Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.

Abstract

Abstract. Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial ceils. Its receptor is the tyrosine kinase encoded by the c-MET protooncogene. Here we show that highly purified recombinant HGF stimulates hemopoietic progenitors to form colonies in vitro. In the presence of erythropoietin, picomolar concentrations of HGF induced the formation of erythroid burst-forming unit colonies from CD34-positive cells purified from human bone marrow, peripheral blood, or umbilical cord blood. The growth stimulatory activity was restricted to the erythroid lineage. HGF also stimulated the formation of multipotent CFU-GEMM colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, which is active on early hemopoietic progenitors. By flow cytometry analysis, the receptor for HGF was found to be expressed on the cell surface in a fraction of CD34 ÷ progenitors. Moreover, in situ hybridization experiments showed that HGF receptor mRNA is highly expressed in embryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a direct role in the control of proliferation and differentiation of erythroid progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic cells within the hemopoietic microenvironment.

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

“…[22][23][24][25][26][27][28][29] c-MET encodes the receptor for the ligand HGF/SF, which belongs to the tyrosine kinase receptor family, and is expressed on CD34 + cells. The HGF/SF receptor is expressed on leukemic cell lines and leukemic blasts 32,33 and in MDS samples.…”

“…23,[26][27][28][29] Peripheral blood or bone marrow samples were obtained from MDS patients with circulating blasts or AML patients. MNC from 10/16 MDS patients responded to HGF/SF as measured by an increase in thymidine incorporation (mean ± s.d.…”

“…[23][24][25] Recently, three different groups, including ours, observed a synergistic proliferative effect of HGF/SF with other growth factors on human HPC, and detected c-MET expression in human CD34 + HPC. [26][27][28][29] In addition, HGF/SF promoted survival of human HPC and was detected in the supernatant of BM stromal cells. 27,29 Apart from normal hemopoiesis, HGF/SF and c-MET seem to be involved in malignant hemopoiesis: In vitro HGF/SF production has been reported by leukemic and lymphoma cells and significant amounts of HGF/SF have been detected in blood and bone marrow plasma of leukemic patients.…”

Cross-talk between the proto-oncogenes Met and Ron

“…The Met receptor is expressed mainly in epithelial cells (Stoker et al, 1987;Di Renzo et al, 1991), but it has also been identi®ed in endothelial cells (Bussolino et al, 1992;Grant et al, 1993), in myoblasts (Anastasi et al, 1997), in cells of the hematopoietic system (Galimi et al, 1994;Nishino et al, 1995) and in spinal motor neurons (Ebens et al, 1996). Inappropriate activation of the HGF/Met pathway has been implicated in the onset and progression of a number of tumors and has been shown to promote the metastatic spread of neoplastic cells (Di Renzo et al, 1991Vande Woude et al, 1997;Giordano et al, 1997).…”

HGF Activates Signal Transduction from EPO Receptor on Human Cord Blood CD34 + /CD45 + Cells

“…In humans, it has not been clarified whether c-met is expressed on the CD34 + multipotent progenitors [18,20]. In this report, we isolate CD34 + cells from the human cord blood (CB) or BM using a fluorescence-activated cell sorter [21] and show that c-met is expressed on CD34 + /CD45 + cells, although the expression levels are different among samples.…”