Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema

Respiratory Research

Patricia RM Rocco⁵  Marcelo M Morales²  Daniel J Weiss³  Débora G Xisto²  Vera L Capelozzi⁸  Nazareth N Rocha⁷  Isalira PRG Freitas⁴  Christina M Takyia⁶  Bruno L Diaz¹  Priscilla C Olsen⁵  Elga Bandeira²  Miquéias Lopes-Pacheco²  Ana Clara Teixeira⁵  Fernanda F Cruz⁵  Soraia C Abreu⁵  Mariana A Antunes⁵ 

[1] Laboratory of Inflammation, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Laboratory of Cellular and Molecular Physiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Department of Medicine, University of Vermont, Vermont, USA;Laboratory of Cellular and Molecular Cardiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Centro de Ciências da Saúde, Federal University of Rio de Janeiro, Avenida Carlos Chagas Filho, s/n, Bloco G-014, Ilha do Fundão – 21941-902, Rio de Janeiro, RJ, Brazil;Laboratory of Cellular Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil;Department of Pathology, University of São Paulo, São Paulo, Brazil

关键词: Mesenchymal stromal cells;    Macrophage;    Remodeling;    Emphysema;    Elastase;   

Others  :  1137260
DOI  :  10.1186/s12931-014-0118-x

 received in 2014-07-20, accepted in 2014-09-25,  发布年份 2014

【 摘 要 】

We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×10⁵), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2.

【 授权许可】

   
2014 Antunes et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Minai OA, Benditt J, Martinez FJ: Natural history of emphysema. Proc Am Thorac Soc 2008, 5(4):468-474.
• [2][http://www.goldcopd.org/] webcite From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD)..
• [3]Weiss DJ: Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells 2014, 32(1):16-25.
• [4]Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, Oh YM, Lee YS, Lee SD: Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol 2011, 301(3):L255-L266.
• [5]Kim SY, Lee JH, Kim HJ, Park MK, Huh JW, Ro JY, Oh YM, Lee SD, Lee YS: Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol 2012, 302(9):L891-L908.
• [6]Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, Feng D, Adamowicz JJ, Van Demark M, Fisher AJ, Kamocki K, Brown MB, Presson RG Jr, Broxmeyer HE, March KL, Petrache I: Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med 2011, 183(2):215-225.
• [7]Zhen G, Xue Z, Zhao J, Gu N, Tang Z, Xu Y, Zhang Z: Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells. Cytotherapy 2010, 12(5):605-614.
• [8]Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP: A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest 2013, 143(6):1590-1598.
• [9]Ostanin AA, Petrovskii YL, Shevela EY, Chernykh ER: Multiplex analysis of cytokines, chemokines, growth factors, MMP-9 and TIMP-1 produced by human bone marrow, adipose tissue, and placental mesenchymal stromal cells. Bull Exp Biol Med 2011, 151(1):133-141.
• [10]Ricciardi M, Malpeli G, Bifari F, Bassi G, Pacelli L, Nwabo Kamdje AH, Chilosi M, Krampera M: Comparison of epithelial differentiation and immune regulatory properties of mesenchymal stromal cells derived from human lung and bone marrow.PLoS One 2012, 7(5):e35639.
• [11]Cruz FF, Antunes MA, Abreu SC, Fujisaki LC, Silva JD, Xisto DG, Maron-Gutierrez T, Ornellas DS, Sa VK, Rocha NN, Capelozzi VL, Morales MM, Rocco PR: Protective effects of bone marrow mononuclear cell therapy on lung and heart in an elastase-induced emphysema model. Respir Physiol Neurobiol 2012, 182(1):26-36.
• [12]Hoffman AM, Paxson JA, Mazan MR, Davis AM, Tyagi S, Murthy S, Ingenito EP: Lung-derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase-injured lung. Stem Cells Dev 2011, 20(10):1779-1792.
• [13]Guan XJ, Song L, Han FF, Cui ZL, Chen X, Guo XJ, Xu WG: Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 2013, 114(2):323-335.
• [14]Ingenito EP, Tsai L, Murthy S, Tyagi S, Mazan M, Hoffman A: Autologous lung-derived mesenchymal stem cell transplantation in experimental emphysema. Cell Transplant 2012, 21(1):175-189.
• [15]da Silva Meirelles L, Chagastelles PC, Nardi NB: Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006, 119(Pt 11):2204-2213.
• [16]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for cellular therapy position statement. Cytotherapy 2006, 8(4):315-317.
• [17]Nora CC, Camassola M, Bellagamba B, Ikuta N, Christoff AP, Meirelles Lda S, Ayres R, Margis R, Nardi NB: Molecular analysis of the differentiation potential of murine mesenchymal stem cells from tissues of endodermal or mesodermal origin. Stem Cells Dev 2012, 21(10):1761-1768.
• [18]Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W: Recommendations for chamber quantification. Eur J Echocardiogr 2006, 7(2):79-108.
• [19]Abbas AE, Franey LM, Marwick T, Maeder MT, Kaye DM, Vlahos AP, Serra W, Al-Azizi K, Schiller NB, Lester SJ: Noninvasive assessment of pulmonary vascular resistance by doppler echocardiography. J Am Soc Echocardiogr 2013, 26(10):1170-1177.
• [20]Thibault HB, Kurtz B, Raher MJ, Shaik RS, Waxman A, Derumeaux G, Halpern EF, Bloch KD, Scherrer-Crosbie M: Noninvasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension. Circ Cardiovasc Imaging 2010, 3(2):157-163.
• [21]Hsia CC, Hyde DM, Ochs M, Weibel ER: Structure AEJTFoQAoL: an official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 2010, 181(4):394-418.
• [22]Weibel ER: Morphometry: Stereological Theory and Practical Methods. In Models of Lung Disease-Microscopy and Structural Methods. Edited by Gil J. Marcel Dekker, New York; 1990:199-247.
• [23]Antunes MA, Abreu SC, Silva AL, Parra-Cuentas ER, Ab'Saber AM, Capelozzi VL, Ferreira TP, Martins MA, Silva PM, Rocco PR: Sex-specific lung remodeling and inflammation changes in experimental allergic asthma. J Appl Physiol 2010, 109(3):855-863.
• [24]Abreu SC, Antunes MA, Maron-Gutierrez T, Cruz FF, Ornellas DS, Silva AL, Diaz BL, Ab'Saber AM, Capelozzi VL, Xisto DG, Morales MM, Rocco PR: Bone marrow mononuclear cell therapy in experimental allergic asthma: intratracheal versus intravenous administration. Respir Physiol Neurobiol 2013, 185(3):615-624.
• [25]Oliveira GP, Oliveira MB, Santos RS, Lima LD, Dias CM, Ab’ Saber AM, Teodoro WR, Capelozzi VL, Gomes RN, Bozza PT, Pelosi P, Rocco PR: Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis.Crit Care 2009, 13(3):R74.
• [26]Antunes MA, Rocco PR: Elastase-induced pulmonary emphysema: insights from experimental models. An Acad Bras Cienc 2011, 83(4):1385-1396.
• [27]Luthje L, Raupach T, Michels H, Unsold B, Hasenfuss G, Kogler H, Andreas S: Exercise intolerance and systemic manifestations of pulmonary emphysema in a mouse model.Respir Res 2009, 10:7.
• [28]Moodley Y, Vaghjiani V, Chan J, Baltic S, Ryan M, Tchongue J, Samuel CS, Murthi P, Parolini O, Manuelpillai U: Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study.PLoS One 2013, 8(8):e69299.
• [29]Ragni E, Montemurro T, Montelatici E, Lavazza C, Vigano M, Rebulla P, Giordano R, Lazzari L: Differential microRNA signature of human mesenchymal stem cells from different sources reveals an “environmental-niche memory” for bone marrow stem cells. Exp Cell Res 2013, 319(10):1562-1574.
• [30]Elman JS, Li M, Wang F, Gimble JM, Parekkadan B: A comparison of adipose and bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of systemic inflammation.J Inflamm 2014, 11(1):1.
• [31]Rasmussen JG, Frobert O, Holst-Hansen C, Kastrup J, Baandrup U, Zachar V, Fink T, Simonsen U: Comparison of human adipose-derived stem cells and bone marrow-derived stem cells in a myocardial infarction model. Cell Transplant 2012, 23(2):195-206.
• [32]Rajashekhar G, Traktuev DO, Roell WC, Johnstone BH, Merfeld-Clauss S, Van Natta B, Rosen ED, March KL, Clauss M: IFATS collection: adipose stromal cell differentiation is reduced by endothelial cell contact and paracrine communication: role of canonical Wnt signaling. Stem Cells 2008, 26(10):2674-2681.
• [33]Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y: Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant 2006, 6(11):2592-2600.
• [34]Antunes MA, Laffey JG, Pelosi P, Rocco PR: Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem 2014, 115(6):1023-1032.
• [35]Ingenito EP, Sen E, Tsai LW, Murthy S, Hoffman A: Design and testing of biological scaffolds for delivering reparative cells to target sites in the lung. J Tissue Eng Regen Med 2010, 4(4):259-272.
• [36]Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN: Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008, 181(6):4389-4396.
• [37]Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, Wang Z, Liao H, Toews GB, Krebsbach PH, Peters-Golden M, Pinsky DJ, Martinez FJ, Thannickal VJ: Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007, 117(4):989-996.
• [38]Curley GF, Ansari B, Hayes M, Devaney J, Masterson C, Ryan A, Barry F, O'Brien T, Toole DO, Laffey JG: Effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilator-induced lung injury. Anesthesiology 2013, 118(4):924-932.
• [39]Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, Matthay MA: Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012, 67(6):533-539.
• [40]Bonios M, Terrovitis J, Chang CY, Engles JM, Higuchi T, Lautamaki R, Yu J, Fox J, Pomper M, Wahl RL, Tsui BM, O’Rourke B, Bengel FM, Marbán E, Abraham MR: Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells. J Nucl Cardiol 2011, 18(3):443-450.
• [41]Tibboel J, Keijzer R, Reiss I, de Jongste JC, Post M: Intravenous and intratracheal mesenchymal stromal cell injection in a mouse model of pulmonary emphysema. COPD 2014, 11(3):310-318.
• [42]Nystedt J, Anderson H, Tikkanen J, Pietila M, Hirvonen T, Takalo R, Heiskanen A, Satomaa T, Natunen S, Lehtonen S, Hakkarainen T, Korhonen M, Laitinen S, Valmu L, Lehenkari P: Cell surface structures influence lung clearance rate of systemically infused mesenchymal stromal cells. Stem Cells 2013, 31(2):317-326.
• [43]Frankenberger M, Menzel M, Betz R, Kassner G, Weber N, Kohlhaufl M, Haussinger K, Ziegler-Heitbrock L: Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers. Clin Exp Immunol 2004, 138(3):507-516.
• [44]Kollert F, Probst C, Muller-Quernheim J, Zissel G, Prasse A: CCL18 production is decreased in alveolar macrophages from cigarette smokers. Inflammation 2009, 32(3):163-168.
• [45]Kunz LI, Lapperre TS, Snoeck-Stroband JB, Budulac SE, Timens W, van Wijngaarden S, Schrumpf JA, Rabe KF, Postma DS, Sterk PJ, Hiemstra PS, Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group: Smoking status and anti-inflammatory macrophages in bronchoalveolar lavage and induced sputum in COPD.Respir Res 2011, 12:34.
• [46]Shaykhiev R, Krause A, Salit J, Strulovici-Barel Y, Harvey BG, O'Connor TP, Crystal RG: Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol 2009, 183(4):2867-2883.
• [47]Salazar KD, Lankford SM, Brody AR: Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2009, 297(5):L1002-L1011.
• [48]Lee SH, Jang AS, Kim YE, Cha JY, Kim TH, Jung S, Park SK, Lee YK, Won JH, Kim YH, Park CS: Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis.Respir Res 2010, 11:16.
• [49]Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, Okada Y, Yamasawa F, Nakahara K, Umeda A: Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2001, 163(6):1476-1483.
• [50]Rodrigues CG, Plentz RD, Dipp T, Salles FB, Giusti II, Sant’anna RT, Eibel B, Nesralla IA, Markoski M, Beyer NN, Kalil RA: VEGF 165 gene therapy for patients with refractory angina: mobilization of endothelial progenitor cells. Arq Bras Cardiol 2013, 101(2):149-153.
• [51]Ye J, Ni P, Kang L, Xu B: Apelin and vascular endothelial growth factor are associated with mobilization of endothelial progenitor cells after acute myocardial infarction. J Biomed Res 2012, 26(6):400-409.
• [52]Keatings VM, Collins PD, Scott DM, Barnes PJ: Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996, 153(2):530-534.
• [53]Bates JH, Davis GS, Majumdar A, Butnor KJ, Suki B: Linking parenchymal disease progression to changes in lung mechanical function by percolation. Am J Respir Crit Care Med 2007, 176(6):617-623.
• [54]Hamakawa H, Bartolak-Suki E, Parameswaran H, Majumdar A, Lutchen KR, Suki B: Structure-function relations in an elastase-induced mouse model of emphysema. Am J Respir Cell Mol Biol 2011, 45(3):517-524.
• [55]Winkler T, Suki B: Emergent structure-function relations in emphysema and asthma. Crit Rev Biomed Eng 2011, 39(4):263-280.