Transforming growth factor-beta potently inhibits the viability-promoting activity of stem cell factor and other cytokines and induces apoptosis of primitive murine hematopoietic progenitor cells.
In contrast with the extensively characterized effects of transforming growth factor-beta (TGF-beta) on proliferation and differentiation of hematopoietic progenitors, little is known about the effects of TGF-beta on viability of normal hematopoietic progenitors. In the present report, we demonstrate that TGF-beta potently counteracts hematopoietic growth factor (HGF)-induced survival of individually cultured primitive Lin-Sca-1+ bone marrow progenitors. Specifically, 74% of single Lin-Sca-1+ cells cultured for 40 hours in the presence of stem cell factor (SCF) survived, whereas only 16% survived in the presence of SCF plus TGF-beta. Similarly, the enhanced survival of primitive hematopoietic progenitors in response to granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-6, or IL-11 was also potently opposed by TGF-beta. Furthermore, it is demonstrated that neutralization of endogenous TGF-beta present in the cultures enhances survival of Lin-Sca-1+ progenitors in the absence, as well as in the presence, of HGFs such as SCF and IL-6. The reduced HGF-induced survival of primitive hematopoietic progenitors in the presence of TGF-beta was associated with increased apoptosis, as detected by an in situ terminal deoxynucleotidyl transferase (TdT) assay. After 16 hours of incubation in the absence of HGFs, 61% +/- 6% of the hematopoietic progenitors had DNA strand breaks characteristic of apoptosis. The presence of SCF reduced the frequency of apoptic cells to 27% +/- 5%, whereas 55% +/- 3% of the cells had signs of apoptosis in the presence of SCF plus TGF-beta.
Jacobsen
F W
FW
Department of Immunology, Biophysics, Norwegian Radium Hospital, Oslo, Norway.
Stokke
T
T
Jacobsen
S E
SE
D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004249:DNA Damage; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000950:Antigens, Ly; D016207:Cytokines; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta