MSCs relieve lung injury of COPD mice through promoting proliferation of endogenous lung stem cells

Abstract

Bone marrow mesenchymal stem cells (MSCs) transplantation could repair injury tissue, but no study confirms whether MSCs can promote the proliferation of endogenous lung stem cells to repair alveolar epithelial cells of mice with chronic obstructive pulmonary disease (COPD). This study was designed to investigate the effect of MSCs on the proliferation of endogenous lung stem cells in COPD mice to confirm the repair mechanism of MSCs. The mice were divided into control group, COPD group, and COPD+MSCs group. The following indexes were detected: HE staining of lung tissue, the mean linear intercept (MLI) and alveolar destructive index (DI), the total cell number in bronchoalveolar lavage fluid (BALF), pulmonary function, alveolar wall apoptosis index (AI) and proliferation index (PI), the number of CD45^-/CD31^-/Sca-1⁺ cells by flow cytometry (FCM), and the number of bronchoalveolar stem cells (BASCs) in bronchoalveolar duct junction (BADJ) by immunofluorescence. As compared with control group, the number of inflammatory cells in lung tissue was increased, alveolar septa was destroyed and the emphysema-like changes were seen, and the changes of lung function were in line with COPD in COPD group; AI of alveolar wall was significantly increased and PI significantly decreased in COPD group. There was no significant difference in the number of CD45^-/CD31^-/Sca-1⁺ cells and BASCs between control group and COPD group. As compared with COPD group, the number of inflammatory cells in BALF was decreased, the number of CD45^-/CD31^-/Sca-1⁺ cells and BASCs was increased, AI of alveolar wall was decreased and PI was increased, and emphysema-like changes were relieved in COPD+MSCs group. These findings suggested that MSCs transplantation can relieve lung injury by promoting proliferation of endogenous lung stem cells in the cigarette smoke-induced COPD mice.

Keywords

mesenchymal stem cells / chronic obstructive pulmonary disease / bronchoalveolar stem cells

References

[1] VestboJ, HurdSS, AgustiAG, et al. . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med, 2013, 187(4): 347-365 PMID: 22878278

[2] QuanjerPH. Correctly defining criteria for diagnosing chronic obstructive pulmonary disease matters. Am J Respir Crit Care Med, 2014, 189(2): 230 PMID: 24428654

[3] CulverB. Defining airflow limitation and chronic obstructive pulmonary disease: the role of outcome studies. Eur Respir J, 2015, 46(1): 8-10 PMID: 26130773

[4] HawkinsPE, AlamJ, McDonnellTJ, et al. . Defining exacerbations in chronic obstructive pulmonary disease. Expert Rev Respir Med, 2015, 9(3): 277-286 PMID: 26013261

[5] AaronSD. Management and prevention of exacerbations of COPD. BMJ, 2014, 349: g5237 PMID: 25245156

[6] GoodwinM, SueblinvongV, EisenhauerP, et al. . Bone marrow-derived mesenchymal stromal cells inhibit Th2-mediated allergic airways inflammation in mice. Stem Cells, 2011, 29(7): 1137-1148 PMCID: 4201366 PMID: 21544902

[7] O’ReillyM, ThebaudB. Cell-based strategies to reconstitute lung function in infants with severe bronchopulmonary dysplasia. Clin Perinatol, 2012, 39(3): 703-725 PMID: 22954277

[8] MatthayMA, ThompsonBT, ReadEJ, et al. . Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest, 2010, 138(4): 965-972 PMCID: 2951759 PMID: 20923800

[9] LeeJW, KrasnodembskayaA, McKennaDH, et al. . Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med, 2013, 187(7): 751-760 PMCID: 3678109 PMID: 23292883

[10] WeissDJ. Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells, 2014, 32(1): 16-25 PMCID: 4208500 PMID: 23959715

[11] RockJR, HoganBL. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol, 2011, 27: 493-512 PMID: 21639799

[12] McQualterJL, BertoncelloI. Concise review: Deconstructing the lung to reveal its regenerative potential. Stem Cells, 2012, 30(5): 811-816 PMID: 22331696

[13] WeissDJ. Stem cells, cell therapies, and bioengineering in lung biology and diseases. Comprehensive review of the recent literature 2010-2012. Ann Am Thorac Soc, 2013, 10(5): S45-97

[14] HatzistergosKE, QuevedoH, OskoueiBN, et al. . Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res, 2010, 107(7): 913-922 PMCID: 3408082 PMID: 20671238

[15] TropeaKA, LederE, AslamM, et al. . Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol, 2012, 302(9): L829-837 PMCID: 3362163 PMID: 22328358

[16] JinZ, PanX, ZhouK, et al. . Biological effects and mechanisms of action of mesenchymal stem cell therapy in chronic obstructive pulmonary disease. J Int Med Res, 2015, 43(3): 303-310 PMID: 25834280

[17] KumarPA, HuY, YamamotoY, et al. . Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell, 2011, 147(3): 525-538 PMCID: 4040224 PMID: 22036562

[18] Nolen-WalstonRD, KimCF, MazanMR, et al. . Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1158-1165 PMCID: 2593913 PMID: 18375744

[19] KimCF, JacksonEL, WoolfendenAE, et al. . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell, 2005, 121(6): 823-835 PMID: 15960971

[20] ZhenG, LiuH, GuN, et al. . Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci, 2008, 13: 3415-3422 PMID: 18508443

[21] AdenugaD, YaoH, MarchTH, et al. . Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol, 2009, 40(4): 464-473 PMCID: 2660563 PMID: 18927347

[22] HuhJW, KimSY, LeeJH, et al. . Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol, 2011, 301(3): L255-266 PMID: 21622846

[23] ChenY, HanaokaM, ChenP, et al. . Protective effect of beraprost sodium, a stable prostacyclin analog, in the development of cigarette smoke extract-induced emphysema. Am J Physiol Lung Cell Mol Physiol, 2009, 296(4): L648-656 PMID: 19201816

[24] KajsturaJ, RotaM, HallSR, et al. . Evidence for human lung stem cells. N Engl J Med, 2011, 364(19): 1795-1806 PMCID: 3197695 PMID: 21561345

[25] ChilosiM, PolettiV, RossiA. The pathogenesis of COPD and IPF: distinct horns of the same devil. Respir Res, 2012, 13: 3 PMCID: 3282644 PMID: 22235752

[26] CrystalRG, RandellSH, EngelhardtJF, et al. . Airway epithelial cells: current concepts and challenges. Proc Am Thorac Soc, 2008, 5(7): 772-777 PMID: 18757316

[27] TzouvelekisA, LaurentG, BourosD. Stem cell therapy in chronic obstructive pulmonary disease. Seeking the Prometheus effect. Curr Drug Targets, 2013, 14(2): 246-252