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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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Viability of engrafted MSCs from young and old donors at day 7 after transplantation.MSCs were pre-stained with DiI before transplantation. At Day 7 after transplantation, MSCs number in MI region of each group was counted under fluorescence microscopy. Representative images and statistics were shown. N = 5 per group. Scale bar: 100 µm. ** p<0.01 all compared with old donor group.
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pone-0111850-g004: Viability of engrafted MSCs from young and old donors at day 7 after transplantation.MSCs were pre-stained with DiI before transplantation. At Day 7 after transplantation, MSCs number in MI region of each group was counted under fluorescence microscopy. Representative images and statistics were shown. N = 5 per group. Scale bar: 100 µm. ** p<0.01 all compared with old donor group.

Mentions: To investigate whether aging affects the implantation and viability of MSCs in vivo, an acute myocardial infarction rat model was implicated. It has been reported that the concentration of ROS may be increased over three-fold in the MI region [14]. Consistently, we found a significantly elevated ROS level in cardiac tissue of the MI model rats by measurement of malondialdehyde (MDA) as previously reported [25] (data not shown). DiI-stained MSCs from young and old donors were transplanted in the border of the infarct region of the MI model rats. At day 0 and day 7 after transplantation, the hearts were sectioned and the fate of the engrafted MSCs was investigated using confocal microscopy. At day 0, right after transplantation, a similar number of young and old MSCs were observed (data not shown). However, as shown in Figure 4, one week after transplantation, fewer old MSCs remained, whose number is only about half of that of the young MSCs. In order to study whether this lowered viability of MSCs from old donors was caused by the increased susceptibility to environmental ROS, we also included a positive control group, where a same number of old MSCs were transplanted in combination with the ROS scavenger NAC. Interestingly, the number of NAC treated old MSCs remained was significantly larger than that of old MSCs injected alone, whereas no significant difference was found between the number of remained young MSCs and the NAC treated old MSCs. Together, these data indicate that old MSCs engrafted are less resistance to the ROS in myocardial infarction micro-environment than the young ones.


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)

Viability of engrafted MSCs from young and old donors at day 7 after transplantation.MSCs were pre-stained with DiI before transplantation. At Day 7 after transplantation, MSCs number in MI region of each group was counted under fluorescence microscopy. Representative images and statistics were shown. N = 5 per group. Scale bar: 100 µm. ** p<0.01 all compared with old donor group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111850-g004: Viability of engrafted MSCs from young and old donors at day 7 after transplantation.MSCs were pre-stained with DiI before transplantation. At Day 7 after transplantation, MSCs number in MI region of each group was counted under fluorescence microscopy. Representative images and statistics were shown. N = 5 per group. Scale bar: 100 µm. ** p<0.01 all compared with old donor group.
Mentions: To investigate whether aging affects the implantation and viability of MSCs in vivo, an acute myocardial infarction rat model was implicated. It has been reported that the concentration of ROS may be increased over three-fold in the MI region [14]. Consistently, we found a significantly elevated ROS level in cardiac tissue of the MI model rats by measurement of malondialdehyde (MDA) as previously reported [25] (data not shown). DiI-stained MSCs from young and old donors were transplanted in the border of the infarct region of the MI model rats. At day 0 and day 7 after transplantation, the hearts were sectioned and the fate of the engrafted MSCs was investigated using confocal microscopy. At day 0, right after transplantation, a similar number of young and old MSCs were observed (data not shown). However, as shown in Figure 4, one week after transplantation, fewer old MSCs remained, whose number is only about half of that of the young MSCs. In order to study whether this lowered viability of MSCs from old donors was caused by the increased susceptibility to environmental ROS, we also included a positive control group, where a same number of old MSCs were transplanted in combination with the ROS scavenger NAC. Interestingly, the number of NAC treated old MSCs remained was significantly larger than that of old MSCs injected alone, whereas no significant difference was found between the number of remained young MSCs and the NAC treated old MSCs. Together, these data indicate that old MSCs engrafted are less resistance to the ROS in myocardial infarction micro-environment than the young ones.

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