Very Small Embryonic-like Stem Cells Are Mobilized in Human Peripheral Blood during Hypoxemic COPD Exacerbations and Pulmonary Hypertension
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Very small embryonic-like stem cells (VSELs) are major pluripotent stem cells involved in vascular and tissue regeneration and constitute a recruitable pool of stem/progenitor cells with putative instrumental role in organ repair. Here, we hypothesized that VSELs might be mobilized from the bone marrow (BM) to peripheral blood (PB) in patients with hypoxic lung disease or pulmonary hypertension (PH). The objective of the present study was then to investigate the changes in VSELs number in peripheral blood of patients with hypoxic lung disease and PH. We enrolled 26 patients with Chronic Obstructive Pulmonary Disease (COPD) with or without hypoxemia, 13 patients with PH and 20 controls without any respiratory or cardiovascular diseases. In PH patients, VSELs levels have been determined during right heart catheterization in pulmonary blood and PB. For this purpose, mononuclear cells were separated by density gradient and VSELs have been quantified by using a multiparametric flow cytometry approach. The number of PB-VSELs in hypoxic COPD patients was significantly increased compared with non-hypoxic COPD patients or controls (p = 0.0055). In patients with PH, we did not find any difference in VSELs numbers between arterial pulmonary blood and venous PB (p = 0.93). However, we found an increase in VSELs in the peripheral blood of patients with PH (p = 0.03). In conclusion, we unraveled that circulating VSELs were increased in peripheral blood of patients with hypoxic COPD or with PH. Thus, VSELs may serve as a reservoir of pluripotent stem cells that can be recruited into PB and may play an important role in promoting lung repair.
KeywordsVery small embryonic-like stem cells VSEL Lung Hypoxia Pulmonary hypertension Progenitor cells
This work was supported by grants from Leg Poix (chancellerie des universités), Région Ile de France-CORDDIM (Domaine d’intérêt majeur Cardiovasculaire Obésité Rein Diabète) and the Conny-Maeva Charitable Foundation. We also thank the technicians of hematology department of Georges Pompidou hospital, in particular Sebastien Bertil, Yann Burnel, Laurent Garcia and Florence Desvard.
Compliance with Ethical Standards
Conflict of Interest
Authors declare no conflict of interest.
- 3.Shin, D. M., Zuba-Surma, E. K., Wu, W., Ratajczak, J., Wysoczynski, M., Ratajczak, M. Z., et al. (2009). Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4(+) very small embryonic-like stem cells. Leukemia, 23(11), 2042–2051.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Shaikh, A., Anand, S., Kapoor, S., Ganguly, R., Bhartiya, D. (2017). Mouse bone marrow VSELs exhibit differentiation into three embryonic germ lineages and germ & hematopoietic cells in culture. Stem Cell Review. doi: 10.1007/s12015-016-9714-0.
- 7.Zbucka-Kretowska, M., Eljaszewicz, A., Lipinska, D., Grubczak, K., Rusak, M., Mrugacz, G., et al. (2016). Effective mobilization of very small embryonic-like stem cells and hematopoietic stem/progenitor cells but not endothelial progenitor cells by follicle-stimulating hormone therapy. Stem Cells International, 2016, 8530207.CrossRefPubMedGoogle Scholar
- 8.Starzynska, T., Dabkowski, K., Blogowski, W., Zuba-Surma, E., Budkowska, M., Salata, D., et al. (2013). An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer. Journal of Cellular and Molecular Medicine, 17(6), 792–799.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Gharib, S. A., Dayyat, E. A., Khalyfa, A., Kim, J., Clair, H. B., Kucia, M., et al. (2010). Intermittent hypoxia mobilizes bone marrow-derived very small embryonic-like stem cells and activates developmental transcriptional programs in mice. Sleep, 33(11), 1439–1446.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Galie, N., Humbert, M., Vachiery, J. L., Gibbs, S., Lang, I., Torbicki, A., et al. (2015). 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). The European Respiratory Journal, 46(4), 903–975.CrossRefPubMedGoogle Scholar
- 18.Smadja, D. M., Duong-van-Huyen, J. P., Dal Cortivo, L., Blanchard, A., Bruneval, P., Emmerich, J., et al. (2012). Early endothelial progenitor cells in bone marrow are a biomarker of cell therapy success in patients with critical limb ischemia. Cytotherapy, 14(2), 232–239.CrossRefPubMedGoogle Scholar
- 25.Smadja, D. M. (2017). Bone marrow very small embryonic-like stem cells: New generation of autologous cell therapy soon ready for prime time? Stem Cell Review. doi: 10.1007/s12015-017-9718-4.
- 27.Montani, D., Perros, F., Gambaryan, N., Girerd, B., Dorfmuller, P., Price, L. C., et al. (2011). C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 184(1), 116–123.CrossRefPubMedGoogle Scholar
- 28.Davie, N. J., Crossno Jr., J. T., Frid, M. G., Hofmeister, S. E., Reeves, J. T., Hyde, D. M., et al. (2004). Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: Contribution of progenitor cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 286(4), L668–L678.CrossRefPubMedGoogle Scholar
- 33.Wang, X. X., Zhang, F. R., Shang, Y. P., Zhu, J. H., Xie, X. D., Tao, Q. M., et al. (2007). Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: A pilot randomized controlled trial. Journal of the American College of Cardiology, 49(14), 1566–1571.CrossRefPubMedGoogle Scholar
- 34.Zhu, J. H., Wang, X. X., Zhang, F. R., Shang, Y. P., Tao, Q. M., Zhu, J. H., et al. (2008). Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: Open-label pilot study. Pediatric Transplantation, 12(6), 650–655.CrossRefPubMedGoogle Scholar
- 38.Ikonomou, L., Freishtat, R. J., Wagner, D. E., Panoskaltsis-Mortari, A., & Weiss, D. J. (2016). The global emergence of unregulated stem cell treatments for respiratory diseases. Professional societies need to act. Annals of the American Thoracic Society, 13(8), 1205–1207.CrossRefPubMedGoogle Scholar
- 42.Zuba-Surma, E. K., Guo, Y., Taher, H., Sanganalmath, S. K., Hunt, G., Vincent, R. J., et al. (2011). Transplantation of expanded bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) improves left ventricular function and remodelling after myocardial infarction. Journal of Cellular and Molecular Medicine, 15(6), 1319–1328.CrossRefPubMedGoogle Scholar