Bone marrow-derived endothelial cells for therapeutic angiogenesis and antiangiogenesis: facts and visions.

Abstract

AT THE BEGINNING of the last century Wilhelm His, a swiss histopathologist, performed extensive histological studies on embryogenesis. He found that blood islands and endothelial cells were always in close proximity during embryonic development and thus he postulated a common precursor cell for hematopoietic cells and cells of the endothelial cell lineage (1). Florence Sabin extended these studies with living tissue. She investigated chick embryos and found that angioblasts are derived from mesodermal cells and generate both blood vessels and red blood cells (2). In 1995, Fouad Shalaby added substantial evidence for the existence of a hemangioblastic progenitor cell. He generated knockout mice with a homozygous defect for flk-1, which encodes the vascular endothelial growth factor (VEGF)-receptor-2. The offspring of those mice died in utero at day 10 post coitum due to a lack of blood islands and endothelial cells. Thus, VEGF and its receptor are essential for the development of blood vessels and blood cells, suggesting a common ancestor, at least during embryonic development (3). Napoleone Ferrara and others added further evidence by the generation of mice deficient for the gene encoding VEGF. They could show that even the absence of a single allele of this gene causes embryonic death due to the lack of normal blood vessel formation and the absence of blood islands (4,5). In 1997, Takayuki Asahara from Jeff Isner’s lab in Boston showed that endothelial cells or at least their progenitors can be generated from CD34/KDR1 blood cells, which reside in hematopoietic tissue of adult species (6). The generation of endothelial cells from bone marrow-derived progenitor cells might have important clinical implications, as suggested by recent clinical studies. ENDOTHELIAL CELL CHIMERISM AFTER TRANSPLANTATION