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

Kim YS, Kim JY, Huh JW, Lee SW, Choi SJ, Oh YM - Tuberc Respir Dis (Seoul) (2015)

Bottom Line: However, the optimal dose of mesenchymal stem cells (MSCs) for the most effective therapy has not yet been determined.But activity of matrix metalloproteinase 9 increased by emphysematous lung was decreased by intravenously injected MSCs.This is the first study on the optimal dose of MSCs as a therapeutic candidate.

View Article: PubMed Central - PubMed

Affiliation: Asan Institute for Life Sciences, Seoul, Korea. ; University of Ulsan College of Medicine, Seoul, Korea.

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 5×10(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.

No MeSH data available.


Related in: MedlinePlus

Optimal dose of mesenchymal stem cells (MSCs) to repair elastase induced emphysema in mice. C57BL/6J mice were administered 0.4 U of elastase on day 0 by intratracheal application and then intravenously injected with MSCs on day 7. Data are measures of the histological staining with hematoxylin and eosin in lung section on day 14. (A) Control (n=5), Ela (elastase only, n=15), Ela+1×104 (elastase+1×104 MSC, n=10), Ela+2.5×104 (elastase+2.5×104 MSC, n=10), Ela+5×104 (elastase+5×104 MSC, n=16), and Ela+1×105 (elastase+1×105 MSC, n=6) (×10). Scale bars=1.0 mm. (B) Morphometic analysis of the mean linear intercept. Values are presented as the mean±SEM.
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Figure 1: Optimal dose of mesenchymal stem cells (MSCs) to repair elastase induced emphysema in mice. C57BL/6J mice were administered 0.4 U of elastase on day 0 by intratracheal application and then intravenously injected with MSCs on day 7. Data are measures of the histological staining with hematoxylin and eosin in lung section on day 14. (A) Control (n=5), Ela (elastase only, n=15), Ela+1×104 (elastase+1×104 MSC, n=10), Ela+2.5×104 (elastase+2.5×104 MSC, n=10), Ela+5×104 (elastase+5×104 MSC, n=16), and Ela+1×105 (elastase+1×105 MSC, n=6) (×10). Scale bars=1.0 mm. (B) Morphometic analysis of the mean linear intercept. Values are presented as the mean±SEM.

Mentions: To identify the optimal dose of MSCs for treatment of emphysema, C57BL/6J mice were treated intratracheally with 0.4 U of elastase on day 0 and were intravenously injected with 1×104, 2.5×104, 5×104, or 1×105 of MSCs on day 7. Lung tissue was then collected on day 14. The mice treated with elastase only showed severe alveolar destruction compared to the control group, while the mice treated with MSCs showed less alveolar destruction (Figure 1A). The level of alveolar destruction was quantified by measuring MLI. The mice treated with the 5×104 MSCs showed significantly lower MLI (78.15 µm) than the mice treated with elastase only (92.28 µm) (Figure 1B). The mice treated with the 1×104 MSCs, 2.5×104, or 1×105 of MSCs also showed a pattern of decreased MLI (81.82 µm, 88.75 µm, or 83.47 µm, respectively) compared to the mice treated with elastase only, but the difference was not significant (Figure 1B).


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

Kim YS, Kim JY, Huh JW, Lee SW, Choi SJ, Oh YM - Tuberc Respir Dis (Seoul) (2015)

Optimal dose of mesenchymal stem cells (MSCs) to repair elastase induced emphysema in mice. C57BL/6J mice were administered 0.4 U of elastase on day 0 by intratracheal application and then intravenously injected with MSCs on day 7. Data are measures of the histological staining with hematoxylin and eosin in lung section on day 14. (A) Control (n=5), Ela (elastase only, n=15), Ela+1×104 (elastase+1×104 MSC, n=10), Ela+2.5×104 (elastase+2.5×104 MSC, n=10), Ela+5×104 (elastase+5×104 MSC, n=16), and Ela+1×105 (elastase+1×105 MSC, n=6) (×10). Scale bars=1.0 mm. (B) Morphometic analysis of the mean linear intercept. Values are presented as the mean±SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499592&req=5

Figure 1: Optimal dose of mesenchymal stem cells (MSCs) to repair elastase induced emphysema in mice. C57BL/6J mice were administered 0.4 U of elastase on day 0 by intratracheal application and then intravenously injected with MSCs on day 7. Data are measures of the histological staining with hematoxylin and eosin in lung section on day 14. (A) Control (n=5), Ela (elastase only, n=15), Ela+1×104 (elastase+1×104 MSC, n=10), Ela+2.5×104 (elastase+2.5×104 MSC, n=10), Ela+5×104 (elastase+5×104 MSC, n=16), and Ela+1×105 (elastase+1×105 MSC, n=6) (×10). Scale bars=1.0 mm. (B) Morphometic analysis of the mean linear intercept. Values are presented as the mean±SEM.
Mentions: To identify the optimal dose of MSCs for treatment of emphysema, C57BL/6J mice were treated intratracheally with 0.4 U of elastase on day 0 and were intravenously injected with 1×104, 2.5×104, 5×104, or 1×105 of MSCs on day 7. Lung tissue was then collected on day 14. The mice treated with elastase only showed severe alveolar destruction compared to the control group, while the mice treated with MSCs showed less alveolar destruction (Figure 1A). The level of alveolar destruction was quantified by measuring MLI. The mice treated with the 5×104 MSCs showed significantly lower MLI (78.15 µm) than the mice treated with elastase only (92.28 µm) (Figure 1B). The mice treated with the 1×104 MSCs, 2.5×104, or 1×105 of MSCs also showed a pattern of decreased MLI (81.82 µm, 88.75 µm, or 83.47 µm, respectively) compared to the mice treated with elastase only, but the difference was not significant (Figure 1B).

Bottom Line: However, the optimal dose of mesenchymal stem cells (MSCs) for the most effective therapy has not yet been determined.But activity of matrix metalloproteinase 9 increased by emphysematous lung was decreased by intravenously injected MSCs.This is the first study on the optimal dose of MSCs as a therapeutic candidate.

View Article: PubMed Central - PubMed

Affiliation: Asan Institute for Life Sciences, Seoul, Korea. ; University of Ulsan College of Medicine, Seoul, Korea.

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 5×10(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.

No MeSH data available.


Related in: MedlinePlus