Infantile hemangioma (IH) is a vascular tumor with a unique lifecycle of rapid growth over the first 6-9 months of infancy, followed by a slow spontaneous involuting phase of several years. For most children, IH does not pose a serious threat and therapy is unnecessary; however, in about 10% of cases, IH can enlarge dramatically, threaten organs and cause permanent disfigurement. Despite the availability of relatively safe therapies, some IH grow so rapidly that significant tissue damage occurs before therapy can be started or take effect, and some IH do not respond. Thus, there is a pressing need to reach a deeper understanding of the cellular and molecular drivers of IH-genesis so that more effective, fast-acting therapies can be developed. In the previous funding cycle, we showed that hemangioma stem cells (HemSC) differentiate into endothelial cells (EC) and pericytes and form functional and perfused vascular networks in vivo (within 7 days). Importantly, the vessels formed in vivo from the HemSC express glucose transporter-1 (GLUT1), a unique marker of IH blood vessels. We also isolated hemangioma pericytes (HemPericytes) for the first time and showed that HemPericytes from proliferating IH are pro-angiogenic, express low angiopoietin-1 and are less contractile compared to normal pericytes. We also re-examined the IH endothelial cells to sort out glucose transporter-1-positive (GLUT1+) EC from GLUT1-negative EC. We made a striking finding that GLUT1+ EC in IH are facultative stem cells - they exhibit phenotypic and functional characteristics of endothelium, but when removed from the IH express stem cell-like properties of clonogenicity and multi-lineage differentiation. With these four distinct cell populations from IH, we will address unsolved questions regarding IH. The first is whether there is a genetic component to explosive vascular growth that occurs in IH.
In Aim 1, the four purified cell populations will be subjected to whole exome sequencing and bioinformatics analysis. Patient peripheral blood mononuclear cells will be sequenced for comparison. This purified cell-based approach will greatly reduce the difficulty of detecting a somatic mutation in heterogenous IH specimens and it will pinpoint the cell types that carry the mutation.
In Aim 2, we will address the role HemPericytes play in the onset of the involuting phase and how they affect the GLUT1+ EC.
In Aim 3, we will study how rapamycin converts GLUT1+EC from IH to a non-proliferative status and decipher the molecular targets rapamycin alters to achieve this. The information gained from our studies may lead to new insights and have impact on clinical management of IH. In addition, the knowledge gained from unraveling vascular growth in IH will yield fundamental insights into the mechanisms of normal, human post-natal neovascularization.

Public Health Relevance

In this proposal we will address two long-standing questions about infantile hemangioma, a common vascular tumor that occurs in 4-5% of children. The first is whether or not genetic mutations contribute to the abnormal vascular growth and if so, what are they and can we pinpoint the exact cell type in which the mutations occur. The second is to decipher how infantile hemangiomas regress because this may lead to ways to speed up the regression process or even prevent the growth of hemangioma.

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)
Program Officer
Gao, Yunling
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Boston Children's Hospital
United States
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Ye, Xi; Abou-Rayyah, Yassir; Bischoff, Joyce et al. (2016) Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma. J Pathol 239:139-51
Ayturk, Ugur M; Couto, Javier A; Hann, Steven et al. (2016) Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma. Am J Hum Genet 98:789-95
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
Jia, Di; Huang, Lan; Bischoff, Joyce et al. (2015) The endogenous zinc finger transcription factor, ZNF24, modulates the angiogenic potential of human microvascular endothelial cells. FASEB J 29:1371-82
Nakayama, Hironao; Huang, Lan; Kelly, Ryan P et al. (2015) Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins. Biochem Biophys Res Commun 464:126-32
Smadja, David M; Levy, Marilyne; Huang, Lan et al. (2015) Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost 114:735-47
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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
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

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