Generation of Functional Blood Vessels from a Single c-kit+ Adult Vascular Endothelial Stem Cell

Petri Salven,Jing Wei,Shentong Fang,Margaret A. Goodell,Nalle Pentinmikko,Hannele Leinonen

doi:10.1371/journal.pbio.1001407

Abstract

Author SummaryAngiogenesis—the growth of blood vessels—is essential for organ growth and repair, but also occurs during tumorigenesis and in certain inflammatory disorders. All blood vessels are lined by endothelial cells (ECs)—thin, flattened cells that form a continuous monolayer throughout the entire circulatory system. The cellular origin of new vascular ECs during blood vessel growth in angiogenic situations in adults is a matter of debate. New ECs could develop, in principle, from as yet undiscovered stem cells, as is well documented for the differentiated cells of skin or epithelia, or by the duplication of existing differentiated ECs. Here, we provide evidence for the existence of vascular endothelial stem cells (VESCs) that reside in the adult blood vessel wall endothelium. VESCs constitute a small subpopulation of ECs capable of clonal expansion, while other ECs have a very limited proliferative capacity. When isolated, these VESCs can produce tens of millions of endothelial daughter cells, and a single transplanted VESC can generate in vivo functional blood vessels that connect to host blood circulation. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization following ischemia and could also be pursued as a novel cellular target of inhibition to block pathological angiogenesis, for example during tumor growth.

Highlights

The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de-novo-forming angioblasts into a primitive vascular plexus
In preliminary experiments we found that rare endothelial colony-forming cells (CFCs) were routinely detected when endothelial cell (EC) were isolated from single cell suspensions prepared by enzymatic digestion of adult mouse tissues, and cultured in vitro in low-cell density adherent semi-solid methylcellulose matrix colony assays
All blood vessels are lined by endothelial cells (ECs)—thin, flattened cells that form a continuous monolayer throughout the entire circulatory system

Summary

Introduction

The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de-novo-forming angioblasts into a primitive vascular plexus (vasculogenesis). Blood vessels arise from endothelial precursors, which share an origin with hematopoietic progenitors [1,2,3]. Weissman and coworkers by performing genetic fate mapping and clonal analysis of individual cells showed that the endothelial stem/progenitor cells involved in adult angiogenesis must be local, non-hematopoietic, and noncirculating tissue resident cells [8]. The definite cellular origin of the new ECs necessary for adult neoangiogenesis has remained unknown [8,9,10,11,12,13,14,15,16]. Creation of new ECs in adult tissues could in principle occur by their so far undiscovered tissue resident stem cells, as is well documented for the differentiated cells of skin or epithelia [17,18,19], or by the duplication of existing differentiated ECs, as has been described for pancreatic beta-cells [20]

Methods

Discussion

Conclusion