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Role of Hemangioma Stem Cell Notch3 in Infantile Hemangioma Blood Vessel Development
Andrew K. Edwards1, Kyle Glithero1, Alison A. Kitajewski1, Justin E. Kung1, Naikhoba Munabi1, Jan Kitajewski2, Carrie Shawber1, 2, June K. Wu1.
1Columbia University Medical Center, Department of Surgery, New York, NY, 2Columbia University Medical Center, Department of Obstetrics and Gynecology, New York, NY

Purpose: Infantile hemangiomas (IHs) are vascular tumors of infancy that occur within the first five years, and proceed through a phase of rapid proliferation followed by involution. IHs are thought to originate from CD133+ hemangioma stem cells (HemSCs). HemSCs are localized in perivascular regions of IH tissue and express NOTCH3, a protein involved in mural cell (vascular smooth muscle cell and pericyte) differentiation and maturation. We hypothesize that NOTCH3 functions in HemSCs to promote mural cell differentiation.
Methods: Isolated CD133+ HemSCs were infected with lentiviruses encoding a NOTCH3 shRNA (N3KD) or scrambled control (SCR). To evaluate NOTCH3 function in HemSC differentiation in vitro, HemSCs were cultured with cord blood endothelial progenitor cells (cbEPCs), which express high levels of the NOTCH ligand, JAGGED1. To assess the role of HemSC in vivo, a mouse IH model was used in which HemSCs and cbEPCs were suspended in Matrigel and engrafted in immunodeficient mice. IH matrigel implants were harvested for histological analysis after 14 days.
Results: HemSCs differentiated into α-SMA+ cells when co-cultured with cbEPCs in vitro. In N3KD HemSCs, α-SMA expression was reduced when compared to control HemSCs. In vivo, Doppler ultrasound revealed vascular structures with blood flow in control HemSC implants. Blood flow was reduced in N3KD HemSCs implants. Histological analysis of control implants revealed ectatic vessels with typical IH morphology supported by α-SMA+ mural cells. In contrast, IH matrigel implants with N3KD HemSCs had decreased α-SMA+ mural cell coverage and poor vessel integrity.
Conclusions: In IHs, NOTCH3 promotes HemSC differentiation into α-SMA+ perivascular cells that may support pathological IH blood vessel stability, suggesting NOTCH3 is a potential therapeutic target.


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