation and the pathogenesis of neointima formation and/or angiographic restenosis, and aid the development of novel therapeutic agents for the prevention of these diseases.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.