1. NOTCH3 regulates stem-to–mural cell differentiation in infantile hemangioma
- Author
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Peter Grzesik, June K. Wu, Naikhoba C. O. Munabi, Jan Kitajewski, Alison A. Kitajewski, Krista L. Hardy, Thaned Kangsamaksin, Qian Kun Tan, Andrew K. Edwards, Carrie J. Shawber, Michael Schonning, and Kyle J Glithero
- Subjects
0301 basic medicine ,CD31 ,Pathology ,medicine.medical_specialty ,Cellular differentiation ,Biology ,Mural cell ,Receptor, Platelet-Derived Growth Factor beta ,Hemangioma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Involution (medicine) ,cardiovascular diseases ,Antigens ,Receptor, Notch3 ,Cell Proliferation ,Cell growth ,Gene Expression Profiling ,Stem Cells ,Endothelial Cells ,Cell Differentiation ,General Medicine ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Cell culture ,Gene Knockdown Techniques ,Disease Progression ,cardiovascular system ,Blood Vessels ,Female ,Proteoglycans ,Stem cell ,Pericytes ,030217 neurology & neurosurgery ,Research Article - Abstract
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.
- Published
- 2017
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