Stem cell factor induction of in vitro murine hematopoietic colony formation by "subliminal" cytokine combinations: the role of "anchor factors".
The high levels of hematopoietic growth factors required for in vitro and in vivo activity raise questions as to their role in normal hematopoietic maintenance. We hypothesize that the use of combinations of cytokines to stimulate hematopoietic progenitors might allow individual factors to exert their influence at lower, more physiologically relevant concentrations. Growth factor combinations were assessed by their ability to stimulate both total colonies and high proliferative potential colony-forming cells (HPP-CFC), an early murine hematopoietic progenitor, in double-layer agar cultures. Very-low-level combinations of colony-stimulating factor (CSF)-1, granulocyte CSF (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin (IL)-1 alpha, and IL-3 had little or no clonogenic capacity. Plateau levels of rr stem cell factor (rrSCF), a c-kit ligand, used alone also had negligible clonogenic capacity, but when combined with the low-level combination of the other five factors produced total colony and HPP-CFC growth approaching that produced by all factors at plateau levels. Delayed addition experiments suggest that this effect may represent sequential activity of SCF and the other factors. We propose a model of the normal hematopoietic microenvironment in which SCF at locally high concentration on the stromal cell surface "anchors" the hematopoietic stem cell's response to multiple other cytokines at physiologically relevant levels.
Lowry
P A
PA
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908.
Deacon
D
D
Whitefield
P
P
McGrath
H E
HE
Quesenberry
P J
PJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D046508:Culture Techniques / Q000379:methods; D016207:Cytokines / Q000494:pharmacology*; D004347:Drug Interactions; D005472:Fluorouracil / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007375:Interleukin-1 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor
D016207:Cytokines; D016298:Hematopoietic Cell Growth Factors; D007375:Interleukin-1; D007377:Interleukin-3; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil