Vascular Stem/Progenitor Cell Migration Induced by Smooth Muscle Cell‐Derived Chemokine (C‐C Motif) Ligand 2 and Chemokine (C‐X‐C motif) Ligand 1 Contributes to Neointima Formation

Recent studies have shown that Sca‐1(+) (stem cell antigen‐1) stem/progenitor cells within blood vessel walls may contribute to neointima formation, but the mechanism behind their recruitment has not been explored. In this work Sca‐1(+) progenitor cells were cultivated from mouse vein graft tissue and found to exhibit increased migration when cocultured with smooth muscle cells (SMCs) or when treated with SMC‐derived conditioned medium. This migration was associated with elevated levels of chemokines, CCL2 (chemokine (C‐C motif) ligand 2) and CXCL1 (chemokine (C‐X‐C motif) ligand 1), and their corresponding receptors on Sca‐1(+) progenitors, CCR2 (chemokine (C‐C motif) receptor 2) and CXCR2 (chemokine (C‐X‐C motif) receptor 2), which were also upregulated following SMC conditioned medium treatment. Knockdown of either receptor in Sca‐1(+) progenitors significantly inhibited cell migration. The GTPases Cdc42 and Rac1 were activated by both CCL2 and CXCL1 stimulation and p38 phosphorylation was increased. However, only Rac1 inhibition significantly reduced migration and p38 phosphorylation. After Sca‐1(+) progenitors labeled with green fluorescent protein (GFP) were applied to the adventitial side of wire‐injured mouse femoral arteries, a large proportion of GFP‐Sca‐1(+)‐cells were observed in neointimal lesions, and a marked increase in neointimal lesion formation was seen 1 week post‐operation. Interestingly, Sca‐1(+) progenitor migration from the adventitia to the neointima was abrogated and neointima formation diminished in a wire injury model using CCL2(−/−) mice. These findings suggest vascular stem/progenitor cell migration from the adventitia to the neointima can be induced by SMC release of chemokines which act via CCR2/Rac1/p38 and CXCR2/Rac1/p38 signaling pathways. Stem Cells 2016;34:2368–2380