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eight years of age, most hemangiomas have reached the """"""""involuted phase"""""""" at which point the tumor mass has been replaced by a fibrofatty residuum. Our goal is to understand precise cellular context for growth/involution of hemangioma in order to identify relevant biochemical and molecular pathways which will lay a foundation for the identification of drugs or therapies that will provide a safe and fast-acting treatment for children with endangering hemangiomas. During the previous funding period, we identified a stem/progenitor cell from proliferating phase infantile hemangiomas that can form hemangioma-like vascular lesions in immune-deficient mice. We used anti-CD 133-coated magnetic beads to isolate these hemangioma stem cells (HemSCs) from 28 different proliferating phase hemangiomas. In vitro, the HemSCs are fast-growing and exhibit multi-lineage differentiation potential, including endothelial differentiation in response to VEGF-B. In vivo (mice), the cells form functional blood vessels within 7 days. The blood vessels express the immunophenotype of hemangioma - glucose transporter-1 (GLUTl) and the basement membrane-associated protein merosin. After 1 month, the experimentally-formed hemangiomas begin to involute: blood vessels diminish and adipocytes appear, closely following the unique natural history that characterizes human infantile hemangioma. Based on these properties, the cells we identified and isolated are the equivalent of a """"""""hemangioma stem cell"""""""" which we call HemSCs. We propose to use these HemSCs to screen FDA-approved drugs with reported anti-angiogenic activity, and for which we know the target is present in HemSCs, for ability to inhibit HemSC proliferation in vitro and hemangioma formation in vivo. We will also analyze effects of mutations discovered by our collaborators in Projects 1 and 3 on the in vitro and in vivo behavior of HemSCs. Finally, we will continue to refine and optimize our in vivo animal model to identify critical factors that drive the proliferative phase of infantile hemangioma.
Project 2 will study stem cells isolated from a common childhood tumor known as infantile hemangioma. We hope to understand how and why these stem cells are 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-ar.tinn and Rafpi troatrnPints fnr nhildrfin with Finrlannerinn hPimanninmas.
|Hu, Kai; Olsen, Bjorn R; Besschetnova, Tatiana Y (2017) Cell autonomous ANTXR1-mediated regulation of extracellular matrix components in primary fibroblasts. Matrix Biol 62:105-114|
|Agarwal, Shailesh; Loder, Shawn; Brownley, Cameron et al. (2016) Inhibition of Hif1? prevents both trauma-induced and genetic heterotopic ossification. Proc Natl Acad Sci U S A 113:E338-47|
|Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R et al. (2016) VEGF stimulates intramembranous bone formation during craniofacial skeletal development. Matrix Biol 52-54:127-140|
|Couto, Javier A; Huang, Lan; Vivero, Matthew P et al. (2016) Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plast Reconstr Surg 137:77e-82e|
|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|
|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|
|Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin et al. (2015) Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis. Matrix Biol 42:56-73|
|Limaye, Nisha; Kangas, Jaakko; Mendola, Antonella et al. (2015) Somatic Activating PIK3CA Mutations Cause Venous Malformation. Am J Hum Genet 97:914-21|
|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|
|Boscolo, Elisa; Limaye, Nisha; Huang, Lan et al. (2015) Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects. J Clin Invest 125:3491-504|
Showing the most recent 10 out of 53 publications