ABSTRACT
Infantile hemangioma is a benign endothelial tumor composed of disorganized blood vessels. It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum. Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice. Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations. The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice. Cell retrieval experiments showed the cells could again form vessels when transplanted into secondary recipients. The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma. Two months after implantation, the number of blood vessels diminished and human adipocytes became evident. Lentiviral expression of GFP was used to confirm that the hemangioma-derived cells formed the blood vessels and adipocytes in the immunodeficient mice. Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma--the formation of blood vessels followed by involution to fatty tissue. In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy.
Subject(s)
Disease Models, Animal , Hemangioma/pathology , Multipotent Stem Cells/transplantation , Neoplastic Stem Cells/transplantation , Adipocytes/chemistry , Adipocytes/pathology , Animals , Antigens, Nuclear/analysis , Antigens, Surface/analysis , Blood Vessels/chemistry , Blood Vessels/pathology , Carrier Proteins , Cell Differentiation/drug effects , Cell Separation , Cell Transplantation/adverse effects , Cell Transplantation/methods , Endothelial Cells/chemistry , Endothelial Cells/pathology , Glucose Transporter Type 1/analysis , Green Fluorescent Proteins/analysis , Green Fluorescent Proteins/genetics , Hemangioma/etiology , Hemangioma/metabolism , Humans , Infant , Laminin/analysis , Male , Mice , Mice, Nude , Multipotent Stem Cells/chemistry , Multipotent Stem Cells/pathology , Neoplastic Stem Cells/chemistry , Neoplastic Stem Cells/pathology , Perilipin-1 , Phosphoproteins/analysis , Platelet Endothelial Cell Adhesion Molecule-1/analysis , Receptors, Vascular Endothelial Growth Factor/analysis , TransfectionABSTRACT
Common infantile hemangioma appears postnatally, grows rapidly, and regresses slowly. Two types of congenital vascular tumors present fully grown at birth and behave differently from infantile hemangioma. These rare congenital tumors have been designated rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH). RICH and NICH are similar in appearance, location, and size, and have some overlapping histologic features with infantile hemangioma. At a molecular level, neither expresses glucose transporter-1, a diagnostic marker of infantile hemangioma. To gain further insight into the molecular differences and similarities between congenital and common hemangioma, we analyzed expression of insulin-like growth factor-2, known to be highly expressed in infantile hemangioma and VEGF-receptors, by quantitative real-time PCR, in three RICH and five NICH specimens. We show that insulin-like growth factor-2 mRNA was expressed in both RICH and NICH, at a level comparable with that detected in common hemangioma over 4 y of age. In contrast, mRNA levels for membrane-associated fms-like tyrosine-kinase receptor, also known as VEGF receptor-1, were uniformly increased in congenital hemangiomas compared with proliferating or involuting phase common hemangioma. These results provide the first evidence of the molecular distinctions and similarities between congenital and postnatal hemangioma.