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Stem Cells, Vol. 18, No. 3, 214-219, May 2000
© 2000 AlphaMed Press

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

J. Sammons, N. Ahmed, M.A. Khokher, H.T. Hassan

School of Health Sciences, University of Wolverhampton, England, United Kingdom

Key Words. Adhesion molecules • Cobblestone area-forming cell • gp130 • Interleukin 6 • Interleukin 11 • Primitive stem cell • Retinoic acid

Professor H.T. Hassan, M.D., Ph.D. (Cambridge), Professor of Oncology, School of Health Sciences, University of Wolverhampton, 62-68 Lichfield Street, Wolverhampton WV1 1DJ, England, UK. Telephone: +44 1902 321155; e-mail: H.T.Hassan{at}wlv.ac.uk


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
All-trans retinoic acid (RA) has generally been found to stimulate late committed (colony-forming unit- granulocyte, 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 105 cells, p < 0.01. Quantitative enzyme-linked immunosorbent assay measurement of interleukin 6 (IL-6) and IL-11 produced from the four-week 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.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
All-trans retinoic acid (RA) exerts profound effects on the proliferation and differentiation of normal and leukemia myeloid cells. In vitro, RA was shown to stimulate the clonal growth of normal human myeloid and erythroid committed progenitor cells in both short- and long-term bone marrow cultures [1-4]. Also, numerous studies have shown RA to inhibit proliferation and induce granulocytic differentiation of several human myeloid leukemia cell lines and certain primary acute myeloid leukemia blast cells [5]. Moreover, RA as induction and/or maintenance treatment in acute promyelocytic leukemia patients improves disease-free and overall survival compared to chemotherapy alone [6].

Recently, several studies have reported the direct inhibitory effect of RA on early normal hemopoietic progenitor cells in both murine and human systems [7, 8]. At the pharmacological concentration of 1 µM that represents the usual clinical dose administered, RA inhibited CD34+ blast cell colony formation (CFU-blast) on the normal human bone marrow stromal layer [8]. On the other hand, there is no information about the effect of RA on functional human primitive hemopoietic stem cells. The four-week-old cobblestone area-forming cells (CAFC), which were equated with long-term culture initiating cells, represent the functional primitive repopulating hemopoietic stem cell in long-term bone marrow culture [9]. Therefore, the present study was performed to examine any similar inhibitory effect of 1 µM RA on the CAFC in long-term human bone marrow cultures and to explore possible mechanism(s) mediating such an inhibitory effect. RA has been shown to inhibit interleukin 6 (IL-6) production in several normal and malignant human cell types including B-lymphocytes, osteoblasts, lung fibroblasts, keratinocytes, epidermoid carcinoma, Kaposi's sarcoma and myeloma cells [10-20]. Hence, the present study investigated the effect of RA on IL-6 and IL–11 production, as well as their soluble signal transducing receptor gp130 (sgp 130) from normal human bone marrow stroma. Also, human bone marrow stroma cells express both adhesion molecules: vascular adhesion molecule-1 ([VCAM-1], CD102, ligand for very late acting antigen-4) and intercellular adhesion molecule-1 ([ICAM-1], CD54, ligand for ß2-integrin), which mediate the primitive human CD34+ stem cell adhesion to marrow stroma [21]. Thus, the effect of RA on soluble VCAM-1 and ICAM-1 production from normal human bone marrow stroma was also examined.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human Long-Term Bone Marrow Culture
Human long-term bone marrow cultures were established in duplicate as described before [22]. Briefly, human bone marrow mononuclear cells were seeded at a concentration of one million cells per ml in {alpha}-modified essential medium containing 12.5% fetal calf serum, 12.5% horse serum, 2 mM glutamine, 100 µM 2-mercaptoethanol to which 1 µM freshly dissolved hydrocortisone (Sigma; Poole, UK) was added in 12-well tissue culture plates at 37°C in humidified incubator with 5% CO2 for four weeks. Medium exchange was performed by removing half the medium and nonadherent cells and adding fresh medium with all supplements to restore original volume on a weekly basis. After four weeks, 1 µM RA was added in darkness to some wells and then both control and RA-treated four-week-old marrow cultures were incubated for five days at 37°C in a humidified incubator with 5% CO2.

Quantitative Assay of Four-Week CAFC
The frequency of four-week CAFC was determined in each control and RA-treated well as described before [22]. CAFC, which is defined as areas of 10 or more small angular cells within the bone marrow stroma, were scored microscopically in each well by two independent hematologists.

Quantitative Enzyme-Linked Immunosorbent Assay (ELISA) Measurement of IL-6, IL-11, and sgp130 Production
ELISA kits were used for the in vitro quantitative determination of human IL-6, sgp130 (R&D Systems; Oxon, UK; http://www.rndsystems.com) and IL-11 concentrations (Diaclone; Boldon, UK; http://www.diaclone.com), in the supernatant of control and RA-treated four-week bone marrow cultures as previously described [13]. RA-treated and control supernatant samples, together with standards and the subsequent addition of biotinylated antibody of IL-6 or sgp130, were incubated for 2 h in a 96-well microtitre plate precoated with an antihuman IL-6 or gp130 (R&D Systems) at room temperature. The plate was washed with the washing buffer provided in the ELISA kit. This was followed by incubation with Streptavidin-horseradish peroxidase conjugate (TCS Biologicals; Buckingham, UK; http://tcsgroup.co.uk) for 30 min at room temperature. After washing, premixed TMB (3,3', 5,5'-tetramethylbenzidine) substrate solution (TCS Biologicals) was added to each well of the microtitre plate and allowed to develop at room temperature in the dark for a further 20 min. The enzymatic reaction was terminated by addition of stop solution, also provided in the ELISA kit, and the intensity of color developed was measured using an ELISA plate reader and a 450 nm filter. A standard curve of absorbance values obtained versus the corresponding IL-6 or sgp130 concentration of the standard ELISA kit was plotted employing the computer software package (Genesis; Hampshire, UK). The concentrations of IL-6 and sgp130 in each sample were determined as pg per ml by extrapolating from the standard curve.

In terms of determining the concentrations of human IL-11, the same ELISA procedure was applied as explained above. Briefly, the monoclonal antibody specific for IL-11 was coated onto the 96 wells of the microtitre plate. Standards and controls were added, alongside bone marrow culture supernatants containing the IL-11 antigen. Biotinylated monoclonal antibody specific for IL-11 was also added simultaneously to the 96 wells. After 2 h incubation and a washing step, the enzyme conjugate was added to the 96 wells. This was proceeded by 2.5 h incubation at room temperature. After washing, substrate solution was added and incubated for 30 min at room temperature. The absorbance was read at 450 nm within 30 min of stopping the enzyme reaction. The concentrations of IL-11 in each sample were measured as pg per ml by extrapolating from the standard curve.

Quantitative ELISA Measurement of Soluble Adhesion Molecules (sVCAM-1 and sICAM-1) Production
ELISA kits were used for the in vitro quantitative determination of human sVCAM-1 and sICAM-1 (Diaclone), in the supernatant of control and RA-treated four-week bone marrow cultures. Briefly, monoclonal antibodies specific for sVCAM-1 or sICAM-1 were coated onto the 96 wells of the microtitre plate. Standards and controls were pipetted, alongside bone marrow culture supernatant containing the sVCAM-1 or sICAM-1 antigen. Biotinylated monoclonal antibodies specific for sVCAM-1 or sICAM-1 were also added simultaneously to the 96 wells. This was followed by incubation for 1 h at room temperature. After washing, the streptavidin-horseradish peroxidase enzyme conjugated to monoclonal antibodies specific for sVCAM-1 or sICAM-1 was added. Incubation was carried out at room temperature for 30 min, followed by washing. TMB substrate solution was added to the 96 wells and the colored reaction product was allowed to develop for 10-15 min. The enzyme-substrate reaction was terminated by the addition of sulphuric acid, and the intensity of the colored product was measured using an ELISA reader and 450 nm filter. A standard curve of absorbance values obtained versus the corresponding sVCAM-1 or sICAM-1 concentration of the standard ELISA kit was plotted employing the computer software package (Genesis). The concentrations of sVCAM-1 and sICAM-1 in each sample were measured as pg per ml by extrapolating from the standard curve.

Statistical Analysis
Results represent the mean ± standard deviation of determinations from three separate experiments performed in duplicate with four normal human bone marrow samples. Statistical significance was evaluated using the two-tailed Student's t-test.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of RA on Four-Week Normal Human Bone Marrow Stroma and CAFC
The morphology and cell viability of the four-week-old normal human bone marrow stroma after five days of 1 µM RA treatment were not different from control cultures. However, the number of week 4 CAFC was significantly reduced after RA treatment from 88 ± 10 in control cultures to only 52 ± 12 per 105 cells, p < 0.01 (Table 1Go). A similar number of normal human bone marrow week 4 CAFC per 105 cells was previously reported on the murine stromal cell line FBMD-1 [23].


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  		Table 1. Effect of RA on CAFC as well as cytokines, sgp130 and soluble adhesion molecule production from normal human bone marrow stroma
 
Effect of RA on IL-6, IL-11, and sgp130 Production
The four-week normal human bone marrow stroma produced 220.1 ± 9.8 ng IL-6 per ml in control cultures. After treatment with 1 µM RA, only a slight increase in IL-6 production to 252.6 ± 12.4 ng per ml was observed on day 5 (Table 1Go).

However, the IL-11 production from the four-week normal human bone marrow stroma increased to a greater extent from 57.2 ± 2.3 pg per ml in control cultures to 88.3 ± 1.1 pg per ml in 1 µM RA-treated cultures, p < 0.05 (Table 1Go).

On the other hand, sgp130 released from the four-week normal human bone marrow stroma was profoundly increased 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 1 µM RA-treated cultures (Table 1Go).

Effect of RA on Soluble Adhesion Molecule Production
The four-week normal human bone marrow stroma released four times more sVCAM-1 (1,499 ± 34 pg per ml) than sICAM-1 (472 ± 42 pg per ml) (Table 1Go). The concentrations of both soluble adhesion molecules released from the marrow stoma were increased after treatment with 1 µM RA. Treatment with 1 µM RA increased the sVCAM-1 released to 1,975 ± 54 pg per ml on day 5, p < 0.01 (Table 1Go). More significantly, the sICAM-1 released was markedly increased by 7.5-fold to 3,464 ± 56 pg per ml on day 5 in 1 µM RA-treated marrow cultures (Table 1Go).


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Vitamin A-derived retinoids, including all-trans RA, play an important role in regulating cellular proliferation and differentiation in many human cell types. They are powerful therapeutic agents used in the treatment of a variety of skin and malignant diseases. The present study shows for the first time that the pharmacological concentration of 1 µM RA exerts an inhibitory effect on week 4 CAFC, the functional human primitive hemopoietic stem cells in long-term bone marrow culture. The present results extend the inhibitory role of RA previously observed in early human hemopoietic progenitor cells (CFU-Blast) [8] to the functional primitive human hemopoietic stem cells (CAFC).

IL-6 has been implicated in the inhibitory effect of RA in several human hemopoietic and nonhemopoietic cells [10-20]. Two molecular mechanisms were identified for the RA-IL-6 antagonism phenomenon: A) RA receptors inhibit IL-6 promoter action by antagonizing the enhancer action of the transcription nuclear factor-IL-6, and B) RA downregulates both IL-6 receptors: the IL-6 binding chain (gp80) and the transducing chain (gp130) [12, 14, 16]. The common transducing signal chain gp130, for all receptors of the IL-6 cytokine family including IL-6, IL-11, oncostatin M, leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotrophin, is homodimerized by both IL-6 and IL-11 in murine bone marrow stroma [24]. gp130 is expressed in most primitive human hemopoietic CD34+ cells [25], and its signaling was shown in numerous studies to synergize with other hemopoietic cytokines to stimulate trilineage human hemopoiesis and expand primitive human hemopoietic stem cells [26-32]. Also, the addition of anti-gp130 monoclonal antibodies completely abrogated the synergistic action [26-30]. Moreover, the genetic insertion of gp130 into primitive hemopoietic stem cells from murine bone marrow has been shown to expand the proliferation of these cells in the presence of stem cell factor [33].

Recently, sgp130 was shown to be a natural potent antagonist of the human IL-6 cytokine family by binding the ligand and thereby reducing its bioavailability [34, 35]. The present results demonstrated a 7.5-fold increase in sgp130 in four-week bone marrow cultures after treatment with 1 µM RA (Table 1Go). This profound and rapid increase in the natural antagonist of the human IL-6 cytokine family 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. The RA-IL-6 antagonism seen in normal human osteoblasts is also profound and rapid [13].

Both adhesion molecules VCAM-1 and ICAM-1 mediate human hemopoietic stem cell adhesion to marrow stroma [21]. Also, the addition of anti-VCAM-1 monoclonal antibody was shown to significantly inhibit human hemopoietic CD34+ cell adhesion to bone marrow stroma [21]. Moreover, both VCAM-1 and ICAM-1 could be involved not only in the homing of hemopoietic stem cells within specific inductive areas of the bone marrow, but also in transducing signals to induce their proliferation [21, 36]. The present results show a significant increase in the soluble form of ICAM-1 and to a lesser extent, of VCAM-1, in four-week bone marrow cultures after treatment with 1 µM RA (Table 1Go). This marked increase in the soluble adhesion molecules could exert a significant antagonist effect on the function of VCAM-1 and ICAM-1, and hence may impair CAFC primitive human hemopoietic stem cell adhesion to marrow stroma. Recently, the adhesion of primitive human hemopoietic stem cells to marrow stroma was shown to be required for an effective proliferation and/or expansion of these stem cells [37].

In conclusion, the pharmacological concentration of RA (1 µM) exerts distinct effects on normal human hemopoietic progenitor and stem cells—stimulatory in late committed progenitor cells and inhibitory in primitive hemopoietic stem cells. Therefore, the 1 µM RA has not only synergistic interaction with many chemotherapy drugs in human leukemia stem cells [5], but also its inhibitory effect on normal hemopoietic stem cells could offer a potential protection of these normal marrow stem cells during chemotherapy. The RA inhibitory effect on the proliferation of primitive human hemopoietic stem cells could be mediated through an impaired hemopoietic stem cell adhesion caused by a significant observed increase in soluble adhesion molecules released from the marrow stroma, and through a significantly reduced gp130 signaling caused by the natural antagonistic effect of a profoundly increased level of sgp130 released after treatment with RA.


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received March 21, 1999; accepted for publication April 12, 1999.



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