Transforming growth factor beta inhibits the action of stem cell factor on mouse and human hematopoietic progenitors.
In agar culture of post 5-fluorouracil mouse bone marrow cells (FUBM), recombinant rat stem cell factor (rrSCF) synergizes with granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3) or interleukin-6 (IL-6) to stimulate primitive progenitor cells (HPP-CFCs). The addition of recombinant human transforming growth factor beta (rhTGF-beta) to cultures of FUBM containing rrSCF plus rhG-CSF, rrSCF plus recombinant murine (rm)IL-3, or rrSCF plus rhIL-6 resulted in 100% inhibition of colony formation. Highly enriched populations of primitive bone marrow cells were obtained by isolating lineage negative (Lin-), Sca-1-positive (Sca-1+) cells from normal mouse bone marrow. RhTGF-beta inhibited 90% of colony formation stimulated by rrSCF plus rmIL-3 in agar culture of the Sca-1+ cells. RhTGF-beta also inhibited colony formation in agar culture of post FU human bone marrow cells. The synergistic increase in colony formation obtained with recombinant human SCF (rhSCF) plus rhGM-CSF and rhSCF plus rhIL-3 was inhibited by rhTGF-beta (approx. 60% and 87% inhibition, respectively). RhTGF-beta also totally inhibited the erythroid colony formation stimulated by rhSCF plus recombinant human erythropoietin (rhEpo). These data demonstrate that TGF-beta inhibits SCF-stimulated colony formation of mouse and human BM. This inhibition on progenitor cells appears to be a direct action of TGF-beta and is consistent with the target cells of SCF being more primitive progenitors than the CFCs stimulated by the CSFs alone.
Amgen Inc., Thousand Oaks, CA 91320-1789.
I K
IK
McNiece
I
I
Bertoncello
J R
JR
Keller
F W
FW
Ruscetti
C A
CA
Hartley
K M
KM
Zsebo
D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D006133:Growth Substances / Q000494:pharmacology; D006410:Hematopoiesis / Q000502:physiology; D016298:Hematopoietic Cell Growth Factors / Q000037:antagonists & inhibitors*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta / Q000502:physiology*
D006133:Growth Substances; D016298:Hematopoietic Cell Growth Factors; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta