THE COMBINED EFFECTS OF ALL-TRANS-RETINOIC ACID AND TGF-BETA ON THE INITIAL PROLIFERATION OF NORMAL HUMAN BONE-MARROW PROGENITOR CELLS

We investigated the cell kinetic effects of retinoic acid (RA) and the functional interaction between RA and TGF-beta on normal human bone m arrow progenitor cells (CD34(+)). Cell cycle progression throughout th e first three consecutive cell cycles and alterations in cell kinetic responses were measured using the BrdU-Hoechst quenching technique. RA stimulates the IL-3-induced growth by additionally recruiting quiesce nt stem and progenitor cells out of the G(0)/G(1)-phase and by increas ing the cell cycle traverse rate. In contrast, TGF-beta addition resul ted in a significant decrease in the number of proliferating cells. Si multaneous addition of RA and TGF-beta resulted in a stronger inhibiti on compared to addition of TGF-beta alone. Preincubation experiments f urther showed that RA is capable of sensitizing the progenitors to the inhibitory action of TGF-beta: the inhibitory effect of TGF-beta was significantly increased when cells were pretreated with RA. These data show that, in combination with IL-3, RA additionally stimulates quies cent bone marrow progenitors in a simultaneous way, and that it increa ses sensitivity of the progenitors to the inhibitory action of TGF-bet a. The combination of RA and TGF-beta on normal and leukemic hematopoi esis has to be further investigated, since this combination may possib ly provide additional therapeutic benefit.