All‐trans retinoic acid shows multiple effects on the survival, proliferation and differentiation of human fetal CD34+ haemopoietic progenitor cells

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Abstract
Summary. To evaluate the effect of all-trans retinoic acid (RA) on fetal haemopoiesis, we performed serum-free liquid and semisolid cultures using CD34+ cells purified from mid-trimester human fetal blood samples. RA, at both physiological (10-n and 10-12M) and pharmacological (10-6 and l(r7M) concentrations, significantly (P+ cells in liquid cultures from day 3 onwards, by suppressing apoptosis induced by serum and growth factor deprivation. On the other hand, RA alone had no significant effect on the proliferation and differentiation of fetal haemopoietic progenitors. In the presence of optimal concentrations of recombinant interleukin-3 (IL-3), stem cell factor (SCF), granulocyte/ macrophage-colony stimulating factor (GM-CSF), and erythropoietin (Epo), low and high doses of RA induced striking differential effects on CD34+ cell proliferation in liquid cultures and colony formation in semisolid assays. In fact, 1CTU M and 1CT12M RA were able to: (i) significantly (P3H-thymidine uptake by fetal CD34+ cells in liquid cultures, and (ii) variably promote the growth of pluripotent (CFU-GEMM, P-6 and 10-7 M RA induced: (i) an overall inhibition (P+ cell growth in liquid cultures; (ii) a marked suppression of BFU-E colony formation (P<0.01) at all Epo concentrations examined (0-002-4IU/ml); and (iii) a significant (P<0.()1) stimulation of CFU-GM with a shift from mixed granulocyte/ macrophage to pure granulocyte colonies, whereas it had little effect on the growth of CFU-GEMM, BFU-meg and CFU-meg. Our data, as a whole, demonstrate that RA has direct complex effects on the survival, growth and clonal expansion of fetal haemopoietic progenitor cells, mainly depending on the presence of recombinant cytokines, the type of progenitor and the concentrations of RA.