Diverse isoforms of colony-stimulating factor-1 have different effects on the development of stroma-dependent hematopoietic cells.
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.
Friel
Jutta
J
Heinrich-Pette-Institut for Experimental Virology and Immunology, Hamburg University, Hamburg, Germany.
Heberlein
Christoph
C
Geldmacher
Maren
M
Ostertag
Wolfram
W
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D003001:Cloning, Molecular; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D007536:Isomerism; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D017154:Stromal Cells / Q000166:cytology; D014161:Transduction, Genetic
D018952:Antigens, CD34; D000950:Antigens, Ly; D006023:Glycoproteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D011509:Proteoglycans; D016173:Macrophage Colony-Stimulating Factor