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Effect of Angiotensin II on Hematopoietic Progenitor Cell Proliferation

Department of Obstetrics and Gynecology, School of Medicine, University of Southern California, Los Angeles, California

Key Words. Angiotensin • Hematopoietic • In vitro • Myeloid • Erythroid

Kathleen E. Rodgers, Ph.D., Livingston Research Center, 1321 N. Mission Rd., Los Angeles, CA 90033, USA. Telephone: 323-227-4965; Fax: 323-222-7038; e-mail: krodgers{at}hsc.usc.edu

	ABSTRACT

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Angiotensin II (AII) induced the proliferation of hematopoietic progenitor cells (HPC) isolated from murine bone marrow or human cord blood. The formation of colonies with more than 50 cells increased approximately five-sevenfold in cultures of murine lineage-negative (Lin^–) bone marrow cells both in the presence (day 10) and absence (day 13) of colony-stimulating factors (CSF). This could be blocked with addition of Losartan, an antagonist of AIITR1. The increase in proliferation of early hematopoietic progenitors (Lin^–Sca l⁺ cells) by AII was approximately threefold and occurred only in the presence of CSF, suggesting that AII may affect mesenchymal stromal cells to induce CSF production and might directly affect early HPC. These in vitro studies were replicated with human HPC isolated from cord blood. AII also accelerated the proliferation and formation of colony-forming units (CFU)-granulocyte/erythroid/macrophage/megakaryocyte and CFU-granulocyte/macrophage colonies by CD34⁺CD38^– enriched progenitors but only in the presence of CSF. Additional studies also indicated that AII can act to increase proliferation in suspension culture. Exposure of CD34⁺ cells to AII in suspension culture, prior to placement in a semisolid medium with erythropoietin, increased the formation of colonies with more than 50 cells and erythroid progenitors approximately five- and 20-fold, respectively. Further, mRNA for the AT1a receptor was expressed by human bone marrow CD34⁺CD38^– cells, CD34⁺CD38^– cells, and lymphocytes, but not mature myeloid cells. Similarly, mRNA for the AT1a receptor was expressed on human stromal cell clones, offering further support to the hypothesis that AII acts partially through the mesenchymal compartment of the bone marrow. These data suggest that AII may be a factor which stimulates the proliferation of hematopoietic progenitors.

	INTRODUCTION

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Bone marrow contains pluripotent stem cells that are capable of reconstituting the hematopoietic system. The hematopoietic system is composed of a multitude of cell types ranging from the terminally differentiated to very primitive hematopoietic progenitor cells (HPC). The term HPC describes a wide range of cell types along the differentiation pathway, including pluripotent progenitor cells that possess the ability to terminally differentiate into hematopoietic lineage-specific progenitor cells. Hematopoiesis is an ongoing process with constant cellular turnover and need for progenitor differentiation into red cells (through BFU-E and colony-forming units-erythroid [CFU-E]), platelets (through CFU-megakaryocytes and megakaryocytes), monocytes (through CFU-granulocyte/macrophage [GM] and CFU-M), granulocytes (through CFU-GM and CFU-G), and lymphocytes (through the lymphoid lineage). Over the last two decades, factors that stimulate the proliferation and differentiation of these cell types, defined here by the cells formed in the colonies, have been elucidated [1].

Therapy involving the transplantation of early hematopoietic progenitors has been successful for a variety of malignant and inherited diseases, and provides myelopoietic support for patients undergoing high-dose chemotherapy or radiotherapy. However, stem or progenitor cell transplantation has been limited by A) the need for a sufficient quantity of stem cells to achieve benefit and B) mature blood cell regeneration after transfusion is slow, requiring one to three weeks [2].

The development of in vitro culture techniques for hematopoietic cells combined with technologies for isolating substantially enriched pure populations of HPC allows for their ex vivo expansion [3, 4]. Successful ex vivo expansion of HPC, both by self-renewal and proliferation with differentiation, promises many clinical benefits, including expanded sources for transplant material (e.g., umbilical cord blood and allogenic cipheresis), and expanded populations of myeloid and megakaryocyte percursors for reinfusion [3].

Angiotensin II (AII) was traditionally recognized as a regulator of blood pressure and drinking responses. However, studies have shown that AII can modify cellular functions unrelated to these physiological events. Over the past decade, numerous studies have shown that AII can modify the proliferation of a variety of cell types, including epidermal stem cells [5, 6]. Further, AII was shown to stimulate the differentiation of erythroid progenitors [7]. In this study, the effect of AII on the ex vivo proliferation of murine and human hematopoietic progenitors was evaluated. These data suggest that AII functions as a hematopoietic factor for in vitro expansion of early and late progenitor cells.

	MATERIALS AND METHODS

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Animals
Female C57Bl/6 mice were purchased from Simonson (City, State, Location??) and used as a source of bone marrow cells in this study. Mice were quarantined at least one week prior to use. Food and water were available ad libitum.

Bone Marrow and Cord Blood Harvest
The bone marrow was harvested from the femur and tibia of mice by flushing with phosphate-buffered saline (PBS), pH 7.4, containing 2% fetal bovine serum (FBS) with a 21-gauge needle. The eluant from the flushing was centrifuged and the pellet was resuspended at 4 x 10⁶ nucleated cells/ml in PBS containing 2% FBS and 5% normal rat serum.

The human hematopoietic progenitors were isolated from cord blood harvested from umbilical cords at delivery in the Los Angeles County General Hospital into vacutainers containing EDTA.

Materials
The reagents for immunomagnetic labeling were purchased from Stem Cell Technologies, Inc. (Vancouver, BC; http://www.stemcell.com). The reagents for cell culture were purchased from Life Technologies, Inc., GIBCO (Grand Island, NY) and Sigma Chemical (St. Louis, MO; http://www.sigma-aldrich.com). The antibody to Sca1 (Ly6-A/E) was purchased from Pharmingen (San Diego, CA; http://www.pharmingen.com). AII was purchased from Bachem (Torrance, CA; http://www.bachem.com) and custom synthesized under Good Manufacturing Processes.

Isolation of Murine Lineage-Negative (Lin^–) Cells
Biotin-labeled monoclonal antibodies to the following murine lineage-specific cell surface antigens were included in a cocktail for HPC enrichment of Lin^– cells and used according to the manufacturer's instructions (Stem Cell Technologies): CD5 (Ly-1), CD45-R (B220), CDllb (Mac 1), myeloid differentiation antigen (Gr-1), and erythroid cells (TER 119). Approximately 2% of the cells loaded onto the column were isolated in the enriched HPC fractions. This process enriched for progenitors by approximately 50-fold.

The enriched HPC cell fractions were diluted into a semisolid medium containing 0.9% methylcellulose in alpha minimal essential medium, 30% fetal calf serum (FCS), 1% bovine serum albumin (BSA), 10 mM 2-mercaptoethanol, 2 mM L-glutamine, and 2% conditioned medium containing CSF (studies in Fig. 1) or recombinant CSF for murine cells including 50 ng/ml recombinant mouse (rm) stem cell factor (SCF) 10 ng/ml rm interleukin 3 (IL-3), 10 ng/ml rm IL-6, and 3 U/ml erythropoietin (EPO) (studies in Figs. 2-4). The conditioned medium was supernatant from splenocyte cultures (1 x 10⁶ cells/ml) incubated for 48 h in RPMI 1640 containing 10 mg/ml pokeweed mitogen, 10% FCS, and antibiotics. Various concentrations of AII, between 0.01 and 100 mg/ml, were added in a small volume to the wells of microtiter dishes, to which 2 x 10³ cells/ml (cultures with CSF) or 4 x 10³ cells/ml (cultures with CSF) were added. The cells were incubated in a humidified atmosphere at 37°C and 5% CO₂ in air, for 14 days. In some experiments (delineated below), 100 nM Losartan, an antagonist of the Type 1 receptor for AII, was added to the cultures.

View larger version (17K): [in this window] [in a new window]   Figure 1. Effect of AII on the formation of colonies by Lin– bone marrow cells. Murine cells were isolated by magnetic immunoaffinity chromatography. Biotin-labeled monoclonal antibodies to murine lineage-specific cell surface antigens were used to label the cells, and Lin+ cells were removed and unlabeled cell-containing medium (enriched HPC Lin– cells) was collected. The enriched HPC cell fractions were diluted into a semisolid medium containing CSF. Various concentrations of AII, between 1 and 100 µg/ml, were added to the wells with 2 x 103 cells/well. The cells were incubated in a humidified atmosphere at 37°C and 5% CO in air, for 14 days. These data are representative of and consistent with four studies.

View larger version (15K): [in this window] [in a new window]   Figure 2. Antagonism of the effect of AII on the formation of colonies by Lin– bone marrow cells. Murine cells were isolated by magnetic immunoaffinity chromatography as described in the Figure 1. The enriched HPC cell fractions were diluted into a semisolid medium containing CSF. Various concentrations of AII, between 0.01 and 100 mg/ml with and without 100 nM Losartan, an antagonist of the Type 1 receptor of AII, were added to the wells with 2 x 103 cells/well. The cells were incubated in a humidified atmosphere at 37°C and 5% CO2 in air, for 14 days. These results are the mean and standard error of data from triplicate wells.

View larger version (15K): [in this window] [in a new window]   Figure 3. Effect of AII on the formation of colonies by Lin-Sca 1lo bone marrow cells. Bone marrow cells were isolated from C57Bl/6 mice and passed over an immunomagnetic affinity column to isolate Lin– cells as described in the legend for Figure 1 and further purified into Sca 1+ cells by flow cytometry. The peak expressed Sca 1, but was dim for this protein is shown in this figure. The cells were then cultured as described in Figure 1. Various concentrations of AII, between 1 and 100 mg/ml were added to the wells with 500 cells/well. The cells were incubated in a humidified atmosphere at 37°C and 5% CO2 in air, for 14 days. These data are representative of and consistent with two studies.

View larger version (18K): [in this window] [in a new window]   Figure 4. Effect of AII on the formation of colonies by Lin–Sca 1hi bone marrow cells. Bone marrow cells were isolated from C57Bl/6 mice and passed over an immunomagnetic affinity column to isolate Lin– cells as described in Figure 1 and further purified into Sca 1+ cells by flow cytometry. The peak that expressed Sca 1 and was bright for this protein is shown in this figure. The cells were then cultured as described in Figure 1. Various concentrations of AII, between 1 and 100 µg/ml were added to the wells with 500 cells/well. The cells were incubated in a humidified atmosphere at 37°C and 5% CO2 in air, for 14 days. These data are representative of and consistent with two studies.

Isolation and Culture of Human CD34⁺ Cells from Cord Blood
Cord blood was obtained from the Los Angeles County General Hospital immediately after delivery into vacutainers containing 10 mM EDTA. The red blood cells were lysed by a hypotonic ammonium chloride solution and the nucleated cells were collected by centrifugation. The pellet from this centrifugation was resuspended at 10⁷ cells/ml. Ten ml of an antibody cocktail were added per ml of cells. The antibody cocktail contained antibodies to glycophorin A, CD2, CD3, CD45, CD24, CD19, CD66b, CD14, and CD16 and was purchased from Stem Cell Technologies and used according to manufacturer's instructions (described above for murine cell isolation). After isolation of the CD34⁺ cells, they were resuspended at 5 x 10⁴ cells/ml in serum-free StemSpan (Stem Cell Technologies) containing the following recombinant human (rHu) factors: 3 IU/ml HuEPO, 20 ng/ml SCF, 20 ng/ml IL-3, and 20 ng/ml GM-CSF. These cells were cultured in 25 cm² flasks for six days at 37°C in a humidified atmosphere of 5% CO₂ in air. After six days, the cells were washed, counted by hematocytometer, and resuspended at 5 x 10⁵ cells/ml. One hundred ml aliquots were added to individual cells of a 96-well microtiter plate in medium containing the above CSF with and without various concentrations of AII (0.01-10 mg/ml). These plates were then incubated for three days at 37°C in 5% CO₂ in air. After this incubation, the cells were washed and placed in semisolid medium containing 0.9% methylcellulose in Iscove's modified Dulbecco's medium (IMDM), 30% FCS, 1% BSA, 10 mM 2-mercaptoethanol, 2 mM L-glutamine, and 10% agar leukocyte conditioned medium with and without 3 IU/ml EPO (Stem Cell Technologies). At various times after initiation of culture, the number and size of colonies, as well as the number of erythroid progenitors per well, were counted.

Isolation and Culture of Human CD34⁺ CD38^– Cells from Cord Blood
The cord blood cells were obtained and isolated as described above. The antibody cocktail used to label the cells contained the antibodies to cell surface proteins described above, but also contained antibodies to CD36, CD45RA, and CD38. These cells were placed directly into semisolid medium containing various concentration of AII. In initial studies, 5 x 10³ cells per well were cultured. However, when AII was added to the cultures, accurate colony enumeration was impossible due to the density of the colonies. In the studies presented, 1 x 10³ cells were cultured per well. In cultures containing rHuCSF, the semisolid medium contained 1% methylcellulose in IMDM, 30% FCS, 1% BSA, 3 U/ml EPO, 10 mM 2-mercaptoethanol, 2 mM L-glutamine, 50 ng/ml SCF, 10 ng/ml GM-CSF, and 10 ng/ml IL-3. These cultures were incubated at 37°C in a humidified atmosphere of 5% CO₂ in air. At various times after initiation of culture, the number and size of colonies were enumerated. On day 12 after initiation of culture, the types of colonies formed were assessed.

Analysis of Receptor Expression by Human HPC and Terminally Differentiated Cells
Oligonucleotide primers were synthesized by the FHCRC Biotech Facility (Seattle, WA) according to sequences described in Haywood [8]. Base pair positions and amplification product size were confirmed by comparison with available sequences in Genbank (http://www.ncbi.nlm.nih.gov/Genbank) (M91464, D13814, U16957, U15592, U20860, U27478, U10273). Both primer pairs were tested on a variety of cDNA templates under the following conditions, an adaptation of the published conditions to our standard procedure: 45 cycles of 94°C 15 sec, 56°C 45 sec, 72°C 30 sec in a phycoerythrin 9600 thermal cycler. The reaction mixture (25 ml) contained 1.5 mM Mg⁺⁺, 200 mM dNTPs, Tris-HCI pH 8.3, 10 pM of each primer, and 4U Taq polymerase. Either 2.5 ng or 1,000 cell equivalents of cDNA template were added to each reaction which were done in duplicate. A description of the isolation of the cell populations, RNA preparation, cDNA synthesis, and actin quantitation is found in Graf and Torok-Storb [9]. These templates had been tested previously by polymerase chain reaction (PCR) and shown to be free of genomic DNA contamination and contain equivalent amounts of actin. Amplification products were separated on a 4% 3:1 GTG agarose gel with ØX174-Hae III molecular weight markers and stained with ethidium bromide.

Statistics
These data were analyzed by analyses of variance and Student's t-test. A p value of <0.05 was considered significant.

	RESULTS

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Effect of AII on Murine Lin^– Bone Marrow Cells
Figure 1 represents the number of colonies containing more than 50 cells/colony as a function of the duration and concentration of AII exposure. The number of cells in colonies (estimated from colonies of 10, 20, or 50 cells per colony) seen after incubation of Lin^– bone marrow cells with various concentrations of AII was also increased (data not shown). The results clearly demonstrate that the number of large (>50 cells/colony) HPC colonies increases proportionately with exposure to increased concentrations of AII, and thus that AII increases HPC proliferation. The number of colonies with greater than 50 cells per colony were increased in both the presence (Fig. 1) and absence (Fig. 5) of CSF. At day 14 only, macroscopic colonies were observed in the wells containing enriched HPC (Lin^– bone marrow cells) in cultures containing CSF (from conditioned medium) treated with 10 µg/ml (18 macroscopic colonies) and 100 µg /ml AII (10 macroscopic colonies). These colonies did not appear to have undergone differentiation during the culture time.

View larger version (13K): [in this window] [in a new window]   Figure 5. Effect of AII on the formation of colonies by Lin– bone marrow cells. Murine cells were isolated by magnetic immunoaffinity chromatography as described in Figure 1. The enriched HPC cell fractions were diluted into a semisolid medium without CSF. AII, 100 mg/ml, was added to the wells with 4 x 103 cells/well. The cells were incubated in a humidified atmosphere at 37°C and 5% CO2 in air, for 13 days. These data are representative of and consistent with two studies.

Effect of AII on Murine Sca1⁺Lin^– Bone Marrow Cells
The effect of AII on the proliferation of Lin^–Sca1⁺ bone marrow cells was then evaluated. In contrast to the data presented above, no growth was observed in wells without CSF (data not shown). In the wells containing CSF, the fractions from Sca 1^lo (Fig. 3) proliferated to a greater extent than the Sca 1^hi fraction (Fig. 4). Further, larger colonies were not observed in the Sca l^hi fraction. However, AII gave a comparable percent increase over baseline in both fractions in number of colonies formed.

Effect of AII on the Proliferation of Human CD34⁺CD38^– Cells from Cord Blood
As with the murine cells, no growth was seen in the wells that lacked rCSF in this more purified population. The data in Figure 6 demonstrate that AII increases colony formation and size. As can be seen in Figure 7, inclusion of AII in the cultures elevated the formation of CFU-GM and CFU-GEMM (mixed colonies), but had no effect on BFU-E in this culture system.

View larger version (15K): [in this window] [in a new window]   Figure 6. Effect of AII on the formation of colonies by CD34+CD38– cells isolated from human cord blood. Human cord blood was harvested, red blood cells were lysed, and the pellet was resuspended at 107 cells/ml. An antibody cocktail was used to isolate cells enriched for CD34+ cells. These cells were placed directly into a semisolid medium containing various concentration of AII and 1 x 103 cells were cultured per well. These cultures contained a semisolid medium (1% methylcellulose in IMDM) with 30% FCS, 1% BSA, 3 u/ml EPO, 10 µM 2-mercaptoethanol, 2 mM L-glutamine, 50 ng/ml SCF, 10 ng/ml GM-CSF, and 10 ng/ml IL-3. At various times after initiation of culture, the number and size of colonies were enumerated.

View larger version (16K): [in this window] [in a new window]   Figure 7. Effect of AII on the formation of myeloid colonies by CD34+CD38– cells isolated from human cord blood. The study was conducted as described in Figure 6. At day 12 after initiation of culture, the types of colonies formed were assessed.

View larger version (20K): [in this window] [in a new window]   Figure 8. Effect of AII on the formation of colonies by CD34+ cells isolated from human cord blood. Human cord blood cells were obtained and isolated as described in Figure 6. The cells were then resuspended at 5 x 104 cells/ml in serum-free StemSpan containing the following human recombinant factors: 3 IU/ml HuEPO, 20 ng/ml SCF, 20 ng/ml IL-3, and 20 ng/ml GM-CSF for six days at 37°C, followed by three additional days in the above medium containing various concentrations, between 0.01 and 10 µg/ml, of AII. After this incubation, the cells were washed and placed in semisolid medium containing CSF and 3 IU/ml EPO. At various times after initiation of culture, the number and size of colonies per well were counted.

View larger version (18K): [in this window] [in a new window]   Figure 9. Effect of AII on the formation of erythroid progenitor by CD34+ cells isolated from human cord blood. The study was conducted as described in Figure 6. However, at various times after initiation of culture, the number of erythroid progenitors per well was determined.

View larger version (57K): [in this window] [in a new window]   Figure 10. The expression of mRNA for AII Type 1 receptors by various human hematopoietic and stromal cells. The results from a reverse-transcriptase-PCR assay using primers for the AII Type 1a receptor are shown. Human stromal cells (HS5), T cells, B cells, CD34+CD38+ cells, and CD34+CD38– cells contained mRNA for the ATIIR1a receptor by this analysis.

	DISCUSSION

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The observation that AII stimulates the formation of BFU-E in human CD34⁺ cells when exposed in suspension culture prior to placement in semisolid medium confirms previous observations by Mrug et al. [7]. These observations were extended to show that AII stimulated the proliferation of cells that form large (greater than 50 cells per colony) colonies both in suspension (CD34⁺) and methylcellulose (CD34⁺CD38^–) cultures. In the latter studies, the cells and AII were added directly to the methylcellulose cultures at the initiation. When the colony types in these latter cultures were assessed, AII was shown to stimulate the formation of myeloid precursors. These data are consistent with clinical observations after long-term use of inhibitors of angiotensin converting enzymes (ACE), which reduce, but do not eliminate, circulating levels of AII, and Losartan. Several studies have shown that clinical use of agents which reduce AII activity can reduce erythropoiesis [19, 20]. It was hypothesized that AII may affect hematopoiesis in the bone marrow [21, 22]. These data provide direct evidence for this hypothesis.

Further, a rare but noted side effect of treatment with ACE inhibitors is neutropenia. This side effect has been observed in 0.3% of patients using this therapy [23-27]. Although other mechanisms have been proposed, lowering of blood AII by ACE inhibitors might contribute to this clinical observation [28].

In vivo blood cell production is thought to be regulated locally by interactions of HPC with a variety of cell-bound and secreted factors produced by adjacent bone marrow stromal cells [3]. The addition of growth factors and cytokines to the culture medium is intended to compensate for the absence of stroma-associated activities. Growth factors and cytokines that have been shown to increase production of HPC (in various combinations) include G-CSF, granulocyte/macrophage-CSF, SCF, macrophage-CSF, and IL-1, -3, -6, and -11. Conversely, inclusion of macrophage inhibitory protein-la, tumor necrosis factor or transforming growth factor ß, in most expansion cultures reported to date, results in decreased cell yields [2]. AII was able to increase the proliferation of Lin^– cells derived from the bone marrow in the absence of CSF. This indicated that AII may induce mesenchymal cells present in these impure preparations to produce such factors. Studies are ongoing to further assess this hypothesis.

These data suggest that AII, added to culture containing numerous CSF, can further increase the number of cells responding to the proliferative signal. Methods that increase the ex vivo proliferation of HPC may greatly increase the clinical benefits of HPC transplantation. Similarly, methods that increase in vivo proliferation of HPC will enhance the utility of HPC transplantation therapy by rapidly increasing local concentrations of early and late progenitor cells in the bone marrow. AII may be an essential component for an optimized in vitro or ex vivo expansion culture system.

The data presented in this report also suggest that AII may be useful as an agent to accelerate hematopoietic recovery after bone marrow injury. The ability of this molecule to act on several levels in the hematopoietic cascade may provide benefit over currently existing therapies, such as G-CSF, GM-CSF, and SCF, which act at specific sites.

	ACKNOWLEDGMENTS

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The RT-PCR studies were conducted in the laboratory of Dr. Beverly Torok-Storb by Dr. Lynn Graf under a grant from the Maret Corporation (Newport Beach, CA; http://www.maretpharma.com).

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