Stem Cells, Vol. 15, No. 6, 455-460,
November 1997
© 1997 AlphaMed Press
Inhibitory Action of the Peptide AcSDKP on the Proliferative State of Hematopoietic Stem Cells in the Presence of Captopril but not Lisinopril
J.E. Chisia,
J. Wdzieczak-Bakalab,
A.C. Richesa
a School of Biological and Medical Sciences, University of St. Andrews, St. Andrews, Fife, Scotland, United Kingdom;
b Institut de Chimie des Substances Naturelles, CNRS,Gif-sur-Yvette, France
Key Words. AcSDKP • Irradiation • Angiotensin 1-converting enzyme (ACE) • Captopril • Lisinopril • Hematopoietic stem cells
Correspondence:
Dr. John Eugenes Chisi, School of Biological and Medical Sciences, University of St. Andrews, St. Andrews, Fife KY16 9TS, Scotland, United Kingdom.
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Abstract
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The effect of Angiotensin I-converting enzyme (ACE) inhibitors on their own and in combination with the peptide AcSDKP on the proliferation of hematopoietic stem cells has been investigated. Hematopoietic stem cells from murine bone marrow induced into cell cycle following exposure to 2 Gy 
-irradiation were incubated in vitro for up to 24 h in the presence of medium, captopril/lisinopril, AcSDKP, and AcSDKP with either ACE inhibitor. Hematopoietic stem cells were monitored using the high proliferative potential-colony forming cell-1 (HPP-CFC-1) population cloned in the presence of human IL-1ß, murine IL-3, and murine M-CSF. No significant inhibitory effect was observed in the presence of AcSDKP on its own and AcSDKP in combination with lisinopril. However, there was a significant inhibition of stem cell cycling when AcSDKP and captopril were combined. This suggests that captopril inhibits AcSDKP breakdown better than lisinopril. The combination of AcSDKP and captopril also had an inhibitory effect on cell recruitment into S phase. The fact that a combination of AcSDKP and captopril switches cycling hematopoietic stem cells out of cycle indicates the importance of the N-active catalytic site of ACE in AcSDKP hydrolysis in vitro. Thus, AcSDKP in combination with appropriate ACE inhibitors may be of use in regulating the proliferation of hematopoietic stem cells in vitro.
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Introduction
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Hematopoietic stem cell proliferation is controlled by a series of positive and negative regulatory factors. Stimulatory factors are produced following insult to the hematopoietic system [1]. This damage induces stem cells to enter into cell cycle. If the insult persists when stem cells are cycling, there is a possibility of stem cell depletion and therefore bone marrow failure [2]. To prevent this depletion, it is suggested that a balance between inhibitory and stimulatory factors be maintained during cytotoxic insults to the hematopoietic system by increasing the concentrations of inhibitors [3]. A number of inhibitory factors have been identified, but some lack specificity while others can be toxic. Some of these inhibitors also suppress tumor cells from cycling [4, 5].
A tetrapeptide, Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP), was first identified in extracts from fetal calf bone marrow [6]. It has been shown to exhibit no effect on the cycling status of tumor cells at a concentration which inhibits normal hematopoietic progenitor cell cycling [7]. It is synthesized in mice under steady-state conditions and is secreted by the bone marrow in long-term culture [8]. AcSDKP opposes the action of stimulators which recruit cells from G0 or early G1 to enter into S phase [9, 10]. Since AcSDKP enhances the adherence of hematopoietic cells to stromal cells [11], it has been suggested that the peptide may influence inhibitory factor production by the stroma. AcSDKP protects normal hematopoietic cells from cytotoxic effects of drugs [12], hyperthermia [13], and phototherapy [14]. This is of clinical significance because these agents are used to purge neoplastic cells from autologous bone marrow transplants. AcSDKP with granulocyte colony-stimulating factor rescues stem cells from the cytotoxic effects of irradiation in vivo [15]. Cells responsible for AcSDKP production in vivo have not yet been identified. However, it has been recently reported that macrophages could be responsible for AcSDKP synthesis [16]. Certain endogenous macromolecules contain the SDKP sequence [17]. There have been suggestions that thymosin ß4, one of these macromolecules, may be the source of AcSDKP. It has also been shown that thymosin ß4 inhibits hematopoietic stem cell proliferation [18].
AcSDKP is degraded by Angiotensin I-converting enzyme (ACE), a ubiquitous dipeptidyl carboxypeptidase. This enzyme is involved in the first rate-limiting step of AcSDKP degradation in human plasma [19]. Human ACE has NH2 and CO2H active catalytic domains which act independently with ACE inhibitors [20]. ACE hydrolyses AcSDKP by the N-active site [21]. Inhibition of ACE activity by captopril in vivo in humans has been shown to increase the plasma concentration of AcSDKP [22].
We have studied the effects of two ACE inhibitors: captopril, which is more potent at the N-active site, and lisinopril, which is more active at the C-active site in combination with AcSDKP on the kinetics of hematopoietic stem cell. The stem cells were studied using the in vitro high proliferative potential colony-forming cells-1 (HPP-CFC-1) assay [23].
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Materials and Methods
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Mice
All experiments were carried out using female 8- to 12-week-old CD1 mice. Animals were bred and housed at the University of St. Andrews, Scotland, UK. Animals in groups of threes were given 2 Gy whole body -irradiation (CIS BioInternational IBL 437C 137Cs -irradiation source. Dose rate 4.66 Gy/minute).
AcSDKP and Ace Inhibitors
AcSDKP (Mr = 487) ( IPSEN-Biotech; Paris, France) was supplied as a lyophilized sample and stored at –20°C. The peptide was dissolved in sterile distilled water, and aliquoted in polypropylene cryotubes (Nunc; Denmark), and stored at –20°C. For use, each sample was diluted in Dulbecco's medium (GIBCO BRL; Paisley, Scotland, UK) supplemented with 2% fetal calf serum (FCS) (Globepharm; Esher, Surrey, UK). A final concentration of 10–9 M was added to a pair of petri dishes or universal tubes containing irradiated bone marrow cell suspensions with 1 mM captopril (Sigma; UK) or 1mM lisinopril (Sigma) [24].
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Stem Cell Assay: HPP-CFC-1
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A feeder layer containing two ml of Dulbecco's medium, 20% horse serum (Globepharm) penicillin 50 UI/ml (Sigma)/streptomycin 50 µg/ml (Sigma) and 2 mM L-glutamine (D20% HS PS/G) with 0.5% (v/v) melted agar (Bacto Agar; Difco Labs; Detroit, MI) and recombinant murine interleukin-3 (IL-3) at 100 ng/ml (R&D; Abingdon, Oxon, UK), recombinant human interleukin-1ß (IL-1ß) at 100 U/ml and recombinant murine macrophage colony-stimulating factor (M-CSF) at 200 ng/ml (R&D) were plated in a 60 mm non-tissue-culture petri dish (Nunc).
Cells were sampled 24 h post-irradiation. Cytosine arabinoside (Ara-C) suicide assay was carried out before plating to analyze the percentage of cells in S-phase [25]. Cells were washed twice after incubation, suspended in D20% HS PS/G with 0.3% melted agar (Bacto Agar; Difco Labs) and plated on the feeder layer at a final dose of 5 x 104 cells per petri dish in four separate petri dishes. Petri dishes were incubated for 14 days at 37°C in 10% CO2 in a fully humidified atmosphere. A day before assaying, 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride (INT) (BDH Chemicals, Ltd.; Poole, UK) was added to all culture dishes [26] and colonies were scored macroscopically. For comparison, normal bone marrow cells were incubated and treated in the same way as irradiated cells. Statistical comparison of the proportion of HPP-CFC-1 population in S phase among the cell populations was determined by using the unpaired Student's t-test.
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Effect of Ace Inhibitors and AcSDKP on Stem Cell Cycling
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The proportion of HPP-CFC-1 in S phase was measured in the presence or absence of ACE inhibitors. It was also measured in the presence of ACE inhibitors with or without AcSDKP and in the presence of AcSDKP on its own. All these protocols were measured using a one-h incubation with Ara-C. The bone marrow cell suspension (2 ml) was transferred to two pairs of 20 ml universal tubes (Sterilin, Stone; Staffordshire, UK). Captopril or lisinopril was added to one pair. 25 µg/ml Ara-C (Sigma) in Dulbecco's medium, 30% FCS, penicillin 50 IU/ml/streptomycin 50 µg/ml and 2 mM L-glutamine (D30% FCS PS/G) was added to one tube of each pair and plain medium (D30% FCS PS/G) to the other. All tubes were incubated for one h at 37°C. To test the effect of AcSDKP, ACE inhibitors plus AcSDKP (10–9 M) or AcSDKP (10–9 M) only were incubated in the same way as above. At the end of the incubation period, cells were washed twice with D20% HS PS/G. Cellularity was adjusted to 2.5 x 104 cells/ml and plated for HPP-CFC-1 assay. The proportion of HPP-CFC-1 in S phase was assessed 24 h after in vitro incubation to test the response of cells to ACE inhibitors and AcSDKP. Bone marrow cell suspension (2 ml) was transferred to each of four 30 mm triple-vent non-tissue-culture grade petri dishes (Sterilin). To one pair, captopril or lisinopril was added. The other pair of dishes had no ACE inhibitors added. For the AcSDKP assay, ACE inhibitors plus AcSDKP (10–9 M) or AcSDKP (10–9 M) alone were added to petri dishes. Dishes were incubated at 37°C in a 10% CO2 fully humidified atmosphere. After 23 h of incubation, an Ara-C suicide assay was performed. Cells were transferred to labeled 20 ml universal tubes, washed, the cellularity adjusted, and plated for HPP-CFC-1 assay. Eight independent experiments were performed in the assay where captopril was incubated in the presence of AcSDKP. Four independent experiments were performed in the rest.
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The Effect of AcSDKP and Captopril on the Cell Cycle
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Irradiated bone marrow cells were flushed from femurs and tibias and incubated in the presence of D10% HS PS/G and 25 µg/ml Ara-C for one h. Cells were immediately washed twice with D20% HS PS/G. They were suspended in D10% HS PS/G then transferred to two pairs of universal tubes each containing 2 ml cell suspension. They were incubated with or without 1 mM captopril and AcSDKP (10–9 M) per pair for three h, after which another S phase suicide assay was performed. At the end of the incubation period, cells were washed twice and the cellularity adjusted for HPP-CFC-1 assay.
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Results
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In Vitro Incubation with Captopril Has No Effect on Normal Hematopoietic Stem Cell Cycling
As shown in Figure 1, in the absence of captopril, 8.13% ± 2.57% of HPP-CFC-1 were in S phase at time 0. The proportion in S phase did not significantly change after 24 h of incubation and was found to be 12.28% ± 4.72% (p > 0.05). Incubation of normal bone marrow cells with captopril in vitro did not significantly change the proportion of stem cells in S phase. While 13.58% ± 2.58% were in S phase at time 0, the proportion in S phase after 24 h of incubation in the presence of captopril was 14.67% ± 3.54% (p > 0.05).
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Figure 1. Normal bone marrow cells were incubated for 24 h in vitro with and without captopril (1 mM). The percentage of HPP-CFC-1 in S phase was not significantly reduced after 24 h incubation in the absence of captopril (T = 0 and T = 24; p > 0.05). Captopril had no effect on the proportion of HPP-CFC-1 in S phase after 24 h incubation (T = 0 and T =24; p > 0.05) (n = 4, error bars = ± SE).
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Effects of Ace Inhibitors and AcSDKP on the Proliferation of Hematopoietic Stem Cells
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As shown in Figures 2 and 3, when irradiated bone marrow cells were incubated for up to 24 h in the absence of ACE inhibitors, they remained in cell cycle. With lisinopril, the proportion in S phase was 38.61% ± 1.68% at time 0 and 43.08% ± 3.39% (p > 0.05) after 24 h of incubation ( Fig. 2A). There was no significant reduction in the proportion of stem cells in S phase after the addition of AcSDKP (10–9 M) in the presence of lisinopril. The initial proportion in S phase was 33.19% ± 0.83%, and it was 25.69% ± 4.44% after 24 h of incubation (p > 0.05) ( Fig. 2B). In the presence of captopril, 45.18% ± 6.17% of cells were in S phase at time 0, and the proportion did not significantly change after 24 h of incubation at 47.74% ± 5.41% (p > 0.05) ( Fig. 3A). In the presence of AcSDKP, 40.19% ± 2.56% of HPP-CFC-1 were in S phase and 31.82% ± 2.95% (p > 0.05) were still cycling after 24 h of in vitro incubation ( Fig. 3B). However, after the addition of AcSDKP (10–9 M) in the presence of captopril, there was a significantly reduced proportion of HPP-CFC-1 in S phase at the end of the 24-h incubation period. While at time 0, 42.12% ± 3.70% of cells were in S phase, only 10.27% ± 1.86% (p < 0.001) ( Fig. 3B) were in S phase after 24 h.
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Figure 2. Bone marrow cells removed one day after 2 Gy irradiation were incubated in the presence and absence of lisinopril. The proportion of HPP-CFC-1 in S phase in irradiated bone marrow cells remained high after in vitro incubation in the presence or absence of lisinopril, where n is the number of individual experiments. A) ± lisinopril (n = 4) , (error bars = ± SE). Following addition of AcSDKP the proportion of HPP-CFC-1 in S phase in the presence of lisinopril was not significantly reduced (p > 0.05). B) ± AcSDKP + lisinopril (n = 4), (error bars = ± SE).
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Figure 3. Bone marrow cells removed one day after 2 Gy irradiation were incubated in the presence and absence of captopril. The proportion of HPP-CFC-1 in S phase in irradiated bone marrow cells remained high after in vitro incubation in the presence or absence of captopril, where n is the number of individual experiments. A) ± captopril (n = 4) , (error bars = ± SE). Following addition of AcSDKP the proportion of HPP-CFC-1 in S phase in the presence of captopril was significantly reduced (p > 0.001). B) ± AcSDKP + captopril (n = 8) AcSDKP had no effect on stem cell cycling both with short and long term incubation. (n = 4), (error bars = ± SE).
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AcSDKP Directly Blocks Cell Entry Into S Phase
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Treating cells for one h with Ara-C kills cell in S phase [25]. Therefore, addition of captopril and AcSDKP soon after Ara-C treatment gives an insight to the mode of action of the peptide. After an initial one-h incubation with Ara-C, there are no cells in S phase at the beginning of the subsequent incubation period. Consequently, the percentage of cells in S phase following this second incubation in the presence or absence of captopril and AcSDKP is the result of cell entry during the second incubation period. Cells were incubated for four h after the initial S phase suicide with Ara-C to allow a large proportion to enter S phase. As shown in Figure 4, the proportion of cells in S phase in the absence of captopril and AcSDKP was 28.44% ± 2.50%. However, there was a significant reduction in cell entry into S phase in the presence of captopril and AcSDKP; only 5.44% ± 1.38% (p < 0.001) had entered S phase after four h of incubation.
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Figure 4. Bone marrow cells removed one day after 2 Gy irradiation were incubated with Ara-C for one h, washed then incubated for a further four h with AcSDKP plus captopril or with medium. The proportion of HPP-CFC-1 that had entered S phase in the absence of AcSDKP plus captopril was high. However, a combination of AcSDKP and captopril blocked cell entry into S phase and the proportion in S phase was low (p < 0.001) (n = 4, error bars = ± SE).
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Discussion
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In vitro incubation with or without ACE inhibitors had no effect on the cycling status of HPP-CFC-1 from both normal or irradiated bone marrow cell suspensions. Incubating cells in the presence of AcSDKP alone did not reduce the proportion of cells in S phase, either after a short or a long incubation period. It has been shown previously that AcSDKP on its own has no inhibitory effect on the proportion of HPP-CFC in S phase in regenerating bone marrow following short incubation periods in serum-free supplemented Dulbecco's medium [9]. AcSDKP has a half life of approximately 3.5 h in FCS [24]. This presumably explains the lack of a noticeable inhibitory effect with the peptide alone. These results indicate that stem cells once induced into cycle remain in cycle until a high enough concentration of inhibitors can switch them out of cycle. The fact that stem cells incubated in the presence of AcSDKP and captopril are switched out of cycle while more remain in cycle when incubated in the presence of AcSDKP and lisinopril suggests the importance of AcSDKP in the regulation of cell cycle if its degradation is prevented. The inhibitory effect of captopril and AcSDKP on regenerating bone marrow also suggests that the peptide may have a direct inhibitory effect on cycling hematopoietic stem cells. However, an indirect effect cannot be excluded as whole bone marrow preparation was used. It is possible that this action is mediated by opposing the effect of stimulators of stem cells as previously shown by Robinson et al. [9]. AcSDKP and captopril blocks the cycling of CFU-S-12 in vitro from regenerating bone marrow [13], and now we have shown that cycling HPP-CFC-1 are also inhibited.
The difference in the ability of the two ACE inhibitors to prevent AcSDKP degradation can be attributed to their varying influence on the two catalytic domains of ACE. Captopril binds preferentially to the NH2-terminal domain of ACE in vitro [20], and it also has the lowest IC50 (10–9 M) for inhibition of AcSDKP hydrolysis by ACE. At 10–8 M captopril inhibits 88% of ACE activity as measured by the hydrolysis of AcSDKP, while lisinopril inhibits only 80%. Enalaprilat, another ACE inhibitor, inhibits 85% of ACE activity on AcSDKP hydrolysis at the same concentration [19]. Thus, it is initially surprising that a differential effect of the two ACE inhibitors was observed in vitro. However, some in vitro work has shown lisinopril to have greater inhibitory potency than captopril on the activity of N-active site when AcSDKP is a substrate [27], but this is highly dependent on Cl– concentration and pH [20]. Thus, lisinopril will not be active in culture medium at the N-active site and AcSDKP action will be compromised.
Captopril is the ACE inhibitor which is most frequently associated with development of neutropenia [28, 29]. Moreover, people at risk of neutropenia are those with renal, collagen, vascular, or autoimmune diseases suggesting high levels of ACE. Since captopril inhibits the N-active catalytic site strongly, it is possible that there is an increase in AcSDKP levels during captopril therapy. Azizi et al. [22] have demonstrated an increase in AcSDKP concentration following in vitro administration of captopril. This could lead to the switching of cycling stem cells out of cycle and/or blocking of stem cell recruitment into cycle and thus contributing to the neutropenia. Captopril, but not lisinopril in vitro, suppresses IL-1ß–induced synthesis of tumor necrosis factor, and IL-1ß-induced synthesis of IL-1
by human peripheral blood mononuclear cells [30]. Since IL-1 is involved in the recruitment of primitive stem cells [31], it implies that captopril on its own may influence cytokine-mediated stem cell proliferation. Captopril and the ability of AcSDKP to inhibit stem cell proliferation in vitro, if realized, could have tremendous implications for purging neoplastic cells from autologous bone marrow transplants.
Administration of the partially purified fractions of fetal calf bone marrow probably containing AcSDKP has been shown to protect mice from the cytotoxic effects of Ara-C [32]. AcSDKP given at an appropriate time after Ara-C administration in vivo prevents colony-forming units-spleen entry into S phase [10]. Therefore, it has rightly been suggested that AcSDKP may be acting at G0/G1 S boundary from the fact that the peptide protects murine hematopoietic cells from the cytotoxic effects of Ara-C. It has now been shown for the first time that AcSDKP in vitro blocks cycling HPP-CFC-1 entry into S phase. In addition, this investigation shows that AcSDKP not only blocks recruitment of stem cells into S phase but also switches them out of cycle. Thus, AcSDKP is active at the G1/S boundary. The possibility that AcSDKP may be active in other phases of the cell cycle cannot be excluded in these studies, which are only investigating the proportion of cells in S phase. It has been suggested that inhibition cell entry into S phase may be mediated by counteracting one or a few key steps of the mitogen signal transduction pathways [33]. AcSDKP has been shown to inhibit the G0/G1 to S phase transition using continuous cell lines.
This study has shown that ACE inhibitors (captopril), presumably by prevention of AcSDKP degradation, act in concert with the peptide to switch cycling hematopoietic stem cells out of cycle. This could be one of the reasons for bone marrow suppression observed after captopril therapy. As captopril is active on the N-domain of ACE, and ACE activity on angiotensin-I is mainly restricted to the C-domain, it should be possible to minimize hematotoxicity by using C-domain-specific ACE inhibitors for treatment of hypertension.
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Acknowledgments
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We thank Tina Briscoe for her technical support. These studies were partly supported by The World Health Organization. IL-1ß was kindly supplied by Immunex; Seattle, Washington.
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accepted for publication on July 16, 1997.
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Abstract
Introduction
