Limits...
Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.

Liang H, Hou H, Yi W, Yang G, Gu C, Lau WB, Gao E, Ma X, Lu Z, Wei X, Pei J, Yi D - Eur. Heart J. (2011)

Bottom Line: Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration.Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion.These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Institute of Cardiovascular Disease of Chinese PLA, Xijing Hospital, the Fourth Military Medical University, No.127, West Changle Road, Xi'an, Shaanxi Province 710032, China.

ABSTRACT

Aims: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI.

Methods and results: Reverse transcriptase-polymerized chain reaction  and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts.

Conclusions: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

Show MeSH

Related in: MedlinePlus

Measurement of left ventricular fibrosis and function. (A) Representative Masson trichrome-stained myocardial sections and bar graph showing fibrotic region measurement (n= 5 mice/group). (B–E) Bar graphs illustrating left ventriculum function parameters (n= 5 mice/group). Data expressed as means ± SEM. *P< 0.05, **P< 0.01, ***P≤ 0.001. Pre-ejection period: left ventricular ejection time ratio, the ratio of the pre-ejection period/left ventricular ejection time. Pmax, maximum pressure. Ped, end-diastolic pressure.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3675387&req=5

EHR131F3: Measurement of left ventricular fibrosis and function. (A) Representative Masson trichrome-stained myocardial sections and bar graph showing fibrotic region measurement (n= 5 mice/group). (B–E) Bar graphs illustrating left ventriculum function parameters (n= 5 mice/group). Data expressed as means ± SEM. *P< 0.05, **P< 0.01, ***P≤ 0.001. Pre-ejection period: left ventricular ejection time ratio, the ratio of the pre-ejection period/left ventricular ejection time. Pmax, maximum pressure. Ped, end-diastolic pressure.

Mentions: In order to study whether different PEDF levels could affect the efficacy of MSCs for MI, we performed gross cardiac morphology and function analyses. As illustrated in Figure 3A, compared to saline treatment, both young and old MSCs significantly attenuated fibrosis post-MI, but to greater extent after young MSC treatment. Compared to saline treatment, administration of young MSCs after MI markedly improved LV functional parameters. Compared to young MSC treatment, administration of old MSCs after MI increased the ratio of the pre-ejection period/left ventricular ejection time (Figure 3B) and LV end-diastolic pressure (Figure 3D), and decreased maximum LV pressure (Figure 3C), as well as the + dp/dt and –dp/dt (Figure 3E and F), all data suggestive of decreased therapeutic ability of old MSCs compared to young MSCs. Importantly, compared with Y&Ad.Null cells, Y&Ad.PEDF not only significantly increased LV fibrosis (Figure 3A), but also impaired LV function (Figure 3B–F). In contrast, O&Ad.shPEDF decreased the LV fibrosis area (Figure 3A), and ameliorated LV function compared with old MSCs transduced with Ad.shctrl (Figure 3B–F), supporting the notion that impaired therapeutic efficacy of old MSCs is associated with increased PEDF secretion.Figure 3


Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.

Liang H, Hou H, Yi W, Yang G, Gu C, Lau WB, Gao E, Ma X, Lu Z, Wei X, Pei J, Yi D - Eur. Heart J. (2011)

Measurement of left ventricular fibrosis and function. (A) Representative Masson trichrome-stained myocardial sections and bar graph showing fibrotic region measurement (n= 5 mice/group). (B–E) Bar graphs illustrating left ventriculum function parameters (n= 5 mice/group). Data expressed as means ± SEM. *P< 0.05, **P< 0.01, ***P≤ 0.001. Pre-ejection period: left ventricular ejection time ratio, the ratio of the pre-ejection period/left ventricular ejection time. Pmax, maximum pressure. Ped, end-diastolic pressure.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675387&req=5

EHR131F3: Measurement of left ventricular fibrosis and function. (A) Representative Masson trichrome-stained myocardial sections and bar graph showing fibrotic region measurement (n= 5 mice/group). (B–E) Bar graphs illustrating left ventriculum function parameters (n= 5 mice/group). Data expressed as means ± SEM. *P< 0.05, **P< 0.01, ***P≤ 0.001. Pre-ejection period: left ventricular ejection time ratio, the ratio of the pre-ejection period/left ventricular ejection time. Pmax, maximum pressure. Ped, end-diastolic pressure.
Mentions: In order to study whether different PEDF levels could affect the efficacy of MSCs for MI, we performed gross cardiac morphology and function analyses. As illustrated in Figure 3A, compared to saline treatment, both young and old MSCs significantly attenuated fibrosis post-MI, but to greater extent after young MSC treatment. Compared to saline treatment, administration of young MSCs after MI markedly improved LV functional parameters. Compared to young MSC treatment, administration of old MSCs after MI increased the ratio of the pre-ejection period/left ventricular ejection time (Figure 3B) and LV end-diastolic pressure (Figure 3D), and decreased maximum LV pressure (Figure 3C), as well as the + dp/dt and –dp/dt (Figure 3E and F), all data suggestive of decreased therapeutic ability of old MSCs compared to young MSCs. Importantly, compared with Y&Ad.Null cells, Y&Ad.PEDF not only significantly increased LV fibrosis (Figure 3A), but also impaired LV function (Figure 3B–F). In contrast, O&Ad.shPEDF decreased the LV fibrosis area (Figure 3A), and ameliorated LV function compared with old MSCs transduced with Ad.shctrl (Figure 3B–F), supporting the notion that impaired therapeutic efficacy of old MSCs is associated with increased PEDF secretion.Figure 3

Bottom Line: Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration.Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion.These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Institute of Cardiovascular Disease of Chinese PLA, Xijing Hospital, the Fourth Military Medical University, No.127, West Changle Road, Xi'an, Shaanxi Province 710032, China.

ABSTRACT

Aims: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI.

Methods and results: Reverse transcriptase-polymerized chain reaction  and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts.

Conclusions: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

Show MeSH
Related in: MedlinePlus