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, Andrew K.; Glithero, Kyle; Grzesik, Peter; Kitajewski, Alison A.; Munabi, Naikhoba C.O.; Hardy, Krista; Tan, Qian Kun; Schonning, Michael; Kangsamaksin, Thaned; Kitajewski, Jan K.; Shawber, Carrie J.; and Wu, June K., "NOTCH3 regulates stem-to-mural cell differentiation in infantile hemangioma" (2017). Open Access Articles. 3315.