HEPATOCYTE GROWTH-FACTOR INDUCES PROLIFERATION AND DIFFERENTIATION OFMULTIPOTENT AND ERYTHROID HEMATOPOIETIC PROGENITORS

Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and ''scattering'' of epithelial and end othelial cells. Its receptor is the tyrosine kinase encoded by the c-M ET protooncogene. Here we show that highly purified recombinant HGF st imulates hemopoietic progenitors to form colonies in vitro. In the pre sence of erythropoietin, picomolar concentrations of HGF induced the f ormation of erythroid burst-forming unit colonies from CD34-positive c ells purified from human bone marrow, peripheral blood, or umbilical c ord blood. The growth stimulatory activity was restricted to the eryth roid lineage. HGF also stimulated the formation of multipotent CFU-GEM M colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, wh ich is active on early hemopoietic progenitors. By flow cytometry anal ysis, the receptor for HGF was found to be expressed on the cell surfa ce in a fraction of CD34(+) progenitors. Moreover, in situ hybridizati on experiments showed that HGF receptor mRNA is highly expressed in em bryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a dire ct role in the control of proliferation and differentiation of erythro id progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic c ells within the hemopoietic microenvironment.