Retinoic acid induces apoptosis of human CD34(+) hematopoietic progenitor cells: Involvement of retinoic acid receptors and retinoid X receptors depends on lineage commitment of the hematopoietic progenitor cells

Retinoids are bifunctional regulators of growth and differentiation of hema topoietic cells. In this study we explored the effects of retinoic acid (RA ) on apoptosis of human CD34(-) hematopoietic progenitor cells isolated fro m normal bone marrow, RA (100 nM) induced an increase in the percentage of dead cells from 24% to 44% at day 6 (p < 0.05, n = 6) as compared to contro l cells cultured in medium alone. The effect was dose dependent and appeare d relatively late, Significant differences Here observed from day 4 onward. Apoptosis, or programmed cell death, was demonstrated as the mode of cell death by using the TUNEL assay, which detects single strand nicks in DNA, o r by the Nicoletti technique demonstrating a subdiploid population by DNA s taining. RA previously was found to inhibit granulocyte colony-stimulating factor-and not granulocyte-macrophage colony-stimulating factor-stimulated proliferation of CD34(+) cells, However, we found that RA opposed anti-apop totic effects of G-CSF and GM-CSF on CD34(+) cells (G-CSF: 8% dead cells at day 6; G-CSF + RA: 20%; GM-CSF: 12%; GM-CSF +; RA: 27%).;Moreover, Ri indu ced apoptosis of CD34(+) cells and CD34(+)CD71(+) cells stimulated with ery thropoietin. To explore the receptor signaling pathways involved in RA-indu ced apoptosis, we used setective ligands for retinoic acid receptors (RARs: RO13-7310) and retinoid X receptors (RXRs; RO 25-6603). We found that RARs were involved in RA-mediated apoptosis of myeloid progenitor cells, wherea s RARs as n ell as RXRs were involved in RA-mediated apoptosis of erythroid progenitor cells. (C) 1999 International Society for Experimental Hematolo gy. Published by Elsevier Science Inc.