Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Department of Surgery, Maimonides Medical Center, Brooklyn, New York, USA.
JCI Insight. 2017 Nov 2;2(21):93764. doi: 10.1172/jci.insight.93764.
Infantile hemangioma (IH) is a vascular tumor that begins with rapid vascular proliferation shortly after birth, followed by vascular involution in early childhood. We have found that NOTCH3, a critical regulator of mural cell differentiation and maturation, is expressed in hemangioma stem cells (HemSCs), suggesting that NOTCH3 may function in HemSC-to-mural cell differentiation and pathological vessel stabilization. Here, we demonstrate that NOTCH3 is expressed in NG2+PDGFRβ+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the αSMA+NG2loPDGFRβlo mural cells in involuting IHs. NOTCH3 knockdown in HemSCs inhibited in vitro mural cell differentiation and perturbed αSMA expression. In a mouse model of IH, NOTCH3 knockdown or systemic expression of the NOTCH3 inhibitor, NOTCH3 Decoy, significantly decreased IH blood flow, vessel caliber, and αSMA+ perivascular cell coverage. Thus, NOTCH3 is necessary for HemSC-to-mural cell differentiation, and adequate perivascular cell coverage of IH vessels is required for IH vessel stability.
婴儿血管瘤（IH）是一种血管肿瘤，在出生后不久即开始快速血管增殖，随后在儿童早期血管退化。我们发现 NOTCH3 是血管壁细胞分化和成熟的关键调节因子，在血管瘤干细胞（HemSCs）中表达，这表明 NOTCH3 可能在 HemSC 向血管壁细胞分化和病理性血管稳定中发挥作用。在这里，我们证明 NOTCH3 在增殖性 IH 中的 NG2+PDGFRβ+血管周 HemSCs 和 CD31+GLUT1+血管瘤内皮细胞（HemECs）中表达，并在退化性 IH 中主要局限于αSMA+NG2loPDGFRβlo 血管壁细胞。HemSCs 中的 NOTCH3 敲低抑制了体外血管壁细胞分化并扰乱了αSMA 的表达。在 IH 的小鼠模型中，NOTCH3 敲低或 NOTCH3 抑制剂 NOTCH3 Decoy 的全身表达显著降低了 IH 的血流、血管口径和αSMA+血管周细胞覆盖。因此，NOTCH3 对于 HemSC 向血管壁细胞分化是必需的，而 IH 血管的足够的血管周细胞覆盖对于 IH 血管的稳定性是必需的。
