title: Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells.
abstract: BACKGROUND
  Infantile hemangiomas can cause significant morbidity during proliferation, yet there is no U.S. Food and Drug Administration-approved treatment. They are believed to form from hemangioma stem cells, which differentiate toward a hemangioma endothelial cell phenotype. Recently, propranolol has demonstrated effectiveness in treating complicated infantile hemangiomas. The authors hypothesize that propranolol facilitates their involution by altering cellular behavior in both hemangioma endothelial and stem cells.
  
  
  METHODS
  Hemangioma endothelial and stem cells were isolated from resected infantile hemangioma specimens. Cells were treated with 100 μM propranolol for 48 hours, and apoptosis was determined by the presence of annexin V antibody. Proliferation of stem and endothelial cells was assessed after treatment with 50 or 100 μM propranolol or vehicle, for 72 and 96 hours, respectively. Adipogenesis was induced in stem cells with and without propranolol. Pro-adipogenic genes PPARδ, PPARγ, C/EBPα, C/EBPβ, C/EBPδ, RXRα, and RXRγ were analyzed by quantitative polymerase chain reaction.
  
  
  RESULTS
  Annexin V levels were increased in propranolol-treated endothelial cells but not in stem cells. Proliferation of stem and endothelial cells was inhibited by propranolol in a dose-dependent manner. Propranolol-treated stem cells demonstrated accelerated adipogenesis when compared with untreated controls. Transcript levels of C/EBPβ (p < 0.05), RXRγ (p < 0.05), and PPARγ (p < 0.02) were significantly increased when treated with 50 or 100 μM propranolol; and C/EBPδ (p < 0.05), RXRα (p < 0.05), and PPARδ (p < 0.01) transcripts were increased when treated with 100 μM propranolol. C/EBPα transcript levels remained unchanged at either dose.
  
  
  CONCLUSIONS
  Propranolol increased apoptosis of hemangioma endothelial cells, but not stem cells, and accelerated adipogenesis of hemangioma stem cells. Thus, propranolol likely accelerates involution to fibrofatty residuum.
authors.affiliation: New York, N.Y. From the Departments of Surgery, Obstetrics and Gynecology, and Pathology, College of Physicians and Surgeons, Columbia University.
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.forename: Krista L
authors.initials: KL
authors.lastname: Hardy
authors.forename: Alex M
authors.initials: AM
authors.lastname: Kitajewski
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Shawber
authors.forename: Jan K
authors.initials: JK
authors.lastname: Kitajewski
authors.forename: June K
authors.initials: JK
authors.lastname: Wu
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D017304:Annexin A5 / Q000097:blood; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology*; D005434:Flow Cytometry; D006391:Hemangioma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D011433:Propranolol / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D000319:Adrenergic beta-Antagonists; D017304:Annexin A5; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol