Macrophage-colony stumulating factor as a hematopoietic and vasculogenic/angiogenic factor in the agm region

Definitive hematopoietic stem cells arise in the AGM (Aorta-Gonad-Mesonephros) region. By using a primary culture system of AGM, we demonstrated that Oncostatin M enhances the development of both hematopoietic and endothelial cells by possibly stimulating their common precursors, hemangioblasts. Here we describe a role of M-CSF in the development of both types of cells in AGM. Endothelial cell clusters were much larger and hematopoietic cells in AGM culture of M-CSF-deficient op/op mice were more immature than those in the wild type AGM culture. The number of CFU-Mix colony in op/op AGM culture was higher than that in wild type culture and the addition of M-CSF to op/op AGM culture reduced the number to the wild type level. Whereas the expression levels of endothelial markers, Flk-1, VE-cad, PECAM-1 and vWF, in the cultured op/op cells were lower than those in the wild type cells, the Flt-1 expression in op/op cells was higher than wild type. Although both Flt-1 and Flk-1 are tyrosine kinase receptors for VEGF, their functions are quite different; Flk-1 mediates VEGF signals for proliferation, but Flt-1 rather antagonizes it. Thus it is possible that M-CSF regulates growth and differentiation of endothelial cells by modulating Flt-1 expression. Consistently, M-CSF enhanced proliferation and differentiation of PCLP-1+/CD45− cells in AGM, which contain hemangioblasts, into endothelial cells. In conclusion, M-CSF affects not only hematopoiesis but also vaslculogenesis and/or angiogenesis in AGM.