Abstract 541: Differential Effects of IGF-1 and VEGF on Migration, Proliferation and Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells
Insulin-like growth factor 1 (IGF-1) induces proliferation, differentiation and survival of multiple cell types, but its effects on stem cells have not been addressed. We determined the effects of IGF-1 (0 –10 ng/ml) and VEGF (0 –10 ng/ml) on migration, proliferation and differentiation of bone marrow-derived mesenchymal stem cells (MSC) from C57BL/6 green mice. MSC expressed high levels of IGF-1 receptor (IGF-1R) (western blot), and very low levels of VEGFR2 (flow cytometry). Consistent with receptor expression, we found that IGF-1 had more potent biological effects on MSC than VEGF. IGF-1 increased CXCR4 (receptor for stromal cell-derived factor-1α, SDF-1α) (IGF-1: 2.4 fold increase; VEGF: 1.2 fold increase), and the levels of matrix metalloproteinase-9 (MMP9) (5 ng/ml of IGF-1, 1.95 ± 0.13 fold increase; 10 ng/ml of IGF-1 1.66 ± 0.16 fold increase, p <0.01) and stem cell factor (SCF) (control= 105.2 ± 2.8 pg/ml; IGF-1= 157.3 ± 10.9 pg/ml, p<0.05), but VEGF did not. IGF-1 or VEGF alone did not increase MSC eNOS mRNA expression. IGF-1 more potently reduced ICAM and VCAM expression compared with VEGF (IGF-1: 66.3% and 30% decrease; VEGF: 39% and 12% decrease, respectively). We used an EndoCult Liquid Medium and fibronectin-coated culture system to stimulate the differentiation of MSC into endothelial cells (EC), and to determine potential effects of IGF-1 on MSC differentiation. During the differentiation process, we found that the size of cells became smaller, c-Kit expression decreased, and CD14 expression increased as determined by flow cytometry. Interestingly, IGF-1 prevented the decrease in c-Kit expression, the increase in CD14 expression, but did not alter VEGFR2 expression and DiI-Ac-LDL uptake during the differentiation process. VEGF (10 ng/ml, 48 h) significantly increase VEGFR2 expression (1.7 fold increase). In conclusion, our data indicate that IGF-1 reduces MSC inflammatory gene expression and reduces differentiation of MSC to monocytes. These findings provide a new paradigm for biological effects of IGF-1 on MSC and have implications for the development of novel stem cell therapeutic strategies.