NOTCH3 调控婴幼儿血管瘤中干细胞向壁细胞的分化。
NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma.
机构信息
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.
出版信息
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。
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