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DOI: 10.1055/s-0037-1607051
Localization of Exogenous Mesenchymal Stem Cells in a Pig Model of Lung Transplantation
Publikationsverlauf
22. Mai 2017
16. August 2017
Publikationsdatum:
09. Oktober 2017 (online)
Abstract
Background Mesenchymal stem cells (MSCs) have a great potential for the treatment of acute lung injury. This study provides a detailed immunohistochemical and stereological analysis of the localization and distribution of exogenous MSC in a pig model of lung transplantation after intravascular or endobronchial application.
Methods MSC derived from human bone marrow were labeled by DiI and administered intravascularly or endobronchially to the lungs of donor pigs after a period of 3 hours warm and 3 hours cold ischemia. The left lung was transplanted to a recipient pig and reperfused for 4 hours before fixation. The right donor lung was fixed for microscopic analysis directly after the ischemia time.
Results After both administration routes, a similar number of exogenous MSC was found in the lungs. Within each animal, the heterogeneity of MSC distribution was high both with respect to left and right lung as well as to the different lobes of each lung. After endobronchial application, MSC were found in alveolar and bronchial/bronchiolar lumen, whereas after intravascular administration, they were mainly observed in blood vessels.
Conclusion Although the administration of exogenous MSC is possible by endobronchial or intravascular application, it yields a heterogeneous distribution in the lungs which may warrant strategies to improve a more homogeneous distribution.
Authors' Contributions
T.P. established the immunohistochemistry and performed parts of the quantitative analysis; C.B. performed parts of the quantitative analysis and prepared the data for publication; P.R., M.Z., and A.S. performed the surgical experiments; Y.H.C. contributed to the preparation of stem cells and to the concept and design of the study; T.W. contributed to the surgical experiments and to the concept and design of the study; T.C.W.W contributed to the concept and design of the study; M.O. contributed to the concept and design of the study; C.M. contributed to the concept and design of the study, performed parts of the quantitative analysis, and wrote major parts of the article. All authors contributed to the critical interpretation of the results and to the critical revision of the article.
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References
- 1 Moss M, Thompson BT. Definitions and clinical risk factors. In: Matthay MA. , ed. Acute Respiratory Distress Syndrome. NewYork/Basel: Marcel Dekker; 2003: 7-36
- 2 Matthay MA. Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome. Ann Am Thorac Soc 2015; 12 (Suppl. 01) S54-S57
- 3 Horie S, Masterson C, Devaney J, Laffey JG. Stem cell therapy for acute respiratory distress syndrome: a promising future?. Curr Opin Crit Care 2016; 22 (01) 14-20
- 4 Ortiz LA, Dutreil M, Fattman C. , et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007; 104 (26) 11002-11007
- 5 Gupta N, Krasnodembskaya A, Kapetanaki M. , et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012; 67 (06) 533-539
- 6 Cai SX, Liu AR, Chen S. , et al. Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice. Stem Cell Res Ther 2015; 6: 65
- 7 Li JW, Wu X. Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells. Eur Rev Med Pharmacol Sci 2015; 19 (13) 2368-2378
- 8 Lu W, Si YI, Ding J. , et al. Mesenchymal stem cells attenuate acute ischemia-reperfusion injury in a rat model. Exp Ther Med 2015; 10 (06) 2131-2137
- 9 Sun CK, Leu S, Hsu SY. , et al. Mixed serum-deprived and normal adipose-derived mesenchymal stem cells against acute lung ischemia-reperfusion injury in rats. Am J Transl Res 2015; 7 (02) 209-231
- 10 Asmussen S, Ito H, Traber DL. , et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 2014; 69 (09) 819-825
- 11 Mühlfeld C, Schaefer IM, Becker L. , et al. Pre-ischaemic exogenous surfactant reduces pulmonary injury in rat ischaemia/reperfusion. Eur Respir J 2009; 33 (03) 625-633
- 12 Wittwer T, Rahmanian P, Choi YH. , et al. Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation. J Cardiothorac Surg 2014; 9: 151
- 13 Wang H, Liang X, Xu ZP, Crawford DHG, Liu X, Roberts MS. A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells. Sci Rep 2016; 6: 22293
- 14 Wu J, Sun Z, Sun HS. , et al. Intravenously administered bone marrow cells migrate to damaged brain tissue and improve neural function in ischemic rats. Cell Transplant 2008; 16 (10) 993-1005
- 15 François S, Bensidhoum M, Mouiseddine M. , et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 2006; 24 (04) 1020-1029
- 16 Ortiz LA, Gambelli F, McBride C. , et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 2003; 100 (14) 8407-8411
- 17 Lu H, Cook T, Poirier C. , et al. Pulmonary retention of adipose stromal cell following intravenous delivery is markedly altered in the presence of ARDS. Cell Transplant 2016; 25 (09) 1635-1643
- 18 Wong AP, Dutly AE, Sacher A. , et al. Targeted cell replacement with bone marrow cells for airway epithelial regeneration. Am J Physiol Lung Cell Mol Physiol 2007; 293 (03) L740-L752
- 19 Gennai S, Monsel A, Hao Q, Park J, Matthay MA, Lee JW. Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Transplant 2015; 15 (09) 2404-2412
- 20 Hayes M, Curley GF, Masterson C, Devaney J, O'Toole D, Laffey JG. Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury. Intensive Care Med Exp 2015; 3 (01) 29
- 21 Islam MN, Das SR, Emin MT. , et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18 (05) 759-765
- 22 Neef K, Choi YH, Weichel A. , et al. The influence of cardiovascular risk factors on bone marrow mesenchymal stromal cell fitness. Cytotherapy 2012; 14 (06) 670-678
- 23 Ochs M, Mühlfeld C. Quantitative microscopy of the lung: a problem-based approach. Part 1: basic principles of lung stereology. Am J Physiol Lung Cell Mol Physiol 2013; 305 (01) L15-L22
- 24 Herrmann G, Knudsen L, Madershahian N. , et al. Effects of exogenous surfactant on the non-heart-beating donor lung graft in experimental lung transplantation - a stereological study. J Anat 2014; 224 (05) 594-602
- 25 Richard JC, Decailliot F, Janier M, Annat G, Guérin C. Effects of positive end-expiratory pressure and body position on pulmonary blood flow redistribution in mechanically ventilated normal pigs. Chest 2002; 122 (03) 998-1005
- 26 Mure M, Domino KB, Lindahl SG, Hlastala MP, Altemeier WA, Glenny RW. Regional ventilation-perfusion distribution is more uniform in the prone position. J Appl Physiol (1985) 2000; 88 (03) 1076-1083
- 27 den Hengst WA, Gielis JF, Lin JY, Van Schil PE, De Windt LJ, Moens AL. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol Heart Circ Physiol 2010; 299 (05) H1283-H1299
- 28 Velazquez M, Weibel ER, Kuhn III C, Schuster DP. PET evaluation of pulmonary vascular permeability: a structure-function correlation. J Appl Physiol (1985) 1991; 70 (05) 2206-2216
- 29 Eggenhofer E, Benseler V, Kroemer A. , et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 2012; 3: 297
- 30 Devine SM, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003; 101 (08) 2999-3001
- 31 Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A 2009; 106 (38) 16357-16362