Browse > Article
http://dx.doi.org/10.4046/trd.2015.78.3.239

The Therapeutic Effects of Optimal Dose of Mesenchymal Stem Cells in a Murine Model of an Elastase Induced-Emphysema  

Kim, You-Sun (Asan Institute for Life Sciences)
Kim, Ji-Young (Asan Institute for Life Sciences)
Huh, Jin Won (Departure of Pulmonary and Critical Care Medicine, Asan Medical Center)
Lee, Sei Won (Departure of Pulmonary and Critical Care Medicine, Asan Medical Center)
Choi, Soo Jin (Biomedical Research Institute, MEDIPOST Co. Ltd.)
Oh, Yeon-Mok (Asan Institute for Life Sciences)
Publication Information
Tuberculosis and Respiratory Diseases / v.78, no.3, 2015 , pp. 239-245 More about this Journal
Abstract
Background: Chronic obstructive pulmonary disease is characterized by emphysema, chronic bronchitis, and small airway remodeling. The alveolar destruction associated with emphysema cannot be repaired by current clinical practices. Stem cell therapy has been successfully used in animal models of cigarette smoke- and elastase-induced emphysema. However, the optimal dose of mesenchymal stem cells (MSCs) for the most effective therapy has not yet been determined. It is vital to determine the optimal dose of MSCs for clinical application in emphysema cases. Methods: In the present study, we evaluated the therapeutic effects of various doses of MSCs on elastase-induced emphysema in mice. When 3 different doses of MSCs were intravenously injected into mice treated with elastase, only $5{\times}10^4$ MSCs showed a significant effect on the emphysematous mouse lung. We also identified action mechanisms of MSCs based on apoptosis, lung regeneration, and protease/antiprotease imbalance. Results: The MSCs were not related with caspase-3/7 dependent apoptosis. But activity of matrix metalloproteinase 9 increased by emphysematous lung was decreased by intravenously injected MSCs. Vascular endothelial growth factor were also increased in lung from MSC injected mice, as compared to un-injected mice. Conclusion: This is the first study on the optimal dose of MSCs as a therapeutic candidate. This data may provide important basic data for determining dosage in clinical application of MSCs in emphysema patients.
Keywords
Emphysema; Mesenchymal Stromal Cells; Therapy;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Senior RM, Anthonisen NR. Chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 1998;157(4 Pt 2):S139-47.   DOI
2 Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004;350:2689-97.   DOI
3 Churg A, Cosio M, Wright JL. Mechanisms of cigarette smokeinduced COPD: insights from animal models. Am J Physiol Lung Cell Mol Physiol 2008;294:L612-31.   DOI
4 Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117:684-94.   DOI
5 Yokohori N, Aoshiba K, Nagai A; Respiratory Failure Research Group in Japan. Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. Chest 2004;125:626-32.   DOI
6 Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89.   DOI
7 Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, et al. Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol 2011;301:L255-66.   DOI
8 Longhini-Dos-Santos N, Barbosa-de-Oliveira VA, Kozma RH, Faria CA, Stessuk T, Frei F, et al. Cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema. Stem Cell Rev 2013;9:210-8.   DOI
9 Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, et al. Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med 2011;183:215-25.   DOI
10 Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006;24:1294-301.   DOI
11 Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM. Adult bone marrow is a rich source of human mesenchymal ‘stem' cells but umbilical cord and mobilized adult blood are not. Br J Haematol 2003;121:368-74.   DOI
12 Saether EE, Chamberlain CS, Leiferman EM, Kondratko-Mittnacht JR, Li WJ, Brickson SL, et al. Enhanced medial collateral ligament healing using mesenchymal stem cells: dosage effects on cellular response and cytokine profile. Stem Cell Rev 2014;10:86-96.   DOI
13 Richardson JD, Bertaso AG, Psaltis PJ, Frost L, Carbone A, Paton S, et al. Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction. J Card Fail 2013;19:342-53.   DOI
14 Cataldo D, Munaut C, Noel A, Frankenne F, Bartsch P, Foidart JM, et al. MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 2000;123:259-67.   DOI
15 Katsha AM, Ohkouchi S, Xin H, Kanehira M, Sun R, Nukiwa T, et al. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther 2011;19:196-203.   DOI
16 Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277-86.   DOI
17 Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro : effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996;166:585-92.   DOI
18 Hegab AE, Kubo H, Yamaya M, Asada M, He M, Fujino N, et al. Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Ther 2008;16:1417-26.   DOI
19 Muyal JP, Muyal V, Kotnala S, Kumar D, Bhardwaj H. Therapeutic potential of growth factors in pulmonary emphysematous condition. Lung 2013;191:147-63.   DOI
20 Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311-9.   DOI
21 Guan XJ, Song L, Han FF, Cui ZL, Chen X, Guo XJ, et al. Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 2013;114:323-35.   DOI
22 Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest 2013;143:1590-8.   DOI
23 Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002;30:215-22.   DOI
24 Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999;5:309-13.   DOI
25 Chang YS, Ahn SY, Yoo HS, Sung SI, Choi SJ, Oh WI, et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr 2014;164:966-72.e6.   DOI
26 Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545-55.   DOI
27 Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 2013;45:e54.   DOI
28 Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 2010;69:1423-9.   DOI