All-trans retinoic acid at low concentration directly stimulates normal adult megakaryocytopoiesis in the presence of thrombopoietin or combined cytokines

In order to investigate the direct effects of retinoids on normal adult hem atopoietic progenitors, purified CD34(+) cells were seeded in serum-free cu ltures in the presence of pharmacological (10(-6)) M or physiological (10(- 12)) M concentrations of all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) plus combinations of specific cytokines. 10(-6) M ATRA and 9-cis RA significantly decreased the number of granulomacrophagic, erythroi d and megakaryocytic (CFU-meg) progenitors. On the other hand, 10(-12) M AT RA significantly promoted the growth of CFU-meg, in the presence either of thrombopoietin or of IL-3 + GM-CSF, and induced a reproducible stimulation of the immature CD34(+)DR(-) subset. In conclusion, our findings suggest th at retinoic acids probably play a direct role in normal adult hematopoietic development at both physiological and pharmacological concentrations. The stimulatory effect on megakaryocytopoiesis should be considered in the pers pective of a potential use of low-dose ATRA, combined with thrombopoietin o r other cytokines, in pathological conditions where the megakaryocytic comp artment is impaired and the stimulation of megakaryocytopoiesis is requeste d.