NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma
Department of Anesthesiology and Perioperative Medicine
Cardiovascular System | Cell Biology | Developmental Biology | Neoplasms
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+PDGFRbeta+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the alphaSMA+NG2loPDGFRbetalo mural cells in involuting IHs. NOTCH3 knockdown in HemSCs inhibited in vitro mural cell differentiation and perturbed alphaSMA 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 alphaSMA+ 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.
DOI of Published Version
JCI Insight. 2017 Nov 2;2(21). pii: 93764. doi: 10.1172/jci.insight.93764. [Epub ahead of print] Link to article on publisher's site
Edwards AK, Glithero K, Grzesik P, Kitajewski AA, Munabi NC, Hardy K, Tan QK, Schonning M, Kangsamaksin T, Kitajewski JK, Shawber CJ, Wu JK. (2017). NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma. Open Access Publications by UMMS Authors. https://doi.org/10.1172/jci.insight.93764. Retrieved from https://escholarship.umassmed.edu/oapubs/3315