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Aging increases the susceptivity of MSCs to reactive oxygen species and impairs their therapeutic potency for myocardial infarction.

Li L, Guo Y, Zhai H, Yin Y, Zhang J, Chen H, Wang L, Li N, Liu R, Xia Y - PLoS ONE (2014)

Bottom Line: By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely.Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed.The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart.

View Article: PubMed Central - PubMed

Affiliation: First Department of Cadres, First Hospital Affiliated to General Hospital of People's Liberation Army, Beijing, China.

ABSTRACT
Myocardial infarction (MI) is one of the leading causes of death worldwide and Mesenchymal Stem Cells (MSCs) transplantation has been considered a promising therapy. Recently, it was reported that the therapeutic effectiveness of MSCs is dependent on the age of the donor, yet the underlying mechanism has not been thoroughly investigated. This study was designed to investigate whether this impaired therapeutic potency is caused by an increased susceptivity of MSCs from old donors to reactive oxygen species (ROS). The MSCs were isolated from the subcutaneous inguinal region of young (8-10 weeks) and old (18 months) Sprague-Dawley (SD) rats. By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely. Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed. Furthemore, H2O2 triggered an increased apoptosis of MSCs from old donors. To study the viability and therapeutic potency of MSCs from young and old donors in vivo, these MSCs were transplanted into acute MI model rats. We observed a more rapidly decreased survival rate of the old MSCs in the infarct region, which may be caused by their increased susceptivity to the micro-environmental ROS, as transplantation of the old MSCs with N-acetyl-L-cysteine (NAC), a ROS scavenger, protected them. The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart. Our study may help to understand the mechanism of MSCs-host interaction during MI, as well as shed light on the design of therapeutic strategy in clinic.

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Assessment of heart function of MI model rats transplanted with young or old MSCs.A. The heart functions of MI model rats were evaluated by echocardiography and hemodynamics examination. LVEF: Left ventricular ejection fraction; LVFS: Left ventricular fractional shortening; LVEDP: Left ventricular end diastolic pressure. B. Capillary density in the infarcted myocardium was measured by Immunohistochemistry. Capillaries were indicated by CD31 stain. Representative images and statistics were shown. Scale bar: 100 µm. * p<0.05 compared with PBS group; ** p<0.01 compared with PBS group; # p<0.05 compared with Old donor group; ## p<0.01 compared with Old donor group.
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pone-0111850-g006: Assessment of heart function of MI model rats transplanted with young or old MSCs.A. The heart functions of MI model rats were evaluated by echocardiography and hemodynamics examination. LVEF: Left ventricular ejection fraction; LVFS: Left ventricular fractional shortening; LVEDP: Left ventricular end diastolic pressure. B. Capillary density in the infarcted myocardium was measured by Immunohistochemistry. Capillaries were indicated by CD31 stain. Representative images and statistics were shown. Scale bar: 100 µm. * p<0.05 compared with PBS group; ** p<0.01 compared with PBS group; # p<0.05 compared with Old donor group; ## p<0.01 compared with Old donor group.

Mentions: Furthermore, we assessed the heart function using echocardiography and hemodynamics examinations. As shown in Figure 6A, parameters including the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end diastolic pressure (LVEDP) and dp/dtmax suggested a significant amelioration after young MSCs' transplantation, while transplantation with old MSCs performed not so well as that with the young ones. In addition, capillary density in the infarcted myocardium was measured by Immunohistochemistry. As shown in Figure 6B, the mean micro-vessel count per field was significantly higher in the young MSCs' transplantation group than the group transplanted with old MSCs. Notably, seen from the results of both the heart histology and the heart function, the transplantation of old MSCs together with NAC had a similar therapeutic efficiency as the transplantation of young MSCs alone. Taken together, these data suggest an impaired potential of aged MSCs in repairing infarcted myocardium, which is caused largely by the ROS in MI micro-environment.


Aging increases the susceptivity of MSCs to reactive oxygen species and impairs their therapeutic potency for myocardial infarction.

Li L, Guo Y, Zhai H, Yin Y, Zhang J, Chen H, Wang L, Li N, Liu R, Xia Y - PLoS ONE (2014)

Assessment of heart function of MI model rats transplanted with young or old MSCs.A. The heart functions of MI model rats were evaluated by echocardiography and hemodynamics examination. LVEF: Left ventricular ejection fraction; LVFS: Left ventricular fractional shortening; LVEDP: Left ventricular end diastolic pressure. B. Capillary density in the infarcted myocardium was measured by Immunohistochemistry. Capillaries were indicated by CD31 stain. Representative images and statistics were shown. Scale bar: 100 µm. * p<0.05 compared with PBS group; ** p<0.01 compared with PBS group; # p<0.05 compared with Old donor group; ## p<0.01 compared with Old donor group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230939&req=5

pone-0111850-g006: Assessment of heart function of MI model rats transplanted with young or old MSCs.A. The heart functions of MI model rats were evaluated by echocardiography and hemodynamics examination. LVEF: Left ventricular ejection fraction; LVFS: Left ventricular fractional shortening; LVEDP: Left ventricular end diastolic pressure. B. Capillary density in the infarcted myocardium was measured by Immunohistochemistry. Capillaries were indicated by CD31 stain. Representative images and statistics were shown. Scale bar: 100 µm. * p<0.05 compared with PBS group; ** p<0.01 compared with PBS group; # p<0.05 compared with Old donor group; ## p<0.01 compared with Old donor group.
Mentions: Furthermore, we assessed the heart function using echocardiography and hemodynamics examinations. As shown in Figure 6A, parameters including the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end diastolic pressure (LVEDP) and dp/dtmax suggested a significant amelioration after young MSCs' transplantation, while transplantation with old MSCs performed not so well as that with the young ones. In addition, capillary density in the infarcted myocardium was measured by Immunohistochemistry. As shown in Figure 6B, the mean micro-vessel count per field was significantly higher in the young MSCs' transplantation group than the group transplanted with old MSCs. Notably, seen from the results of both the heart histology and the heart function, the transplantation of old MSCs together with NAC had a similar therapeutic efficiency as the transplantation of young MSCs alone. Taken together, these data suggest an impaired potential of aged MSCs in repairing infarcted myocardium, which is caused largely by the ROS in MI micro-environment.

Bottom Line: By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely.Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed.The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart.

View Article: PubMed Central - PubMed

Affiliation: First Department of Cadres, First Hospital Affiliated to General Hospital of People's Liberation Army, Beijing, China.

ABSTRACT
Myocardial infarction (MI) is one of the leading causes of death worldwide and Mesenchymal Stem Cells (MSCs) transplantation has been considered a promising therapy. Recently, it was reported that the therapeutic effectiveness of MSCs is dependent on the age of the donor, yet the underlying mechanism has not been thoroughly investigated. This study was designed to investigate whether this impaired therapeutic potency is caused by an increased susceptivity of MSCs from old donors to reactive oxygen species (ROS). The MSCs were isolated from the subcutaneous inguinal region of young (8-10 weeks) and old (18 months) Sprague-Dawley (SD) rats. By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely. Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed. Furthemore, H2O2 triggered an increased apoptosis of MSCs from old donors. To study the viability and therapeutic potency of MSCs from young and old donors in vivo, these MSCs were transplanted into acute MI model rats. We observed a more rapidly decreased survival rate of the old MSCs in the infarct region, which may be caused by their increased susceptivity to the micro-environmental ROS, as transplantation of the old MSCs with N-acetyl-L-cysteine (NAC), a ROS scavenger, protected them. The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart. Our study may help to understand the mechanism of MSCs-host interaction during MI, as well as shed light on the design of therapeutic strategy in clinic.

Show MeSH
Related in: MedlinePlus