Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells.
Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells.
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DOI：
10.1056/nejmoa0903036
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发表时间：
2010-03-18
期刊：
影响因子：
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通讯作者：
Bischoff J
中科院分区：
文献类型：
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作者：
Greenberger S;Boscolo E;Adini I;Mulliken JB;Bischoff J
皮质类固醇常用于治疗婴儿血管瘤，但这种疗法的作用机制尚不清楚。我们研究了皮质类固醇在先前描述的婴儿血管瘤体内模型和培养的血管瘤衍生细胞中的作用。我们测试了血管瘤源性干细胞植入免疫缺陷（裸）小鼠体内后的血管生成活性。我们研究了植入前细胞和植入后小鼠的地塞米松治疗。我们还测试了血管瘤源性干细胞的表达血管内皮生长因子A（VEGF-A）在体外和研究的抑制VEGF-A的表达，使用短发夹RNA（shRNA）在体内和体外。在小鼠模型中，地塞米松全身治疗导致肿瘤血管生成的剂量依赖性抑制。血管瘤源性干细胞在植入前的体外预处理也抑制血管生成。地塞米松在体外抑制血管瘤源性干细胞产生VEGF-A，但不抑制血管瘤源性内皮细胞或人脐静脉内皮细胞产生。在血管瘤来源的干细胞中沉默VEGF-A减少了体内血管生成。VEGF-A在血管瘤标本中的增殖期检测到，但在消退期检测不到，并通过免疫染色显示其位于血管外。皮质类固醇治疗抑制血管瘤源性干细胞中的其他促血管生成因子，包括尿激酶纤溶酶原激活物受体、白细胞介素-6、单核细胞趋化蛋白1和基质金属蛋白酶1。在小鼠模型中，地塞米松抑制来自人类婴儿血管瘤的干细胞的血管生成潜能。皮质类固醇还抑制血管瘤源性干细胞的VEGF-A表达，并且这些细胞中VEGF-A表达的沉默抑制体内血管发生。
Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells. We tested hemangioma-derived stem cells for vasculogenic activity in vivo after implantation into immune-deficient (nude) mice. We studied dexamethasone treatment of both the cells before implantation and the mice after implantation. We also tested hemangioma-derived stem cells for expression of vascular endothelial growth factor A (VEGF-A) in vitro and studied the inhibition of VEGF-A expression, using short hairpin RNA (shRNA) in vivo and in vitro. Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. Pretreatment of hemangioma-derived stem cells in vitro before implantation also inhibited vasculogenesis. Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. Silencing VEGF-A in hemangioma-derived stem cells reduced vasculogenesis in vivo. VEGF-A was detected in hemangioma specimens in the proliferating phase but not in the involuting phase and was shown by immunostaining to reside outside of vessels. Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1. In a murine model, dexamethasone inhibited the vasculogenic potential of stem cells derived from human infantile hemangioma. The corticosteroid also inhibited the expression of VEGF-A by hemangioma-derived stem cells, and silencing of VEGF-A expression in these cells inhibited vasculogenesis in vivo.