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

• Published in: Experimental hematology 1999-04, Vol.27 (4), p.642-653
• Main Authors: Josefsen, Dag, Blomhoff, Heidi Kiil, Lømo, Jon, Blystad, Anne Kirsti, Smeland, Erlend B
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Benzoates - pharmacology; CD34 + cells—Apoptosis—Retinoic acid—Retinoid acid receptor-selective ligand—Retinoid X receptor-selective ligands; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Lineage; Cells, Cultured; Cyclohexanes - pharmacology; Dose-Response Relationship, Drug; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Erythropoietin - pharmacology; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; In Situ Nick-End Labeling; Ligands; Pentanoic Acids - pharmacology; Receptors, Retinoic Acid - metabolism; Retinoid X Receptors; Retinoids - pharmacology; Signal Transduction - drug effects; Transcription Factors - metabolism; Tretinoin - pharmacology
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/S0301-472X(98)00073-3

Retinoids are bifunctional regulators of growth and differentiation of hematopoietic cells. In this study we explored the effects of retinoic acid (RA) on apoptosis of human CD34 + hematopoietic progenitor cells isolated from 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 control cells cultured in medium alone. The effect was dose dependent and appeared relatively late. Significant differences were 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, or by the Nicoletti technique demonstrating a subdiploid population by DNA staining. 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-apoptotic 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, RA induced apoptosis of CD34 + cells and CD34 + CD71 + cells stimulated with erythropoietin. To explore the receptor signaling pathways involved in RA-induced apoptosis, we used selective ligands for retinoic acid receptors (RARs; RO13-7410) and retinoid X receptors (RXRs; RO 25-6603). We found that RARs were involved in RA-mediated apoptosis of myeloid progenitor cells, whereas RARs as well as RXRs were involved in RA-mediated apoptosis of erythroid progenitor cells.