This project aims to provide insight into the poorly understood cellular and molecular mechanisms underlying the involution of infantile hemangioma. Hemangiomas are the most common vascular tumors of infancy affecting 5-10% of children. The vast majority of these tumors occur in the skin. Hemangioma is characterized by an initial phase of rapid growth during infancy and subsequent spontaneous involution in early childhood (1). Histopathologically, robust angiogenesis highlights the proliferative phase (2). Apoptosis of endothelial cells and marked accumulation of adipocytes occurs during involution (3). Strikingly, in the final involuted stage, hemangioma appears as all fibrofatty tissue. This fibrofatty tissue is often disfiguring such that plastic surgery is required. Current therapies are largely non-specific and somewhat inadequate. Clearly, identifying regulators that accelerate the normal involution process and/or prevent growth of hemangioma may provide effective therapies. Previously, we have shown that hemangioma-derived endothelial cells (Hem-ECs) are clonal and exhibit abnormal behavior in vitro (4,5). This suggests that hemagioma arises from clonal expansion of a single endothelial cell (the "tumor" cell). Identification of somatic mutation(s) in Hem-ECs as the cause of hemangioma is currently underway. Recently, we have isolated mesenchymal. Recently, we have isolated mesenchymal stem cells (MSCs) from hemangiomas. Human MSCs can differentiate into multiple lineages including adipocytes (6). These hemangiomas-derived MSCs (Hem-MSCs) are not clonal, suggesting they are not the "tumor cells", but the stromal element. In preliminary data, we showed that conditioned medium extracted from fresh hemangioma tissue can induce the adipogenic differentiation of Hem-MSCs in vitro. Taken together, we have identified a novel cellular component of hemangioma that may play a significant role in the involution of hemangioma. We hypothesize that hemangioma ECs contribute to the recruitment of MSCs from surrounding skin tissue or blood circulation and subsequently, induce differentiation of MSCs into adipocytes in the tumor. This hypothesis is difficult to address in vivo due to the lack of an available animal model. However, the Hem-ECs and Hem-MSCs that we have developed in culture will allow us to study the tumor and stromal cell interactions. Specifically, we propose, using a co-culture system, to investigate the role of soluble factors secreted from Hem-ECs and cell-cell contacts between the two cell types in mediating the migration and adipogenic differentiation of Hem-MSCs. Specific Aims: 1. To test the hypothesis that Hem-ECs secrete factors to mediate the migration of Hem-MSCs. 2. To test the hypothesis that Hem-ECs mediate the adipogenic differentiation of Hem-MSCs. 3. To identify the molecular targets that regulate the migration and differentiation of Hem-MSCs.
NIH ExPorter
NIH ExPorter