Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells
Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells
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巨噬细胞通过调节血管瘤干细胞的增殖和分化促进婴儿血管瘤的进展
DOI：
10.1038/jid.2015.321
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发表时间：
2015-12-01
影响因子：
6.5
通讯作者：
Zhao, Yi-Fang
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Chen, Gang;Zhao, Yi-Fang
巨噬细胞浸润已牵连在婴儿血管瘤（IH），最常见的婴儿肿瘤。然而，巨噬细胞在IH中的确切作用仍然未知。本研究旨在阐明巨噬细胞在IH进展中的功能意义。分析了巨噬细胞在人IH中的分布，我们的结果显示，极化的巨噬细胞在增殖的IH中比在退化的IH中更普遍，这与增殖的IH中增加的巨噬细胞相关的细胞因子一致。体外实验结果进一步证明极化巨噬细胞以Akt和细胞外信号调节激酶1/2（Erk 1/2）依赖的方式有效地促进血管瘤干细胞（HemSCs）的增殖并抑制其脂肪形成。此外，M2-而不是M1-极化的巨噬细胞促进HemSCs的内皮分化。此外，在小鼠血管瘤模型中混合巨噬细胞增加了微血管密度并推迟了脂肪组织的形成，这与Akt和Erk 1/2信号的激活有关。聚类分析显示巨噬细胞标志物Ki 67、血管内皮生长因子（VEGF）、p-Akt和p-Erk 1/2在人IH组织中密切相关。总的来说，我们的研究结果表明，IH中的巨噬细胞通过促进增殖和内皮分化，同时抑制HemSCs的脂肪生成，从而促进肿瘤进展。这些发现表明，靶向IH中的浸润性巨噬细胞是加速IH消退的有希望的治疗方法。
Macrophage infiltration has been implicated in infantile hemangioma (IH), the most common tumor of infancy. However, the exact role of macrophages in IH remains unknown. This study aims to clarify the functional significance of macrophages in the progression of IH. The distribution of macrophages in human IH was analyzed, and our results revealed that polarized macrophages were more prevalent in proliferating IHs than in involuting IHs, which was consistent with the increased macrophage-related cytokines in proliferating IHs. In vitro results further demonstrated that polarized macrophages effectively promoted the proliferation of hemangioma stem cells (HemSCs) and suppressed their adipogenesis in an Akt- and extracellular signal-regulated kinase 1/2 (Erk1/2)-dependent manner. Moreover, M2-but not M1-polarized macrophages promoted the endothelial differentiation of HemSCs. Furthermore, mixing macrophages in a murine hemangioma model elevated microvessel density and postponed fat tissue formation, which was concomitant with the activation of Akt and Erk1/2 signals. Cluster analysis revealed a close correlation among the macrophage markers, Ki67, vascular endothelial growth factor (VEGF), p-Akt, and p-Erk1/2 in human IH tissues. Collectively, our results suggest that macrophages in IH contribute to tumor progression by promoting the proliferation and endothelial differentiation while suppressing the adipogenesis of HemSCs. These findings indicate that targeting the infiltrating macrophages in IH is a promising therapeutic approach to accelerate IH regression.