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Bv8 and Endocrine Gland-Derived Vascular Endothelial Growth Factor Stimulate Hematopoiesis and Hematopoietic Cell Mobilization

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Bv8 and Endocrine Gland-Derived Vascular Endothelial Growth Factor Stimulate Hematopoiesis and Hematopoietic Cell Mobilization Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization Jennifer LeCouter*†, Constance Zlot*, Max Tejada‡, Franklin Peale§, and Napoleone Ferrara†‡ Departments of *Physiology, §Pathology, and ‡Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080 Communicated by Richard H. Scheller, Genentech, Inc., South San Francisco, CA, October 21, 2004 (received for review July 20, 2004) Bv8 and endocrine-gland-derived VEGF (EG-VEGF), or prokineticins, account for VEGF function in progenitor and mature blood cell are two highly related, secreted proteins that we previously types. described as selective angiogenic mitogens. Here we describe the In addition to the recognized role of VEGF in solid tumor expression and functional characterization of Bv8 in peripheral progression, the contribution of VEGF to hematological malignan- blood cells, notably monocytes, neutrophils, and dendritic cells, cies has been investigated. Inhibition of VEGF or VEGFR in and in the bone marrow. In human and mouse, the two Bv8 G cultured leukemia cell lines inhibited proliferation or chloroma and protein-coupled receptors are expressed in hematopoietic stem leukemia progression in mouse models (19, 20) cells and specific mature blood cells, including lymphocytes. Bv8 is In the present study, we characterized the distribution of Bv8 and highly expressed by neutrophils at sites of inflammation and can its receptors, EG-VEGFR-1͞prokineticin R-1͞GPCR73 and EG- stimulate migration of monocytes, in a pertussis toxin-sensitive VEGFR-2 in hematopoietic cell types. Ligand and receptors ex- manner. Bv8, or EG-VEGF that shares the same receptors, increased pression are differentially regulated in activated monocytes, and numbers of colony-forming units granulocytic and monocytic in Bv8 or the homologous protein, EG-VEGF, stimulates migration. cultures of human or mouse hematopoietic stem cells. Systemic in Bv8 or EG-VEGF increased colony formation of granulocytic and vivo exposure to Bv8 or EG-VEGF resulted in significant increases monocytic lineages in human and mouse hematopoietic stem cell in total leukocyte, neutrophil, and monocyte counts. Additionally, (HSC) cultures. Finally, we determined that overexpression of these adenovirus (Av)Bv8 or AvEG-VEGF delivered just before 5-fluorou- ligands increased circulating leukocyte numbers in intact or 5- racil injury promoted the survival of hematopoietic cells and fluorouracil (5-FU)-challenged mice. enhanced progenitor mobilization. In conclusion, Bv8 can promote Materials and Methods survival and differentiation of the granulocytic and monocytic lineages. Bv8 potentially modulates growth, survival, and function Expression Analyses. Reagents and conditions for Taqman for of cells of the innate and adaptive immune systems, possibly EG-VEGF, Bv8, EG-VEGFR-1, EG-VEGFR-2, VEGF, through autocrine or paracrine signaling mechanisms. VEGFR-1, and VEGFR-2 have been described (2). RNA was prepared from low-density human cell lines purchased from the prokineticins ͉ angiogenesis ͉ G protein-coupled receptor American Type Culture Collection; human primary cell RNA was from AllCells (Berkeley, CA) and human tissue RNA was from Becton Dickinson. v8 (1, 2) and endocrine gland-derived VEGF (EG-VEGF) (3), Tissues were processed for in situ hybridization, and 33P-UTP- Bsecreted proteins also referred to as prokineticin-2 and -1, labeled RNA probes were generated as described (21). Sequences respectively (4, 5), are structurally related to a larger class of for sense and antisense probes for Bv8 have been reported (2). peptides that are defined by a five disulphide-bridged motif called a colipase fold (6–8). We previously demonstrated that these Recombinant Protein and Adenovirus (Av) Production. Baculovirus ligands promote proliferation of endothelial cells derived from the production of EG-VEGF and Bv8 has been described (2, 3). Avs adrenal cortex and stimulate angiogenic responses in the ovary (3) encoding LacZ, Bv8, EG-VEGF, or Fltsel (VEGF mutant selective and testis (2). A variety of additional activities have been reported, for VEGFR-1) were generated and titered as described (2, 22). Av including effects on gastrointestinal motility (4), neuronal survival granulocyte͞macrophage-colony-stimulating factor (GM-CSF) (9), pain sensation (10), and circadian locomotor rhythm (5). was purchased from Qbiogene (Quebec). Expression and signal transduction of the two EG-VEGF͞Bv8 G protein-coupled receptors (GPCRs) have been characterized. In Colony Formation Assays. Presorted CD34ϩ human bone marrow specific endothelial cells (11), neurons (9) and transfected lines cells were purchased from AllCells. Cells (5,000) were seeded into (12–14), receptor activation stimulates calcium mobilization, phos- methylcellulose culture media (complete Methocult GF H4434 or phoinositol turnover, and mitogen-activated protein kinase and Akt basic H4230) from Stem Cell Technologies (Vancouver) as rec- pathway activation. ommended by the manufacturer. Human HSC experiments were Endothelial cell responses mediated by EG-VEGF receptor replicated with three independent donors. Colony numbers and (EG-VEGFR) activation in selective primary cultures and in the phenotypes were determined after 7–14 days. gonads were comparable to those induced by VEGF. A well Mouse HSC, from femurs and tibia, were purified through a characterized, potent angiogenic factor and inducer of permeabil- series of enrichment steps as described (15). In brief, bone marrow ity, VEGF has been more recently evaluated for its ability to mobilize and promote the proliferation and survival of bone marrow-derived cell types (15). A link between endothelial and Freely available online through the PNAS open access option. hematopoietic cell development was suggested by the common Abbreviations: GPCR, G protein-coupled receptor; GM-CSF, granulocyte͞macrophage col- ony-stimulating factor; HSC, hematopoietic stem cell; ERK, extracellular signal-regulated anatomical site for development of the progenitor cells of these kinase; Ptx, pertussis toxin; Av, adenovirus; 5-FU, 5-fluorouracil; EG-VEGF, endocrine gland- systems in the embryo. Moreover, gene ablation experiments in the derived VEGF; EG-VEGFR, EG-VEGF receptor; VEGFR, VEGF receptor. mouse indicated that VEGF (16, 17) and VEGFR (18) were †To whom correspondence may be addressed. E-mail: [email protected] or required for endothelial cell and blood island development. Both [email protected]. CELL BIOLOGY autocrine- (15, 19) and paracrine-signaling mechanisms appear to © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0407697101 PNAS ͉ November 30, 2004 ͉ vol. 101 ͉ no. 48 ͉ 16813–16818 Downloaded by guest on September 25, 2021 cells were collected by flushing bones with 2% FCS. After eryth- clear cells, CD8ϩ lymphocytes, and HSCs. EG-VEGFR-2 tran- rocyte lysis, other mature cells were depleted by using conjugated script level is high in CD8ϩ lymphocytes, neutrophils, and mono- lineage-specific antigen Abs [CD4͞L3T3, CD8͞Ly2.3, B-220͞ cytes and also detected in B cells, CD4ϩ lymphocytes, and AC133 CD45 (Caltag), Gr-1, Mac-1, and Ter-119 (Pharmingen)], magnetic or CD34ϩ cells (Fig. 1B). Mouse HSCs (ScaϩKitϩLinlo) also beads, and the AutoMacs system (Miltenyi Biotec). This depleted express Bv8 and its receptors. The relative transcript levels in a fraction was further sorted (Elite ESP FACS) to isolate the representative experiment were Bv8, 9.10; EG-VEGFR-1, 4.30; and double-positive (ScaϩKitϩLinlo) population by using anti-Sca-1- EG-VEGFR-2 2.05, using testis RNA to generate standard curves FITC, anti-cKit-biotin, and avidin-CyChrome. Cultures were (data not shown). initiated with 2,000 cells in Methocult media (complete media GF Cell lines including Hel (erythroleukemia), U937 (histiocytic M3434, media without CSFs M3334). Additional cytokines lymphoma) and KG-1 (acute myelogenous leukemia) express Bv8 included in assays were IL-3, IL-6 (10 ng͞ml), G-CSF, or stem mRNA (Fig. 1A). Hel, CMK (megakaryoblast), and KG-1 cell lines cell factor (0.1–5 ng͞ml each) all purchased from Stem Cell express EG-VEGFR-1 and EG-VEGFR-2 transcripts (Fig. 1B). Technologies. Coexpression of ligand and receptors in several of these lines, To determine spleen-colony-forming unit (CFU), single cells including HEL and TF (erythroleukemia), HL60 (promyelomono- were isolated after disrupting the tissue. Cells were counted and 1 ϫ cytic), CMK, U937, and KG-1 suggest that this system may con- 104 cells (n ϭ 3) from each of two animals per group were plated tribute in an autocrine manner to the survival or growth of these in GF M3434 media. The colony phenotypes were determined after cells. Additionally, EG-VEGFR-2 expression is high in the HS-5 7–14 days. Experiments were replicated at least twice for all bone marrow stromal cell line. treatment groups. We also examined expression of VEGF and its receptors because Bv8 or EG-VEGF can induce similar angiogenic responses in Monocyte Assays. Human primary monocytes were isolated from specific contexts, and the VEGF system has been implicated in bone heparinized blood by using the Miltenyi Biotec kit according to the marrow cell survival, mobilization (15, 23), and leukemias. VEGF manufacturer’s instructions. RNA was purified from cells before or (Fig. 1C) and VEGFR-1 (Fig. 1D) expression are highest in tissues after3hinculture, with or without 1 ␮g͞ml LPS, 055:B5 (Sigma). examined, including fetal liver, lymph node, small
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