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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2244.)
© 2006 American Heart Association, Inc.

Vascular Biology

Sca-1⁺ Progenitors Derived From Embryonic Stem Cells Differentiate Into Endothelial Cells Capable of Vascular Repair After Arterial Injury

Qingzhong Xiao; Lingfang Zeng; Zhongyi Zhang; Andriana Margariti; Ziad A Ali; Keith M. Channon; Qingbo Xu; Yanhua Hu

From the Department of Cardiac and Vascular Sciences (Q.X., L.Z., Z.Z., A.M., Y.H., Q.X.), St George’s, University of London, London, United Kingdom; Department of Cardiovascular Medicine (Z.A., K.C), University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Correspondence to Qingbo Xu, MD, PhD, Department of Cardiac and Vascular Sciences, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK. E-mail q.xu{at}sgul.ac.uk

Background— Embryonic stem cells possess the ability to differentiate into endothelium. The ability to produce large volumes of endothelium from embryonic stem cells could provide a potential therapeutic modality for vascular injury. We describe an approach that selects endothelial cells using magnetic beads that may be used therapeutically to treat arterial injury.

Methods and Results— Large numbers of endothelial cells (ECs) with high purity were produced using Sca-1⁺ cells isolated with magnetic beads from predifferentiated embryonic stem cells (ESCs) cultured in -MEM containing 10 ng/mL VEGF₁₆₅ for a minimum of 21 days (esEC). The transcription regulator histone deacetylase (HDAC3) was essential for VEGF-induced EC differentiation. Immunofluorescence or fluorescence-activated cell sorter (FACS) analysis revealed that esECs expressed a full range of EC lineage-specific markers including CD31, CD106, CD144, Flk-1, Flt-1, and von Willebrand factor (vWF). FACS analysis confirmed that 99% of esECs were CD31-positive and 75% vWF-positive. Furthermore, almost all cells were positive for DiI-acLDL uptake. When matrigel containing esECs was subcutaneously implanted into mice, various vessel-like structures were observed indicating their endothelial cell like phenotype. In keeping with this, when esECs infected with adenovirus-LacZ were injected into denuded femoral arteries of mice, they were found to form a neo-endothelium that covered the injured areas (86%±13.6%), which resulted in a 73% decrease in neointimal area 2 weeks after injury.

Conclusions— We conclude that Sca-1⁺ cells can differentiate into functional ECs via activation of HDAC3, accelerating re-endothelialization of injured arteries and reducing neointima formation.

We have successfully established a method for producing large numbers of endothelial cells (esECs) with high purity from embryonic stem cells and evaluated the therapeutic effect of esECs on re-endothelialization and neointima formation in a mouse model of arterial injury. We also demonstrate for the first time to our knowledge that HDAC3 is involved in VEGF-induced EC differentiation in Sca-1⁺ progenitor cells.

Key Words: endothelial cells • histone deacetylase 3 • progenitor cells • stem cells • stem cell therapy • vascular injury

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