Angiogenic Role of MMP-2/9 Expressed on the Cell Surface of Early Endothelial Progenitor Cells/Myeloid Angiogenic Cells

Abstract

Since the introduction of angiogenic cell therapy using early endothelial progenitor cells (EPCs), myeloid angiogenic cells (MACs) have been expected to be useful in treating ischemic diseases. In order to elucidate the angiogenic properties of MACs/EPCs, we clarified the characteristics of MACs as compared to M2 macrophages (Mϕs). Comparison of the gene expression profiles of MACs and late EPCs revealed that MACs expressed greater amounts of metalloproteinase (MMP)-9. It should be noted that the profile of MMP-2/9 expression on the cell surface of MACs was similar to that of M2 Mϕs, and that cell surface MMP-2/9 might be an active form based on molecular size. In addition, the invasion of MACs was prohibited not only by MMP-2/9 inhibitor, but also by the hyaluronidase treatment that caused the down-regulation of MMP-9 on the cell surface of MACs and inhibited their invasion activity. These results indicate that cell surface MMP-2/9 plays an important role in the high invasion ability of MACs. The conditioned medium of both MACs and M2 Mϕs stimulated tube formation of endothelial cells in vitro. MACs caused an increase in vessel formation in in vivo models through the production of IL-8. We propose that the role of MACs with cell surfaces expressing MMP-2/9 is rapidly invading ischemic tissue.

The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1β

“…Likewise, there is also preclinical evidence to show that M2 polarized macrophages promote tissue repair in a model of retinal ischemia . While phenotypic and functional similarity have been shown between MACs and M2‐activated macrophages in our own lab and by others , this current study further characterized and distinguished MACs from the M2‐activated macrophage population (Fig. ).…”

Cell-Surface MMP-9 Protein Is a Novel Functional Marker to Identify and Separate Proangiogenic Cells from Early Endothelial Progenitor Cells Derived from CD133+ Cells

“…In order to differentiate CBMCs to early EPCs, we cultured CBMCs in 2% FBS endothelial cell growth medium (EGM)‐2 (Lonza) as reported . Two days after inoculation, floating cells were discarded, and the medium was changed every 2–3 days.…”

“…Cells (1.5 × 10 5 per well) were added to the inserts with 8‐μm‐pore size and allowed to invade for 23 hours against 10 ng/ml VEGF in the lower wells. The MMP‐2/9 inhibitor V (Calbiochem, La Jolla, CA, http://www.emdbiosciences.com) was used at a concentration of 500 nM, which inhibited the invasion of early EPCs from CBMCs completely . The cells invading the lower surface of the membrane were counted.…”

“…The sufficient characterization of CD31 bright cells remains to be elucidated, because of the difficulty of separating CD31 bright cells from CD31 + cells. However, we recently showed that early EPCs derived from CD14 + cells expressed metalloproteinase (MMP)‐2 and 9 proteins on the cell surface, resulting in high invasion ability similar to regulatory M2 macrophages which have a high ability to induce vascular formation, suggesting that the cell surface expression of MMP‐2/9 is a property of angiogenic cells .…”

Endothelial progenitor cells accelerate the resolution of deep vein thrombosis

“…Potentiates vascular endothelial growth factor-induced proliferation and network formation of endothelial progenitor cells; 2. Induces smooth muscle cell apoptosis [121][122][123] [44,131,132] Ang: angiopoietin; EPCs: endothelial progenitor cells; VSMCs: vascular smooth muscle cells; HGF: hepatic growth factor; IL6: Interleukin-6; IL8: Interleukin-8; NO: nitric oxide; NOS: nitric oxide synthase; eNOS: endothelial nitric oxide synthase; iNOS: inducible nitric oxide synthase; MMPs: metal matrix proteinases; uPA: urokinase plasminogen activator; tPA: tissue plasminogen activator; TGFβ: transforming growth factor-β; VEGF: vascular endothelial growth factor; PGI 2: prostaglandin I 2 ; PDGF: platelet-derived growth factor; SDF-1α: stromal cell-derived factor 1α.…”