Transforming Growth Factor-β Potently Inhibits the Viability-Promoting Activity of Stem Cell Factor and Other Cytokines and Induces Apoptosis of Primitive Murine Hematopoietic Progenitor Cells

Abstract

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.