Mechanisms Mediating the Inhibitory Effect of All‐Trans Retinoic Acid on Primitive Hematopoietic Stem Cells in Human Long‐Term Bone Marrow Culture

Abstract

All-trans retinoic acid (RA) has generally been found to stimulate late committed (colony-forming unitgranulocyte, macrophage [CFU-GM]) and inhibit early (CFU-Blast) normal human myeloid progenitor cells. The present study provides the first evidence that the pharmacological concentration of 1 µM RA, exerts an inhibitory effect on the proliferation of functional human primitive hemopoietic stem cells (cobblestone area-forming cell [CFAC]) in long-term bone marrow cultures. Treatment of four-week confluent bone marrow culture with 1 µM RA for five days significantly reduced week 4 CAFC from 88 ± 10 in control cultures to only 52 ± 12 per 10 5 cells, p < 0.01. Quantitative enzyme-linked immunosorbent assay measurement of interleukin 6 (IL-6) and IL-11 produced from the fourweek bone marrow stroma culture revealed only a slight and moderate increase of IL-6 and IL-11 production after treatment with RA. On the other hand, treatment with RA profoundly increased the soluble receptor gp130 released from the four-week bone marrow stroma by 7.5-fold from only 145 ± 2.1 pg per ml in control cultures to 1,069.9 ± 3.8 pg per ml in RA-treated cultures. A similar marked increase in the soluble adhesion molecules ICAM-1, and to a lesser extent VCAM-1, released from the four-week bone marrow stroma was observed after RA treatment.IL-6 has been implicated in the inhibitory effect of RA in several human hemopoietic and nonhemopoietic cells. The common transducing signal chain gp130, for all receptors of the IL-6 cytokine family, is expressed in most primitive human hemopoietic CD34 + cells and its signaling was shown to synergize with other hemopoietic cytokines to expand primitive human hemopoietic stem cells. Recently, soluble gp130 was shown to be a natural potent antagonist of the human IL-6 cytokine family by binding the ligand and thereby reducing its bioavailability.The profound and rapid 7.5-fold increase in the natural antagonist of human IL-6 cytokine family after RA treatment could abrogate the gp130 signaling required for proliferation and/or expansion of human primitive hemopoietic stem cells and lead to the observed inhibitory effect of RA on CAFC. Both adhesion molecules VCAM-1 and ICAM-1 mediate human hemopoietic stem cell adhesion to marrow stroma. The present significant increase in the soluble form of these adhesion molecules after RA treatment could exert a significant antagonist effect on their function and hence may impair CAFC adhesion to marrow stroma.In conclusion, the RA inhibitory effect on the proliferation of primitive human hemopoietic stem cells could be mediated through: A) an impaired hemopoietic stem cell adhesion due to the significant increase in soluble adhesion molecules released from the marrow stroma after RA treatment, and B) a significantly reduced gp130 signaling that is necessary for stem cell proliferation due to the natural antagonistic effect of the profoundly increased level of soluble gp130 released from the marrow stroma after treatment with RA.

Retinoic acid represses invasion and stem cell phenotype by induction of the metastasis suppressors RARRES1 and LXN

“…The differentiated TA and CB cells were more responsive to atRA and consequently induced RARRES1 and LXN expression to a greater magnitude than in the SC fraction. These results correlate with previous studies, which showed that RA promoted differentiation of SCs from a range of different tissues, including human HSC, 32, 33 mouse embryonic SC, 34 rabbit bone marrow-derived mesenchymal SC 35 and human breast cancer SC. 36 In the converse experiment, inhibition of retinoid signalling pathways has been shown to induce the expansion of human HSC.…”

Prenatal treatment with retinoic acid accelerates type 1 alveolar cell proliferation of the hypoplastic lung in the nitrofen model of congenital diaphragmatic hernia

“…The effect of RA on ICAM-1 expression in tumor cell lines or cultured cells has been studied [23][24][25]. Retinoic acid induced ICAM-1 expression in many cases, but the intracellular signalling events that participate in the upregulation of ICAM-1 are not fully understood.…”

Effect of human cytomegalovirus infection on the expression of Hoxb2 and Hoxb4 genes in the developmental process of cord blood erythroid progenitors

“…ATRA was found to stimulate the differentiation of granulopoietic cells to terminal cells and influenced the differentiation of hematopoietic stem cells during the embryonic period of mammals (28). ATRA (1 µmol/l) was found to inhibit proliferation and differentiation of human hematopoietic stem cells in vitro (29). The inhibition rate of human leukemia cell strains such as HL-60 was 50% as induced by 3x10 -10 to 10 -9 mmol/l of ATRA while the proliferation rate was increased to 150% after treatment with 3x10 -9 to 10 -8 mmol/l of ATRA.…”