Infantile hemangioma is a common childhood tumor composed of disorganized blood vessels and immature endothelial cells. Hemangioma follows a unique life-cycle in which the tumor appears soon after birth and grows dramatically during infancy. This "proliferating phase" is followed by a spontaneous but slow "involuting phase" that begins after age one. By five to eight years of age, most hemangiomas have reached the "involuted phase" at which point the tumor mass has been replaced by a fibrofatty residuum. Hence, infantile hemangioma is a human vascular anomaly from which we might gain important insight into how blood vessels are formed and how they regress. Our goal has been to find the cell that initiates growth and expansion of IH and to establish an animal model that closely reflects this human vascular tumor. Indeed, we have now isolated a multi-potent hemangioma stem cell (HemSC) from 30 different proliferating hemangioma specimens removed from infants with endangering hemangiomas, and demonstrated their robust self-renewal capacity, multi- lineage differentiation potential and ability to form hemangioma-like blood vessels in vivo in immunodeficient mice (Khan, Boscolo et al, J Clin Invest. 2008). In summary, this paper identifies the HemSC as the cellular origin of infantile hemangioma and provides the first animal model that truly reflects this vascular lesion. We had previously isolated and studied hemangioma-derived endothelial cells (HemECs) and hemangioma-derived endothelial progenitor cells (HemEPCs) but these cells do not form blood vessels when injected into immune-deficient mice, suggesting that the cells may be too differentiated to recapitulate infantile hemangioma. Our current goal is to further our studies on HemSC and HemEPCs/HemECs and how these cells interact to cause the aberrant vessel formation that occurs in infantile hemangioma. We will purse three specific aims. The first will focus on HemSC differentiation into pericytes and the potential influence of EPCs on hemangioma vessel development.
The second aim will focus on VEGF-R1 in HemSC differentiation into endothelial cells.
The third aim will be to screen FDA-approved drugs with anti-angiogenic activity for ability to inhibit HemSC growth in vitro and blood vessel formation in vivo using the models we have developed. These three aims represent cellular (Aim 1), molecular (Aim 2) and translational (Aim 3) approaches to advance our understanding of hemangioma and to identify potential drugs that will stop the growth and blood vessel formation that occurs in hemangima. Furthermore, this research may have relevance to other vascular anomalies, vascular tumors and tumor angiogenesis. Finally, because this research focuses on mechanisms leading to blood vessel formation, it may reveal insights into how human vascular progenitor cells can be used to rebuild vascular networks for tissue regeneration.

Public Health Relevance

This proposal will study stem cells isolated from a common childhood tumor known as infantile hemangioma. We hope to understand how and why these stem cells have become disrupted, such that instead of following a normal healthy pathway to become normal cells and tissue, the hemangioma-derived stem cells form a mass of disorganized blood vessels that grows dramatically during infancy. The results from this study may lead to new, fast-acting and safe treatments for children with endangering hemangiomas. In addition, the studies may provide fundamental insights into the behavior of human vascular progenitor cells which could then be applied to strategies to use such progenitor cells for tissue repair and regeneration, and specifically to build healthy vascular networks.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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Children's Hospital Boston
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Huang, Lan; Nakayama, Hironao; Klagsbrun, Michael et al. (2015) Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33:133-45
Gelfand, Maria V; Hagan, Nellwyn; Tata, Aleksandra et al. (2014) Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding. Elife 3:e03720
Smadja, David M; Guerin, Coralie L; Boscolo, Elisa et al. (2014) *6-Integrin is required for the adhesion and vasculogenic potential of hemangioma stem cells. Stem Cells 32:684-93
Lee, D; Boscolo, E; Durham, J T et al. (2014) Propranolol targets the contractility of infantile haemangioma-derived pericytes. Br J Dermatol 171:1129-37
Boscolo, Elisa; Mulliken, John B; Bischoff, Joyce (2013) Pericytes from infantile hemangioma display proangiogenic properties and dysregulated angiopoietin-1. Arterioscler Thromb Vasc Biol 33:501-9
Greenberger, S; Bischoff, J (2013) Pathogenesis of infantile haemangioma. Br J Dermatol 169:12-9
Boscolo, Elisa; Stewart, Camille L; Greenberger, Shoshana et al. (2011) JAGGED1 signaling regulates hemangioma stem cell-to-pericyte/vascular smooth muscle cell differentiation. Arterioscler Thromb Vasc Biol 31:2181-92
Greenberger, Shoshana; Yuan, Siming; Walsh, Logan A et al. (2011) Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J Invest Dermatol 131:2467-76
Boscolo, Elisa; Mulliken, John B; Bischoff, Joyce (2011) VEGFR-1 mediates endothelial differentiation and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol 179:2266-77
Greenberger, Shoshana; Boscolo, Elisa; Adini, Irit et al. (2010) Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 362:1005-13

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