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Cleavage Fragments of the Third Complement Component (C3

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Cleavage Fragments of the Third Complement Component (C3 Leukemia (2007) 21, 973–982 & 2007 Nature Publishing Group All rights reserved 0887-6924/07 $30.00 www.nature.com/leu ORIGINAL ARTICLE Cleavage fragments of the third complement component (C3) enhance stromal derived factor-1 (SDF-1)-mediated platelet production during reactive postbleeding thrombocytosis M Wysoczynski1, M Kucia1, J Ratajczak1 and MZ Ratajczak1,2 1Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA and 2Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland We hypothesized that the third complement component (C3) The a-chemokine stromal-derived factor-1 (SDF-1) has been cleavage fragments (C3a and des-ArgC3a) are involved in stress/ proposed as a new regulator of Megs maturation and platelet inflammation-related thrombocytosis, and investigated their 11–16 potential role in reactive thrombocytosis induced by bleeding. formation. A recently published study clearly demonstrated We found that platelet counts are lower in C3-deficient mice in that SDF-1, together with fibroblast growth factor-4 (FGF-4), À/À À/À response to excessive bleeding as compared to normal restored thrombopoiesis in Tpo and Mpl mice by directing littermates and that C3a and des-ArgC3a enhance stromal- trans-localization of megakaryocytic progenitors positive for derived factor-1 (SDF-1)-dependent megakaryocyte (Megs) CXCR4, the receptor for SDF-1, from the endostial to the migration, adhesion and platelet shedding. At the molecular vascular niche, thereby promoting survival, maturation to level, C3a stimulates in Megs MAPKp42/44 phosphorylation, 17 and enhances incorporation of CXCR4 into membrane lipid megakaryocytes and platelet production. rafts increasing the responsiveness of Megs to SDF-1. We Furthermore, there is growing evidence that the responsiveness found that perturbation of lipid raft formation by statins of hematopoietic cells to SDF-1 is optimal when the CXCR4 decreases SDF-1/C3a-dependent platelet production in vitro receptor is included into membrane lipid rafts.18–20 The formation and in an in vivo model statins ameliorated post-bleeding of lipid rafts in vivo may be perturbed by cholesterol- thrombocytosis. Thus, inhibition of lipid raft formation could lowering drugs, for example, statins,18–20 which are effective find potential clinical application as a means of ameliorating in lowering LDL cholesterol and exert pleiotropic effects on some forms of thrombocytosis. 21 Leukemia (2007) 21, 973–982. doi:10.1038/sj.leu.2404629; mature platelets, for example, inhibit their activation. This published online 1 March 2007 latter effect is probably due to lowering of the cholesterol Keywords: megakaryopoiesis; platelets; complement; chemokines; content in the platelet membranes leading to disruption of CXCR4; lipid rafts membrane lipid raft formation, as lipid rafts are necessary for proper platelet activation and signaling21 and, as we hypothe- sized, platelet production. However, under steady-state condi- tions, statins do not influence thrombopoiesis, no direct experimental studies have been performed on their effects on platelet production in reactive thrombocytosis. We recently reported that the complement (C) system and Introduction third complement protein (C3) cleavage fragments C3a and C3a enhance the responsiveness of hematopoietic cells to Megakaryopoiesis is regulated by several factors that affect the des-Arg an SDF-1 gradient.22 C3a binds to G -protein-coupled seven proliferation and differentiation of megakaryopoietic cells.1,2 ai transmembrane receptor (C3aR) and we reported that C3aR is The fact that mice with ‘knockout’ of thrombopoietin (TPO) and expressed on human and murine hematopoietic stem/progenitor thrombopoietin receptor (c-mpl) show a 90% reduction in both cells (HSPC).22,23 In contrast, the receptor for C3a has not the number of megakaryocytes (Megs) in bone marrow (BM) and des-Arg been identified yet. As C is activated in several clinical circulating platelets indicates that TPO is a crucial regulator of conditions associated with high platelet counts (e.g., chronic megakaryopoiesis.3–5 Nevertheless, the fact that some Megs and inflammation, hemorrhage), we hypothesized that C3a and platelets are still present in these animals even in the total C3a are involved in stress/inflammation-related thrombo- absence of TPO suggests that some other factors can compen- des-Arg cytosis. Supporting this are the observations that C3-deficient sate for TPO deficiency and the cytokines that signal through mice, which have normal platelet counts in steady-state gp130 such as interleukin-6 (IL-6), IL-11, leukemia inhibitory conditions,23 display delayed recovery of platelets after sub- factor, cilliary neurotropic factor and oncostatin M have been lethal irradiation or hematopoietic transplants.23 suggested to be such factors.6–9 However, recent data show that We report that C3a and C3a modulate the responsiveness IL-6 and IL-11 do not induce platelet production in thrombo- des-Arg of Megs to SDF-1 and postulate that the crosstalk between cytopenic, TPO-deficient (TpoÀ/À) and TPO-receptor-deficient C3aR and CXCR4 receptors, we have newly identified, here (MplÀ/À) mice.10 Thus, it is unlikely that gp130 signaling plays an important and previously unrecognized role in stress/ cytokines are significantly involved in platelet production in inflammation-dependent Megs maturation and platelet formation. these animals.4–10 Correspondence: Dr MZ Ratajczak, Stem Cell Biology Program, James Materials and methods Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. þ E-mail: [email protected] Human CD34 cells, megakaryoblasts and platelets Received 4 December 2006; revised 16 January 2007; accepted 25 Light-density BM mononuclear cells (BM MNC) were obtained January 2007; published online 1 March 2007 from consenting healthy donors and enriched for CD34 þ cells Complement as a new regulator of megakaryopoiesis M Wysoczynski et al 974 by immunoaffinity selection with MiniMACS paramagnetic on human Megs with mouse anti-human C3aR monoclonal beads (Miltenyi Biotec, Auburn, CA, USA) (purity 495%) and antibody (MoAb), clone no. 8H1 and a fluorescein isothiocya- were expanded in a serum-free liquid system, and growth of nate (FITC)-labeled goat anti-mouse antibody. Subsequently, the CFU-Meg was stimulated with recombinant human (rh) TPO cells were stained with phycoerythrin (PE)-labeled anti-CD41 (100 ng/ml) (R&D Systems, Minneapolis, MN, USA) as de- MoAb (Becton Dickinson, San Jose, CA, USA), washed, fixed in scribed.16 After incubation for 11 days at 371C, about 85% of 1% paraformaldehyde and subjected to FACS analysis using a the expanded cells were positive for the megakaryocytic- FACScan analyser (Becton Dickinson). specific marker CD41, and this population was further enriched to 495% purity by additional selection with immunomagnetic beads (Miltenyi Biotec) as described previously by us.16 Gel- Isolation of mRNA and RT-PCR for detection of C3aR filtered platelets (GFP) were prepared from four individuals as and C5L2 described previously.13,16 Total mRNA was isolated with the RNeasy Mini Kit (Quiagen Marrow aspiration and blood donation from normal volun- Inc., Valencia, CA, USA) as described.20 We employed teers was carried out with the donors’ informed consent following primers – for detection of C3aR forward 50-GCC obtained through the Institutional Review Board. GCC TGG AGA AAT GAA TGA TAG G-30 and reverse 50-AGA AAG ACA GCC ACC ACC ACG-30, and for detection of C5L2 forward 50-CCT GGT GGT CTA CGG TTC AG-30 and reverse CFU-Meg assay 50-GGG CAG GAT TTG TGT CTG TT-30. Amplified products þ CD34 BMMNC were resuspended in 1% methylcellulose in (10 ml) were electrophoresed on a 2% agarose gel. Iscove’s DMEM (Gibco BRL, Grand Island, NJ, USA) (104/ml) supplemented with 25% artificial serum as described.9,16 CFU- Meg growth was stimulated with a suboptimal (10 ng/ml) and Real-time PCR analysis of MMPs and VEGF optimal dose of rhTPO (100 ng/ml). Cultures were incubated at Detection of MMP2, MMP9, VEGF and b2-microglobulin 371C in a fully humidified atmosphere supplemented with 5% mRNA levels was performed by real-time RT-PCR using an CO2. Under these conditions, after 11 days, approximately ABI PRISM 7000 Sequence Detection System (ABI). Each 25 ml 9,16 100% of the colonies were glycoprotein aIIb/b3 positive. reaction mixture contained 12.5 ml SYBR Green PCR Master Mix, 10 ng of cDNA template and primer for MMP9 forward 50- GGA CGA CGT GGG CTA CGT-30, reverse 50-AAT CTC ACC Cell lines GAC AGG CAG CT-30, for MMP2 forward 50-TGG GAC AAG The MO7E cell line used in these studies was purchased from AAC CAG ATC ACA TA-30, reverse 50-TTT CGA GTC TCC ACG ATCC (Rockville, MD, USA) and maintained in Iscove medium CAT CTC-30, for VEGF forward 50-TGA GCG GCT CAT CTA CTT (Gibco BRL, Long Island, NY, USA) supplemented with 10% CTA TGT-30, reverse 50-CAC CGG CTG GCC CTC TA-30, for bovine calf serum (BCS) (Hyclone, Logan, UT, USA) and 5 ng/ml b2-microglobulin forward 50-TGA CTT TGT CAC AGC CCA of GM-CSF (R&D Systems). AGA TA-30, reverse 50-AAT GCG GCA TCT TCA AAC CT-30. Relative quantitation of MMP2, MMP9 and VEGF mRNA expression was calculated with the comparative threshold cycle Bleeding procedure 24 Mice were anesthetized by i.p. injection of Ketamine (100 mg/kg, (Ct) method described elsewhere. Sigma, St Louis, MO, USA) and bled from the retro-orbital plexus as recommended by the Animal Resource Center, Case Western Reserve University (http://labanimals.case.edu/ Apoptosis assay templates_retro_orbital_bleeding.html). Apoptosis of Megs was assessed by cytometric analysis after staining cells with FITC-Annexin V (apoptosis detection kit from R&D Systems) according to the manufacturer’s protocol as 9,16 ELISA on serum from murine BM described. Blood samples were collected into EDTA tubes and plasma was separated immediately by centrifugation at 2000 g for 15 min at 41C.
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