Abstract
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 membrane‐spanning cell‐surface (cs) growth factors. CSF‐1 is expressed by stroma as a soluble glycoprotein, as proteoglycan, or as a membrane‐spanning cs glycoprotein. CSF‐1 regulates the survival, proliferation, and differentiation of mononuclear phagocytes. Whereas the biological role of soluble CSF‐1 is well characterized, the function of the membrane‐spanning cell‐surface CSF‐1 (csCSF‐1) remains unclear. To analyze the biological significance of csCSF‐1 in vitro, we used an epithelial cell line to ectopically express the different CSF‐1 isoforms. In co‐cultures of CSF‐1 transduced epithelial cells with primary, early hematopoietic progenitor cells we examined whether interaction between csCSF‐1 and its receptor mediates cell proliferation, self‐renewal, or differentiation. csCSF‐1 induces long‐lasting proliferation of stimulated cells and furthermore supports self‐renewal. Ectopic secretion of soluble CSF‐1 does not permit long‐term growth of progenitor cells but induces differentiation of monocytes into macrophages. Previously, we showed that the soluble and cs isoforms of stroma‐encoded SCF differently affect the development of hematopoietic cells. Cell‐surface SCF (csSCF) promotes self‐renewal of stimulated cells whereas soluble SCF causes clonal extinction. These results and those presented here for CSF‐1 provide evidence for diverse functions of the isoforms of the ligands SCF and CSF‐1 for two tyrosine kinase receptors of the subclass III both regulating hematopoiesis on stroma. J. Cell. Physiol. 204: 247–259, 2005. © 2005 Wiley‐Liss, Inc.