Role of CXCR2 in the Ac-PGP-Induced Mobilization of Circulating Angiogenic Cells and its Therapeutic Implications

Abstract

Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N‐acetylated proline‐glycine‐proline (Ac‐PGP; a collagen‐derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac‐PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac‐PGP on blood perfusion and CAC mobilization (Sca1+Flk1+ cells) into peripheral blood were assessed. Intramuscular administration of Ac‐PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac‐PGP‐induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2‐knockout mice. In addition, Ac‐PGP‐induced CAC mobilization was found to occur in wild‐type mice but not in CXCR2‐knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild‐type mice showed bone marrow‐derived cells homed to ischemic limbs after Ac‐PGP administration and that GFP‐positive cells contributed to the formation of ILB4‐positive capillaries and α smooth muscle actin (α‐SMA)‐positive arteries. These results suggest CXCR2 activation in bone marrow after Ac‐PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. Stem Cells Translational Medicine 2019;8:236&246

Combined administration of laminin-221 and prostacyclin agonist enhances endogenous cardiac repair in an acute infarct rat heart

“…4 ). On the other hand, the number of mature capillaries 12 , 13 indicated with ILB4-positive vessels 14 undercoated with SMA-positive cell in LM221- and ONO1301-administrated hearts (240.6 ± 15.5 cells/mm 2 ) tended to be higher than that in LM221-administrated hearts (153.8 ± 10.4 cells/mm 2 cells/mm 2 ). In addition, the number of mature capillaries in LM221- and ONO1301-administrated hearts significantly increased compared to that in control hearts (57.9 ± 8.4 cells/mm 2 , p < 0.05) and ONO1301-administrated hearts (83.7 ± 0.7 cells/mm 2 , p < 0.05) (Fig.…”

Increasing The Therapeutic Potential Of Stem Cell Therapies For Critical Limb Ischemia

“…Recently, new strategies have been developed to increase stem/progenitor cells in the circulatory system. Kwon et al administered daily Intramuscular (IM) injections of Ac-PGP (N-acetyl Proline-Glycine-Proline, a collage-derived chemotactic tripeptide) to a murine model of hindlimb ischemia and evaluated the extent of progenitor cell mobilization (Sca1 + Flk1 + cells)and the effects on ischemic limb reperfusion in a hindlimb ischemia model [ 21 ]. The same investigators had previously shown that this peptide, which is a byproduct of collagen breakdown by Matrix Metalloproteinase (MMP) and prolyl endopeptidases [ 22 ], was able to accelerate wound neovascularization and wound repair by promoting homing and engraftment of exogenous human Endothelial Progenitor Cells (EPCs) in the setting of tissue ischemia [ 23 ].…”

“…The same investigators had previously shown that this peptide, which is a byproduct of collagen breakdown by Matrix Metalloproteinase (MMP) and prolyl endopeptidases [ 22 ], was able to accelerate wound neovascularization and wound repair by promoting homing and engraftment of exogenous human Endothelial Progenitor Cells (EPCs) in the setting of tissue ischemia [ 23 ]. In their more recent work, IM injections of Ac-PGP improved limb reperfusion, and increased mobilization of progenitor cells [ 21 ]. Zhang et al, have also demonstrated a therapeutic increase in circulating EPCs and enhancement of their homing and angiogenic activity via the administration of recombinant growth differentiation factor-11 (rGDF11) [ 24 ].…”

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“…Recent evidence suggests that vascular repair requires circulating angiogenic cells (CAC), although it has also been shown that highest risk patients have low numbers of poorly migratory CAC . In a recent article in Stem Cells Translational Medicine , Kwon et al investigated the role of N‐acetylated proline‐glycine‐proline (Ac‐PGP) in mediation of angiogenesis, ischemic tissue repair, and mobilization of CAC in a mouse model of hind limb ischemia (HLI) . They found that intramuscular administration of Ac‐PGP into ischemic limbs of surgically induced HLI mice significantly increased angiogenesis and reduced necrosis.…”

“…Understanding the specific pathway used by this chemical can shed light on other potential strategies for intervention in the recruitment of stem cells in bone repair. In a related article, Kwon et al examined the use of N‐acetylated proline‐glycine‐proline (Ac‐PGP) to induce mobilization of angiogenic cells to promote revascularization in a mouse model of peripheral arterial disease . Overcoming hurdles of cell mobilization and recruitment is essential for the success of autologous stem cell therapies.…”