Propranolol Accelerates Adipogenesis in Hemangioma Stem Cells and Causes Apoptosis of Hemangioma Endothelial Cells

New York, N.Y. From the Departments of Surgery, Obstetrics and Gynecology, and Pathology, College of Physicians and Surgeons, Columbia University.
Plastic and Reconstructive Surgery (Impact Factor: 2.99). 11/2012; 130(5):1012-21. DOI: 10.1097/PRS.0b013e318267d3db
Source: PubMed


: 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.
: 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.
: 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.
: 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.

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Available from: June K Wu, Oct 30, 2014
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    • "involution of IH accompanies the appearance of adipocytes and the completely involuted hemangioma tissues are filled with fibrofatty tissues, the regulatory mechanism of the onset of IH involution may coincide with the onset of adipogenesis. Actually, the inhibition of b-adrenergic signaling with propranolol is effective in IH treatment by inducing both the apoptosis of HemECs and differentiation of hemangioma-derived stem cells into adipocytes [32]. "
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    ABSTRACT: Hemangioma is a benign tumor derived from abnormal blood vessel growth. Unlike other vascular tumor counterparts, a hemangioma is known to proliferate during its early stage but it is followed by a stage of involution where regression of the tumor occurs. The critical onset leading to the involution of hemangioma is currently not well understood. This study focused on the molecular identities of the involution of hemangioma. We demonstrated that a soluble factor released from the involuting phase of hemangioma-derived endothelial cells (HemECs) and identified pigment epithelium-derived factor (PEDF) as an anti-angiogenic factor that was associated with the growth inhibition of the involuting HemECs. The growth inhibition of the involuting HemECs was reversed by suppression of PEDF in the involuting HemECs. Furthermore, we found that PEDF was more up-regulated in the involuting phase of hemangioma tissues than in the proliferating or the involuted. Taken together, we propose that PEDF accelerates the involution of hemangioma by growth inhibition of HemECs in an autocrine manner. The regulatory mechanism of PEDF expression could be a potential therapeutic target to treat hemangiomas. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 11/2014; 454(2):282-8. DOI:10.1016/j.bbrc.2014.10.052 · 2.30 Impact Factor
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    • "While our studies were underway, a report showed that presence of propranolol in adipogenic differentiation media increased the differentiation level in hemSCs as compared to cells in adipogenic media alone (21). Higher levels of C/EBPβ and δ were found at day 4. Interestingly, when the cells were maintained in the differentiation media supplemented with propranolol for 7 days, significant cell death was observed. "
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    ABSTRACT: Background Infantile hemangioma (IH) is the most common tumor of infancy. The first-line therapy for IH is propranolol, a non-selective β-adrenergic receptor antagonist. However, mechanisms for the therapeutic effect of propranolol and regrowth of IH following cessation of treatment in some cases are not clear. We have recently shown that IH arises from multipotent stem cells. Whether IH stem cells are responsive to propranolol and are selectively targeted is unknown, and is the focus of this study. Methods IH stem cells were exposed to propranolol and assayed for cellular and molecular alterations. We used endothelial cells (ECs) as controls and bone marrow-mesenchymal progenitor cells (bm-MPCs) as normal stem/progenitor counterparts to determine selectivity. Results Our results show that propranolol significantly reduced IH stem cell growth but failed to induce caspase-3 activation. Normal bm-MPCs and mature ECs showed maintained or increased caspase-3 activation and significantly reduced cyclin-D1 levels. We further show that IH stem cells may escape apoptosis by inducing anti-apoptotic pathways. Conclusions This study reveals that propranolol does not induce apoptosis in IH stem cells, which is in contrast to ECs. Escape from apoptosis in IH stem cells may involve induction of anti-apoptotic pathways.
    Pediatric Research 12/2013; 75(3). DOI:10.1038/pr.2013.231 · 2.31 Impact Factor
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    • "These data provide an explanation for the excellent performance of propranolol in the treatment of infantile hemangiomas. Propranolol-induced apoptosis of hemangioma endothelial cells has been documented in previous studies (18,19). "
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    ABSTRACT: Propranolol, a non-selective β-blocker, is emerging as an effective treatment for complicated hemangiomas. The aim of this study was to investigate the molecular mechanism(s) underlying the therapeutic effects of propranolol against hemangiomas, using primary infantile hemangioma endothelial cells (IHECs). IHECs were treated with various concentrations of propranolol and morphological changes and apoptosis were assessed. Changes in the expression levels of apoptosis-related genes were examined. Annexin-V staining revealed that propranolol at 40, 50 and 60 μg/ml caused a concentration-dependent increase in the apoptosis of IHECs. Morphological analyses revealed that exposure to 50 μg/ml propranolol resulted in typical apoptotic changes, including shrinkage, the formation of apoptotic bodies and retention of plasma membrane integrity. Gene expression analyses revealed that propranolol treatment led to a marked increase in the expression of caspase-8, cytochrome c, apoptosis-inducing factor, caspase-3 and poly (ADP-ribose) polymerase 1, as well as a concomitant reduction in lamin B1 expression. Our data collectively demonstrate that propranolol induces apoptosis of IHECs through activation of the intrinsic and extrinsic apoptotic pathways, which represents an important mechanism for its therapeutic effects against infantile hemangiomas.
    Experimental and therapeutic medicine 08/2013; 6(2):574-578. DOI:10.3892/etm.2013.1159 · 1.27 Impact Factor
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