Abstract 12390: Pro-angiogenic Mesenchymal Stem Cells Reside in Skeletal Muscle and are Potentiated by Erythropoietin
Mesenchymal stem/progenitor cells (MSCs) exist in multiple organs such as bone marrow, adipose tissue and skeletal muscle. Skeletal muscle MSCs (smMSCs) have shown to be associated with fat accumulation and fibrosis in degenerated muscle tissues, but it is not determined whether the smMSCs are involved in intrinsic reparative mechanisms in injured muscles after ischemic event. Here we report that smMSCs have pro-angiogenic property and are activated via erythropoietin receptor (EpoR) signaling. In rat ischemic limbs, smMSCs were detected in perivascular area. The smMSCs were immunopositive for platelet derived growth factor receptor (PDGFR)-α and produced vascular endothelial growth factor (VEGF). The smMSCs were isolated from adult rat hindlimb skeletal muscle and cultured. ELISA assay demonstrated that VEGF concentration was significantly higher in conditioned medium from the smMSCs than in conditioned media from rat skeletal myoblasts and bone marrow MSCs. The smMSC-conditioned medium significantly promoted endothelial tube formation in culture study (20% increase, p< 0.05 vs. control). Implantation of the smMSCs (5x 106 cells) into ischemic limbs also accelerated neovascularization in rats (vessel density, 0.40± 0.06 in the smMSC (n= 9) vs. 0.27± 0.10 in the control (n= 9), p< 0.01). Since we identified EpoR in smMSCs, effect of Epo on the cells was examined. Recombinant Epo significantly induced proliferation of the cultured smMSCs (15% increase of cell number, p< 0.01 vs. control), whereas endothelial cells were not propagated by the Epo treatment. Epo significantly enhanced phospholyration of Akt and STAT3 and transcription of VEGF in the smMSCs. There were significant increases in number of Ki67-positive cells in perivascular area (15± 8% vs. 5± 3%, p< 0.05), capillary density (0.62± 0.24 vs. 0.25± 0.11, p< 0.01) and blood flow recovery index (0.88± 0.05 vs. 0.81± 0.06, p< 0.05) in the rat ischemic limbs treated with Epo (n= 11) compared with the controls (n= 11). The perivascular proliferating cells were PDGFR-α-positive smMSCs. Taken together, results of the present study indicate that resident smMSCs contribute to neovascularization after limb ischemia, which is potentiated by erythropoietin.
- © 2012 by American Heart Association, Inc.