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 marrow progenitor cells (CD34+). Cell cycle progression throughout the 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 quiescent stem and progenitor cells out of the G0/G1-phase and by increasing the cell cycle traverse rate. In contrast, TGF-beta addition resulted in a significant decrease in the number of proliferating cells. Simultaneous addition of RA and TGF-beta resulted in a stronger inhibition compared to addition of TGF-beta alone. Preincubation experiments further 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 quiescent bone marrow progenitors in a simultaneous way, and that it increases sensitivity of the progenitors to the inhibitory action of TGF-beta. The combination of RA and TGF-beta on normal and leukemic hematopoiesis has to be further investigated, since this combination may possibly provide additional therapeutic benefit.
Lardon
F
F
Laboratory of Experimental Hematology, University of Antwerp (UIA/UZA), Belgium.
Snoeck
H W
HW
Haenen
L
L
Lenjou
M
M
Nijs
G
G
Weekx
S F
SF
Van Ranst
P C
PC
Berneman
Z N
ZN
Van Bockstaele
D R
DR
D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004347:Drug Interactions; D004996:Ethidium; D005434:Flow Cytometry / Q000379:methods; D016193:G1 Phase / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D007377:Interleukin-3; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D004996:Ethidium; D001973:Bromodeoxyuridine