Function of the Membrane-Bound Isoform Ligands of the Receptor Tyrosine Kinase Subclass III in Inducing Inducing Self-Renewal of Early Hematopoietic Progenitor Cells

摘要

Maintenance and differentiation of hematopoietic stem and progenitor cells are controlled by complex interactions with the stroma microenvironment. Stroma-cell interactions can be supported by locally expressed membranespanning cell-surface growth factors. Ligands of the tyrosine receptor kinases subclass III like SCF or CSF-1 are expressed by stroma as soluble glycoproteins, proteoglycans or membrane-bound glycoproteins. SCF synergizes with other growth factors in enhancing growth of early progenitor cells whereas CSF-1 is known to regulate the survival, proliferation and differentiation of mononuclear phagocytes. Whereas the biological role of the soluble isoforms of SCF and CSF- 1 are well characterized, the function of the membrane-bound ligands remain unclear. To analyze the biological significance of membrane-bound SCF and -CSF-1 in vitro we used an epithelial cell line to ectopically express the different isoforms. In cocultures of SCF- or CSF-1 transduced epithelial cells with primary early hematopoietic progenitor cells we examined whether interaction between the membrane-bound isoforms of SCF and CSF-1 and their receptors mediate cell proliferation, self-renewal or differentiation. We show here that the membranebound isoforms of SCF and CSF-1 both have functions in inducing self-renewal of early hematopoietic cells. In contrast, soluble SCF and CSF-1 exert specific functions: SCF by itself causes clonal extinction whereas CSF-1 is involved in the macrophage differentiation. In context with the stroma-hematopoietic cell interaction we also show that CSF-1 can sustain the self-renewal of a murine stem cell line Myl-D7.