title: 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.
abstract: 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.
authors: Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo. dag.josefsen@labmed.uio.no
authors: D
authors: D
authors: Josefsen
authors: H K
authors: HK
authors: Blomhoff
authors: J
authors: J
authors: Lømo
authors: A K
authors: AK
authors: Blystad
authors: E B
authors: EB
authors: Smeland
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008024:Ligands; D010421:Pentanoic Acids / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001565:Benzoates; D003510:Cyclohexanes; D008024:Ligands; D010421:Pentanoic Acids; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; C097599:Ro 25-6603; D014157:Transcription Factors; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor