There is growing evidence that in addition to hematopoietic progenitor cells, the bone marrow also contains endothelial progenitor cells (BM-EPCs) that can differentiate in the presence of defined cytokines into cells that have the morphologic as well as molecular properties of endothelial cells. Studies to investigate the role of BM-EPCs in angiogenesis have shown that when bone marrow cells are injected into adult mice, donor derived cells incorporate into foci of new capillaries in areas of ischemia, tumors and iatrogenic wounds, but not normal tissues. To further characterize the role of EPCs in neovascularization we have utilized the newborn β-glucoronidase (GUSB) deficient mouse as a model system. The GUSB deficient mouse has been used previously to study and track, with single cell sensitivity, syngeneic GUSB-positive murine cells in vivo based on the fact that donor murine cells express GUSB. We hypothesized that BM-EPCs may play a role in normal tissue maintenance during the rapid growth and concomitant neovascularization of the neonatal period. IV administration of 5X10' nucleated syngeneic bone marrow cells/g weight to both newborn and adult GUSB deficient mice in the absence of ablative radiation resulted in widespread tissue distribution of GUSB-positive cells. To assess if BM-EPCs differentiated and incorporated into neovasculature in either newborn or adult recipients, we performed immunofluorescence using a monoclonal antibody to mouse GUSB and a polyclonal antibody to von Willebrands Factor (vWF), an endothelial specific marker. Colocalization of vWF and GUSB-positive cells were detected in association with vascular structures in heart, liver, skeletal muscle and kidney of newborn recipients. By contrast, no colocalization was detected in the heart, liver, or lung of adult recipients. Interestingly, GUSB-positive endothelial cells were detected in adult kidney and, like the newborn recipients, colocalization of GUSB and vWF was restricted to vasculature associated with glomerular tufts. Taken together, these data suggest that administration of syngeneic bone marrow cells to newborn recipients results in incorporation of donor-derived cells in neovasculature of a variety of tissues. These findings have widespread implications regarding novel approaches of therapeutic angiogenesis, which include delivery of genetically modified BM-EPCs to new blood vessel growth in neonates without the adverse effects associated with radioablative regiments.
|Issue number||11 PART I|
|State||Published - Dec 1 2000|