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Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis

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Abstract

This study was designed to investigate the role of increased adipocytes in the bone marrow (BM) niche induced by high-dose chemotherapy in hematopoietic recovery. Arabinosylcytosine (Ara-C) was administered to adult C57BL/6J mice to induce adipogenesis in the BM. We investigated the effects of adipogenesis on hematopoietic recovery following chemotherapy, using the peroxisome proliferator-activated receptor gamma inhibitor, bisphenol A diglycidyl ether (BADGE). Adipocyte hyperplasia could be induced by Ara-C treatment in BM and inhibited by BADGE. The accelerated recovery of leukocyte counts, increased colony forming units, and a higher proportion of Ki67+CD45+ BM cells and Ki67+Lin−Sca1+c-kit+ hematopoietic stem cells were observed in the long bone marrow of adipocyte-inhibited mice, as well as an increase in the number of CD45+ BM cells in the tail fatty marrow compared to controls. Adipocytes participated in creating a distinctive niche for hematopoietic cells. In addition, lower expression of stromal cell-derived factor-1α and hypoxia-inducible factor-1 alpha were detected in the BADGE-treated group. These results indicate that hematopoietic recovery is improved following chemotherapy in adipogenesis-inhibited mice. In addition, adipocytes may create an individual niche that affects the proliferation and migration of hematopoietic cells in vitro and in vivo.

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References

  1. Gimble JM, Robinson CE, Wu X, Kelly KA. The function of adipocytes in the bone marrow stroma: an update. Bone. 1996;19(5):421–8.

    Article  PubMed  CAS  Google Scholar 

  2. McKinstry CS, Steiner RE, Young AT, Jones L, Swirsky D, Aber V. Bone marrow in leukemia and aplastic anemia: mR imaging before, during, and after treatment. Radiology. 1987;162(3):701–7.

    PubMed  CAS  Google Scholar 

  3. Payne MW, Uhthoff HK, Trudel G. Anemia of immobility: caused by adipocyte accumulation in bone marrow. Med Hypotheses. 2007;69(4):778–86.

    Article  PubMed  CAS  Google Scholar 

  4. Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T, Kassem M. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology. 2001;2(3):165–71.

    Article  PubMed  CAS  Google Scholar 

  5. Wodnar-Filipowicz A, Lyman SD, Gratwohl A, Tichelli A, Speck B, Nissen C. Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia. Blood. 1996;88(12):4493–9.

    PubMed  CAS  Google Scholar 

  6. Lishner M, Curtis JE. Aplastic anaemia following successful treatment of malignant epithelial tumours with radiation and/or chemotherapy. Br J Haematol. 1989;73(3):416–7.

    Article  PubMed  CAS  Google Scholar 

  7. Rozman C, Feliu E, Rozman M, Reverter JC, Climent C, Berga L. Acquired aplastic anemia: a stereological analysis of bone marrow fatty tissue and its clinical correlations. Med Clin (Barc). 1993;101(12):441–5.

    CAS  Google Scholar 

  8. Krech R, Thiele J. Histopathology of the bone marrow in toxic myelopathy. A study of drug induced lesions in 57 patients. Virchows Arch A Pathol Anat Histopathol. 1985;405(2):225–35.

    Article  PubMed  CAS  Google Scholar 

  9. Islam A, Catovsky D, Galton DA. Histological study of bone marrow regeneration following chemotherapy for acute myeloid leukaemia and chronic granulocytic leukaemia in blast transformation. Br J Haematol. 1980;45(4):535–40.

    Article  PubMed  CAS  Google Scholar 

  10. Islam A. Pattern of bone marrow regeneration following chemotherapy for acute myeloid leukemia. J Med. 1987;18(2):108–22.

    PubMed  CAS  Google Scholar 

  11. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259–63.

    Article  PubMed  CAS  Google Scholar 

  12. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev. 2000;14(11):1293–307.

    PubMed  CAS  Google Scholar 

  13. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137(1):354–66.

    Article  PubMed  CAS  Google Scholar 

  14. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8(10):1224–34.

    Article  PubMed  CAS  Google Scholar 

  15. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56.

    Article  PubMed  CAS  Google Scholar 

  16. Dworzanski T, Celinski K, Korolczuk A, Slomka M, Radej S, Czechowska G, et al. Influence of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, rosiglitazone and antagonist, biphenol-A-diglicydyl ether (BADGE) on the course of inflammation in the experimental model of colitis in rats. J Physiol Pharmacol. 2010;61(6):683–93.

    PubMed  CAS  Google Scholar 

  17. Wright HM, Clish CB, Mikami T, Hauser S, Yanagi K, Hiramatsu R, et al. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem. 2000;275(3):1873–7.

    Article  PubMed  CAS  Google Scholar 

  18. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25(11):1315–21.

    Article  PubMed  CAS  Google Scholar 

  19. Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem. 1997;64(2):278–94.

    Article  PubMed  CAS  Google Scholar 

  20. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.

    Article  PubMed  CAS  Google Scholar 

  21. Diez JJ, Iglesias P. The role of the novel adipocyte-derived protein adiponectin in human disease: an update. Mini Rev Med Chem. 2010;10(9):856–69.

    Article  PubMed  CAS  Google Scholar 

  22. Marr E, Tardie M, Carty M, Brown Phillips T, Wang IK, Soeller W, et al. Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2). Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006;62(Pt 11):1058–60.

    Article  PubMed  Google Scholar 

  23. Belaid Z, Hubint F, Humblet C, Boniver J, Nusgens B, Defresne MP. Differential expression of vascular endothelial growth factor and its receptors in hematopoietic and fatty bone marrow: evidence that neuropilin-1 is produced by fat cells. Haematologica. 2005;90(3):400–1.

    PubMed  CAS  Google Scholar 

  24. Endl E, Hollmann C, Gerdes J. Antibodies against the Ki-67 protein: assessment of the growth fraction and tools for cell cycle analysis. Methods Cell Biol. 2001;63:399–418.

    Article  PubMed  CAS  Google Scholar 

  25. Drouet M, Mourcin F, Grenier N, Delaunay C, Mayol JF, Lataillade JJ, et al. Mesenchymal stem cells rescue CD34+ cells from radiation-induced apoptosis and sustain hematopoietic reconstitution after coculture and cografting in lethally irradiated baboons: is autologous stem cell therapy in nuclear accident settings hype or reality? Bone Marrow Transpl. 2005;35(12):1201–9.

    Article  CAS  Google Scholar 

  26. Dutt P, Wang JF, Groopman JE. Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol. 1998;161(7):3652–8.

    PubMed  CAS  Google Scholar 

  27. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858–64.

    Article  PubMed  CAS  Google Scholar 

  28. Eliasson P, Rehn M, Hammar P, Larsson P, Sirenko O, Flippin LA, et al. Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture. Exp Hematol. 2010;38(4):301.e2–310.e2.

    Article  Google Scholar 

  29. Hermitte F, Brunet de la Grange P, Belloc F, Praloran V, Ivanovic Z. Very low O2 concentration (0.1%) favors G0 return of dividing CD34+ cells. Stem Cells. 2006;24(1):65–73.

    Article  PubMed  Google Scholar 

  30. Kemp K, Morse R, Wexler S, Cox C, Mallam E, Hows J, et al. Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy. Ann Hematol. 2010;89(7):701–13.

    Article  PubMed  CAS  Google Scholar 

  31. Georgiou KR, Scherer MA, Fan CM, Cool JC, King TJ, Foster BK, et al. Methotrexate chemotherapy reduces osteogenesis but increases adipogenic potential in the bone marrow. J Cell Physiol. 2012;227(3):909–18.

    Article  PubMed  CAS  Google Scholar 

  32. Winkler IG, Pettit AR, Raggatt LJ, Jacobsen RN, Forristal CE, Barbier V, et al. Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. Leukemia. 2012;26(7):1594–601.

    Article  PubMed  CAS  Google Scholar 

  33. Belaid-Choucair Z, Lepelletier Y, Poncin G, Thiry A, Humblet C, Maachi M, et al. Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition. Stem Cells. 2008;26(6):1556–64.

    Article  PubMed  CAS  Google Scholar 

  34. Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202(11):1599–611.

    Article  PubMed  CAS  Google Scholar 

  35. Babyn PS, Ranson M, McCarville ME. Normal bone marrow: signal characteristics and fatty conversion. Magn Reson Imaging Clin N Am. 1998;6(3):473–95.

    PubMed  CAS  Google Scholar 

  36. Kricun ME. Red-yellow marrow conversion: its effect on the location of some solitary bone lesions. Skeletal Radiol. 1985;14(1):10–9.

    Article  PubMed  CAS  Google Scholar 

  37. Oh I, Ozaki M, Miyazato A, Sato K, Meguro A, Muroi K, et al. Screening of genes responsible for differentiation of mouse mesenchymal stromal cells by DNA micro-array analysis of C3H10T1/2 and C3H10T1/2-derived cell lines. Cytotherapy. 2007;9(1):80–90.

    Article  PubMed  CAS  Google Scholar 

  38. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med. 1997;185(1):111–20.

    Article  PubMed  CAS  Google Scholar 

  39. Lataillade JJ, Domenech J, Le Bousse-Kerdiles MC. Stromal cell-derived factor-1 (SDF-1)\CXCR4 couple plays multiple roles on haematopoietic progenitors at the border between the old cytokine and new chemokine worlds: survival, cell cycling and trafficking. Eur Cytokine Netw. 2004;15(3):177–88.

    PubMed  CAS  Google Scholar 

  40. Yun HJ, Jo DY. Production of stromal cell-derived factor-1 (SDF-1)and expression of CXCR4 in human bone marrow endothelial cells. J Kor Med Sci. 2003;18(5):679–85.

    CAS  Google Scholar 

  41. Netelenbos T, van den Born J, Kessler FL, Zweegman S, Merle PA, van Oostveen JW, et al. Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells. Leukemia. 2003;17(1):175–84.

    Article  PubMed  CAS  Google Scholar 

  42. Jung Y, Wang J, Schneider A, Sun YX, Koh-Paige AJ, Osman NI, et al. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone. 2006;38(4):497–508.

    Article  PubMed  CAS  Google Scholar 

  43. Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, et al. White fat progenitor cells reside in the adipose vasculature. Science. 2008;322(5901):583–6.

    Article  PubMed  CAS  Google Scholar 

  44. Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res. 2008;102(1):77–85.

    Article  PubMed  CAS  Google Scholar 

  45. Srinivas V, Zhu X, Salceda S, Nakamura R, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a non-heme iron protein. Implications for oxygen sensing. J Biol Chem. 1999;274(2):1180.

    PubMed  CAS  Google Scholar 

  46. Pistollato F, Rampazzo E, Abbadi S, Della Puppa A, Scienza R, D’Avella D. Molecular mechanisms of HIF-1alpha modulation induced by oxygen tension and BMP2 in glioblastoma derived cells. PLoS ONE. 2009;4(7):e6206.

    Article  PubMed  Google Scholar 

  47. Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K, Whitelaw ML, et al. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment. J Biol Chem. 2006;281(32):22575–85.

    Article  PubMed  CAS  Google Scholar 

  48. Hofer T, Wenger H, Gassmann M. Oxygen sensing, HIF-1alpha stabilization and potential therapeutic strategies. Pflugers Arch. 2002;443(4):503–7.

    Article  PubMed  CAS  Google Scholar 

  49. Salter AB, Meadows SK, Muramoto GG, Himburg H, Doan P, Daher P, et al. Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo. Blood. 2009;113(9):2104–7.

    Article  PubMed  CAS  Google Scholar 

  50. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA. 2004;101(8):2476–81.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Prof. Youyi Zhang for assistance in the preparation of the paper, Zhiyong Liu and Huiqin Jiao for help with histopathological work, Qing Zhang for flow cytometric support, and the Animal Care Center of this hospital for the excellent care of our mice. This study is supported by the National Natural Science Foundation of China (81270572) and the Major national science and technology programs (2012ZX09303019).

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The authors indicate no potential conflict of interest.

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Authors and Affiliations

  1. Peking University People’s Hospital and Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China

    Rong-Jia Zhu, Yao Zhang & Kai-Yan Liu

  2. Department of Hematology, Beijing Ji Shui Tan Hospital, 4th Clinical Medical College of Peking University, Beijing, China

    Meng-Qing Wu

  3. Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Science, Beijing, China

    Zi-Jian Li

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  1. Rong-Jia Zhu
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  2. Meng-Qing Wu
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  3. Zi-Jian Li
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  4. Yao Zhang
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  5. Kai-Yan Liu
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Correspondence to Kai-Yan Liu.

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Financial Support: NNSF Grant #81270572 and MNSTP Grant #2012ZX09303019.

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12185_2012_1233_MOESM1_ESM.tif

Supplemental Figure 1. a. Bisphenol A diglycidyl ether (BADGE) inhibited adipogenic differentiation of murine marrow stromal progenitors (Passage three) (Oil red O staining, scale bar 200 μm). b. BADGE inhibited the expression of the adipocyte specific genes, PPARγ-2 and aP2 as assessed by quantitative polymerase chain reaction (qPCR) Data represent the mean of three independent wells + SD, *, p < 0.01, **, p < 0.05.(TIFF 2711 kb)

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Zhu, RJ., Wu, MQ., Li, ZJ. et al. Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis. Int J Hematol 97, 58–72 (2013). https://doi.org/10.1007/s12185-012-1233-4

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  • DOI: https://doi.org/10.1007/s12185-012-1233-4

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