Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

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.