The impact of myogenic cell transplantation on collateral capillary arteriogenesis

Abstract

Current treatments for peripheral arterial occlusive disease (PAOD), including angioplasty and bypass grafting fail in up to 25% of patients, or are not indicated in up to 50%, so there is a need to develop additional treatment options. Patients with native collaterals have a better prognosis, so a treatment such as cell transplantation that promotes collateral arteriogenesis is a potential PAOD treatment. Unfortunately, bone marrow derived stem cells, the main cell type that has been investigated, have limited clinical effectiveness in enhancing pre‐existing collateral growth. Therefore, delivering a stem cell type native to the collateral‐containing tissue, such as myogenic stem cells, could have improved outcomes. Additionally, about 20% of patients never develop collaterals, and no one, to our knowledge, has evaluated the effect of cell therapy on collateral capillary arteriogenesis (CCA), which can reperfuse ischemic tissue in animals without native arteriolar collaterals and therefore represents a potential therapeutic target in patients who lack native collaterals. To test the hypothesis that myogenic cells enhance CCA, we ligated the spinotrapezius feed artery in Balb/C mice to induce CCA, and delivered myogenic cells, thrombin (positive control), or vehicle to the muscle. Seven days post ligation, ‐‐‐‐arterialized collateral capillary (ACC) number and diameter were determined. As expected, thrombin increased ACC number, but myogenic cells had no effect, 9.3 ± 0.5 vs 7.1 ± 0.4, respectively. However, myogenic cells increased ACC diameter as compared to untreated (12.1 ± 0.8 μm vs 10.3 ± 0.3 μm, respectively) and both myogenic cells and thrombin increased the maximum ACC diameter (29.9 ± 3.4 μm and 27.9 ± 2.0 μm vs 18.8 ± 1.1 μm, respectively). These results are consistent with previous studies indicating that thrombin enhances arteriogenesis and suggest that myogenic cells have a similar effect, but likely without the deleterious pro‐inflammatory effects of thrombin. Because myogenic cells increase arteriogenesis and macrophages are an essential part of arteriogenesis, we also tested the hypothesis that myogenic cells increase macrophage content by performing CD68 staining. Although macrophage number increased following ligation, neither myoblasts nor thrombin further increased macrophage number. The lack of difference in macrophage number despite enhanced CCA could be because the day‐7 timepoint was too late, as macrophages peak around day‐3, or because a shift towards either classically‐activated macrophages or alternatively‐activated macrophages, which have a greater effect on arteriogenesis, would not be detected by the CD68 stain. Therefore, future studies may include a day‐3 timepoint and a stain for alternatively‐activated macrophages.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.