Insulin-like growth factor 2 promotes the adipogenesis of hemangioma-derived stem cells

Infantile hemangioma (IH), which is the most common tumor in infants, is characterized by rapid proliferation followed by spontaneous regression into fibro-fatty tissue in childhood. However, its specific mechanism has not been clarified. Our previous studies showed that insulin-like growth factor 2 (IGF-2) is increased in the proliferative phase of IH, which is deemed to form from hemangioma-derived stem cells (HemSC). However, it remains unclear whether IGF-2 can promote the adipogenic differentiation of HemSCs and the signaling mechanisms involved require further elucidation. In the present study, CCK-8 assay was used to detect the effect of different concentrations of IGF-2 on the proliferation of HemSCs. Immunohistochemistry was applied to observe the expression of IGF-2 and its receptors in cells. Oil red o-staining of adipogenesis was conducted after cells recevied no treatment or were induced with IGF-2 or IGF-2 plus OSI-906 for 10 days. Cells were cultured in EGM-2/FBS-10% alone or containing IGF-2, IGF-2 plus OSI-906 or IGF-2 plus LY294002 and the protein expression of C/EBPα, C/EBPβ, PPARγ, adiponectin, p-AKT and total AKT was determined using western blot analysis. In another experiment, cells were treated with 25, 50 or 100 μM propranolol, or vehicle. C/EBPα, C/EBPβ, PPARγ and IGF-2 were analyzed using western blot analysis or reverse transcription-quantitative polymerase chain reaction. Results indicated that IGF-2 significantly promoted the cell proliferation and lipid accumulation of HemSCs. The expression of phosphorylated AKT (p-AKT), C/EBPα, C/EBPβ, PPARγ and adiponectin was increased in IGF-2-treated HemSCs culture, whereas these changes were repressed by the inhibition of either the IGF-1 receptor (IGF-1R) or phosphoinositide 3-kinase (PI3K). Our previous research showed that propranolol accelerated adipogenesis in HemSCs and induced the upregulation of IGF-2. The results of the present study indicate that IGF-2 is able to accelerate adipogenesis, and the propranolol-induced promotion of dysregulated adipogenesis may be mediated by the IGF-2 via IGF-1R and PI3K pathways. Keywords: adipogenesis; hemangioma-derived stem cells; infantile hemangiomas; insulin-like growth factor 2.