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Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms remain unclear but involve a concomitant accumulation of scar tissue together with myofibroblasts activation. Microparticles (MPs) have been investigated in several human lung diseases as possible pathogenic elements, prognosis markers and therapeutic targets. We postulated that levels and cellular origins of circulating MPs might serve as biomarkers in IPF patients and/or as active players of fibrogenesis. Flow cytometry analysis showed a higher level of Annexin-V positive endothelial and platelet MPs in 41 IPF patients compared to 22 healthy volunteers. Moreover, in IPF patients with a low diffusing capacity of the lung for carbon monoxide (DLCO<40%), endothelial MPs (EMPs) were found significantly higher compared to those with DLCO>40% (p = 0.02). We then used EMPs isolated from endothelial progenitor cells (ECFCs) extracted from IPF patients or controls to modulate normal human lung fibroblast (NHLF) properties. We showed that EMPs did not modify proliferation, collagen deposition and myofibroblast transdifferentiation. However, EMPs from IPF patients stimulated migration capacity of NHLF. We hypothesized that this effect could result from EMPs fibrinolytic properties and found indeed higher plasminogen activation potential in total circulating MPs and ECFCs derived MPs issued from IPF patients compared to those isolated from healthy controls MPs. Our study showed that IPF is associated with an increased level of EMPs in the most severe patients, highlighting an active process of endothelial activation in the latter. Endothelial microparticles might contribute to the lung fibroblast invasion mediated, at least in part, by a fibrinolytic activity.

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References

  1. Raghu, G., Rochwerg, B., Zhang, Y., Garcia, C. A. C., Azuma, A., Behr, J., et al. (2015). An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. American Journal of Respiratory and Critical Care Medicine, 192(2), e3–19.

    Article  PubMed  Google Scholar 

  2. Smadja, D. M., Mauge, L., Nunes, H., d’Audigier, C., Juvin, K., Borie, R., et al. (2013). Imbalance of circulating endothelial cells and progenitors in idiopathic pulmonary fibrosis. Angiogenesis, 16(1), 147–157.

    Article  CAS  PubMed  Google Scholar 

  3. Toshner, M., Voswinckel, R., Southwood, M., Al-Lamki, R., Howard, L. S. G., Marchesan, D., et al. (2009). Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 180(8), 780–787.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Malli, F., Koutsokera, A., Paraskeva, E., Zakynthinos, E., Papagianni, M., Makris, D., et al. (2013). Endothelial progenitor cells in the pathogenesis of idiopathic pulmonary fibrosis: an evolving concept. PloS One, 8(1), e53658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Amabile, N., Guignabert, C., Montani, D., Yeghiazarians, Y., Boulanger, C. M., & Humbert, M. (2013). Cellular microparticles in the pathogenesis of pulmonary hypertension. The European Respiratory Journal, 42(1), 272–279.

    Article  CAS  PubMed  Google Scholar 

  6. Nieri, D., Neri, T., Petrini, S., Vagaggini, B., Paggiaro, P., & Celi, A. (2016). Cell-derived microparticles and the lung. European Respiratory Review: an Official Journal of European Respiratory Society, 25(141), 266–277.

    Article  Google Scholar 

  7. Bakouboula, B., Morel, O., Faure, A., Zobairi, F., Jesel, L., Trinh, A., et al. (2008). Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 177(5), 536–543.

    Article  CAS  PubMed  Google Scholar 

  8. Amabile, N., Heiss, C., Real, W. M., Minasi, P., McGlothlin, D., Rame, E. J., et al. (2008). Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 177(11), 1268–1275.

    Article  CAS  PubMed  Google Scholar 

  9. Iversen, L. V., Ullman, S., Østergaard, O., Nielsen, C. T., Halberg, P., Karlsmark, T., et al. (2015). Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis. BMC Musculoskeletal Disorders, 16, 191.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nomura, S., Inami, N., Ozaki, Y., Kagawa, H., & Fukuhara, S. (2008). Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets, 19(3), 192–198.

    Article  CAS  PubMed  Google Scholar 

  11. Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A., & Ratajczak, M. Z. (2006). Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia, 20(9), 1487–1495.

    Article  CAS  PubMed  Google Scholar 

  12. Ratajczak, M. Z., & Ratajczak, J. (2016). Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clinical and Translational Medicine, 5(1), 7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Mauge, L., Sabatier, F., Boutouyrie, P., D’Audigier, C., Peyrard, S., Bozec, E., et al. (2014). Forearm ischemia decreases endothelial colony-forming cell angiogenic potential. Cytotherapy, 16(2), 213–224.

    Article  CAS  PubMed  Google Scholar 

  14. Evrard, S. M., d’Audigier, C., Mauge, L., Israël-Biet, D., Guerin, C. L., Bieche, I., et al. (2012). The profibrotic cytokine transforming growth factor-β1 increases endothelial progenitor cell angiogenic properties. Journal of Thrombosis and Haemostasis, 10(4), 670–679.

    Article  CAS  PubMed  Google Scholar 

  15. Amabile, N., Cheng, S., Renard, J. M., Larson, M. G., Ghorbani, A., McCabe, E., et al. (2014). Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham Heart Study. European Heart Journal, 35(42):2972–2979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Empana, J.-P., Boulanger, C. M., Tafflet, M., Renard, J. M., Leroyer, A. S., Varenne, O., et al. (2015). Microparticles and sudden cardiac death due to coronary occlusion. The TIDE (Thrombus and Inflammation in Sudden Death) study. European Heart Journal. Acute Cardiovascular Care, 4(1), 28–36.

    Article  PubMed  Google Scholar 

  17. Poncelet, P., Robert, S., Bouriche, T., Bez, J., Lacroix, R., & Dignat-George, F. (2016). Standardized counting of circulating platelet microparticles using currently available flow cytometers and scatter-based triggering: forward or side scatter? Cytometry Part A: the Journal of the International Society for Analytical Cytology, 89(2), 148–158.

    Article  CAS  Google Scholar 

  18. Yoder, M. C., Mead, L. E., Prater, D., Krier, T. R., Mroueh, K. N., Li, F., et al. (2007). Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood, 109(5), 1801–1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Silvestre, J. S., Smadja, D. M., & Levy, B. I. (2013). Postisch-emic revascularization: from cellular and molecular mechanisms to clinical applications. Physiological Reviews, 93, 1743–1802.

  20. Sapet, C., Simoncini, S., Loriod, B., Puthier, D., Sampol, J., Nguyen, C., et al. (2006). Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2. Blood, 108(6):1868–1876.

    Article  CAS  PubMed  Google Scholar 

  21. Smadja, D. M., Bièche, I., Silvestre, J.-S., Germain, S., Cornet, A., Laurendeau, I., et al. (2008). Bone morphogenetic proteins 2 and 4 are selectively expressed by late outgrowth endothelial progenitor cells and promote neoangiogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(12), 2137–2143.

    Article  CAS  PubMed  Google Scholar 

  22. Smadja, D. M., Levy, M., Huang, L., Rossi, E., Blandinières, A., Israel-Biet, D., et al. (2015). Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thrombosis and Haemostasis, 114(4), 735–747.

    PubMed  Google Scholar 

  23. Sabatier, F., Roux, V., Anfosso, F., Camoin, L., Sampol, J., & Dignat-George, F. (2002). Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood, 99(11):3962–3970.

    Article  CAS  PubMed  Google Scholar 

  24. Abid Hussein, M. N., Böing, A. N., Biró, E., Hoek, F. J., Vogel, G. M. T., Meuleman, D. G., et al. (2008). Phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties. Thrombosis Research, 121(6), 865–871.

    Article  CAS  PubMed  Google Scholar 

  25. Lacroix, R., Plawinski, L., Robert, S., Doeuvre, L., Sabatier, F., Martinez de Lizarrondo, S., et al. (2012). Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis. Haematologica, 97(12), 1864–1872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Crooks, M. G., & Hart, S. P. (2015). Coagulation and anticoagulation in idiopathic pulmonary fibrosis. European Respiratory Review: an Official Journal of European Respiratory Society, 24(137), 392–399.

    Article  Google Scholar 

  27. Novelli, F., Neri, T., Tavanti, L., Armani, C., Noce, C., Falaschi, F., et al. (2014). Procoagulant, tissue factor-bearing microparticles in bronchoalveolar lavage of interstitial lung disease patients: an observational study. PloS One, 9(4), e95013.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lin, C., Borensztajn, K., & Spek, C. A. (2017). Targeting coagulation factor receptors - protease-activated receptors in idiopathic pulmonary fibrosis. Journal of Thrombosis and Haemostasis, 15(4), 597–607.

    Article  CAS  PubMed  Google Scholar 

  29. Scotton, C. J., Krupiczojc, M. A., Königshoff, M., Mercer, P. F., Lee, Y. C. G., Kaminski, N., et al. (2009). Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. The Journal of Clinical Investigation, 119(9), 2550–2563.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cointe, S., Judicone, C., Robert, S., Mooberry, M. J., Poncelet, P., Wauben, M., et al. (2017). Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop. Journal of Thrombosis and Haemostasis, 15(1), 187–193.

    Article  CAS  PubMed  Google Scholar 

  31. Renzoni, E. A., Walsh, D. A., Salmon, M., Wells, A. U., Sestini, P., Nicholson, A. G., et al. (2003). Interstitial vascularity in fibrosing alveolitis. American Journal of Respiratory and Critical Care Medicine, 167(3), 438–443.

    Article  PubMed  Google Scholar 

  32. Ratajczak, J., Kucia, M., Mierzejewska, K., Marlicz, W., Pietrzkowski, Z., Wojakowski, W., et al. (2013). Paracrine proangiopoietic effects of human umbilical cord blood-derived purified CD133 + cells–implications for stem cell therapies in regenerative medicine. Stem Cells and Development, 22(3), 422–430.

    Article  CAS  PubMed  Google Scholar 

  33. Wang, J., Chen, S., Ma, X., Cheng, C., Xiao, X., Chen, J., et al. (2013). Effects of endothelial progenitor cell-derived microvesicles on hypoxia/reoxygenation-induced endothelial dysfunction and apoptosis. Oxidative Medicine and Cellular Longevity, 2013, 572729.

    PubMed  PubMed Central  Google Scholar 

  34. Bitzer, M., Ben-Dov, I. Z., & Thum, T. (2012). Microparticles and microRNAs of endothelial progenitor cells ameliorate acute kidney injury. Kidney International, 82(4), 375–377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Doeuvre, L., & Angles-Cano, E. (2009). Cell-derived microparticles unveil their fibrinolytic and proteolytic function. Medical Science, 25(1), 37–44.

    Google Scholar 

  36. Gobin, A. S., & West, J. L. (2002). Cell migration through defined, synthetic ECM analogs. FASEB Journal: an Official Publication Federation American Society Experimental Biology, 16(7), 751–753.

    Article  CAS  Google Scholar 

  37. Warejcka, D. J., Narayan, M., & Twining, S. S. (2011). Maspin increases extracellular plasminogen activator activity associated with corneal fibroblasts and myofibroblasts. Experimental Eye Research, 93(5), 618–627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Strieter, R. M., Keeley, E. C., Hughes, M. A., Burdick, M. D., & Mehrad, B. (2009). The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. Journal of Leukocyte Biology, 86(5), 1111–1118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ruehl, M., Muche, M., Freise, C., Erben, U., Neumann, U., Schuppan, D., et al. (2011). Hydroxyproline-containing collagen analogs trigger the release and activation of collagen-sequestered proMMP-2 by competition with prodomain-derived peptide P33-42. Fibrogenesis Tissue Repair, 4(1), 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Phillips, R. J., Burdick, M. D., Hong, K., Lutz, M. A., Murray, L. A., Xue, Y. Y., et al. (2004). Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. The Journal of Clinical Investigation, 114(3), 438–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Moore, B. B., Murray, L., Das, A., Wilke, C. A., Herrygers, A. B., & Toews, G. B. (2006). The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. American Journal of Respiratory Cell and Molecular Biology, 35(2), 175–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Smadja, D. M., Dorfmüller, P., Guerin, C. L., Bieche, I., Badoual, C., Boscolo, E., et al. (2014). Cooperation between human fibrocytes and endothelial colony-forming cells increases angiogenesis via the CXCR4 pathway. Thrombosis and Haemostasis, 112(5), 1002–1013.

    PubMed  PubMed Central  Google Scholar 

  43. Smadja, D. M., Bièche, I., Emmerich, J., Aiach, M., & Gaussem, P. (2006). PAR-1 activation has different effects on the angiogenic activity of endothelial progenitor cells derived from human adult and cord blood. Journal of Thrombosis and Haemostasis, 4(12), 2729–2731.

    Article  CAS  PubMed  Google Scholar 

  44. Ingram, D. A., Mead, L. E., Tanaka, H., Meade, V., Fenoglio, A., Mortell, K., et al. (2004). Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood, 104(9):2752–2760.

    Article  CAS  PubMed  Google Scholar 

  45. Nadaud, S., Poirier, O., Girerd, B., Blanc, C., Montani, D., Eyries, M., et al. (2013). Small platelet microparticle levels are increased in pulmonary arterial hypertension. European Journal of Clinical Investigation, 43(1), 64–71.

    Article  CAS  PubMed  Google Scholar 

  46. Simoncini, S., Chateau, A.-L., Robert, S., Todorova, D., Yzydorzick, C., Lacroix, R., et al. (2017). Biogenesis of pro-senescent microparticles by endothelial colony forming cells from premature neonates is driven by SIRT1-dependent epigenetic regulation of MKK6. Scientific Reports, 7(1), 8277.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants of Chancellerie des Universities (Legs Poix) and Coeny-maeva charitable foundation.

Nour C. Bacha is supported by a grant from « Fonds de dotation pour la Recherche en Santé Respiratoire ».

We thank the technicians and engineers of hematology department of Georges Pompidou hospital, in particular Sebastien Bertil, Alexandre Kisaoglou, Florence Desvard, Nadège Ochat and Yann Burnel.

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Authors and Affiliations

  1. Inserm UMR-S1140, Paris, France

    Nour C. Bacha, Adeline Blandinieres, Elisa Rossi, Nicolas Gendron, Nathalie Nevo, Séverine Lecourt, Pascale Gaussem, Eduardo Angles-Cano, Dominique Israel-Biet & David M. Smadja

  2. Sorbonne Paris Cite, Université Paris Descartes, Paris, France

    Nour C. Bacha, Adeline Blandinieres, Elisa Rossi, Nicolas Gendron, Nathalie Nevo, Jean Marie Renard, Pascale Gaussem, Eduardo Angles-Cano, Chantal M. Boulanger, Dominique Israel-Biet & David M. Smadja

  3. Hematology Department and UMR-S1140, AP-HP, European Hospital Georges Pompidou, 20 rue Leblanc, 75015, Paris, France

    Adeline Blandinieres, Nicolas Gendron, Pascale Gaussem & David M. Smadja

  4. National Cytometry Platform, Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg, France

    Coralie L. Guerin

  5. Inserm UMR-S970, PARCC, Paris, France

    Jean Marie Renard & Chantal M. Boulanger

  6. Pneumology Department, AP-HP, European Hospital Georges Pompidou, Paris, France

    Dominique Israel-Biet

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  1. Nour C. Bacha
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  2. Adeline Blandinieres
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Correspondence to David M. Smadja.

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Bacha, N.C., Blandinieres, A., Rossi, E. et al. Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis. Stem Cell Rev and Rep 14, 223–235 (2018). https://doi.org/10.1007/s12015-017-9778-5

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