Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.
Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial cells. 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.
Galimi
F
F
Institute for Cancer Research and Treatment (I.R.C.C.), University of Torino Medical School, Italy.
Bagnara
G P
GP
Bonsi
L
L
Cottone
E
E
Follenzi
A
A
Simeone
A
A
Comoglio
P M
PM
D000818:Animals; D015703:Antigens, CD; D018952:Antigens, CD34; D016367:Baculoviridae / Q000235:genetics; D001853:Bone Marrow / Q000196:embryology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D017403:In Situ Hybridization; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016184:Receptors, Colony-Stimulating Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018411:Spodoptera / Q000166:cytology; D019089:Stem Cell Factor
D015703:Antigens, CD; D018952:Antigens, CD34; D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D017228:Hepatocyte Growth Factor; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases