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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.

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Schematic illustrating mesenchymal stem cells can regulate the cellular profile in the myocardial infarction area via paracrine factor pigment epithelium-derived factor. Older mesenchymal stem cells express and secrete more pigment epithelium-derived factor in infarct region than young mesenchymal stem cells, leading to fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts in the infarct region after older mesenchymal stem cell administration. (Biological effects of pigment epithelium-derived factor upon endothelial cells, vascular smooth muscle cells, macrophages, and fibroblasts mentioned in schematic are based on present study results and previous literatures).
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EHR131F6: Schematic illustrating mesenchymal stem cells can regulate the cellular profile in the myocardial infarction area via paracrine factor pigment epithelium-derived factor. Older mesenchymal stem cells express and secrete more pigment epithelium-derived factor in infarct region than young mesenchymal stem cells, leading to fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts in the infarct region after older mesenchymal stem cell administration. (Biological effects of pigment epithelium-derived factor upon endothelial cells, vascular smooth muscle cells, macrophages, and fibroblasts mentioned in schematic are based on present study results and previous literatures).

Mentions: Overall, the current study confirmed that MSCs can regulate MI pathological processes through paracrine actions. Thus, MSCs could be considered an “organizer” in the MI area, manipulating tissue cellular profile by secreting various growth factors and cytokines. We demonstrated that PEDF was one of the most important factors involved in MSC paracrine function. Pigment epithelium-derived factor secreted by MSCs can act upon several cell types in the infarct region (Figure 6). However, our experiments were not designed to address all discrepancies in the paracrine profile between young and older MSCs. Further experiments defining the exact alteration of the aged MSCs paracrine profile are clearly necessary. One method for increasing injury repair efficiency, and minimizing undesirable outcomes, would be directly manipulating the cell types controlling the pathological processes at work.32 Therefore, our results imply that the most efficacious aged-donor MSC utilization must focus upon optimizing paracrine profile to favorably manipulate the cellular profile in the infarct region. For such means, our study supports PEDF as a promising novel genetic modification target for augmenting aged MSC therapeutic efficacy.Figure 6


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)

Schematic illustrating mesenchymal stem cells can regulate the cellular profile in the myocardial infarction area via paracrine factor pigment epithelium-derived factor. Older mesenchymal stem cells express and secrete more pigment epithelium-derived factor in infarct region than young mesenchymal stem cells, leading to fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts in the infarct region after older mesenchymal stem cell administration. (Biological effects of pigment epithelium-derived factor upon endothelial cells, vascular smooth muscle cells, macrophages, and fibroblasts mentioned in schematic are based on present study results and previous literatures).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

EHR131F6: Schematic illustrating mesenchymal stem cells can regulate the cellular profile in the myocardial infarction area via paracrine factor pigment epithelium-derived factor. Older mesenchymal stem cells express and secrete more pigment epithelium-derived factor in infarct region than young mesenchymal stem cells, leading to fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts in the infarct region after older mesenchymal stem cell administration. (Biological effects of pigment epithelium-derived factor upon endothelial cells, vascular smooth muscle cells, macrophages, and fibroblasts mentioned in schematic are based on present study results and previous literatures).
Mentions: Overall, the current study confirmed that MSCs can regulate MI pathological processes through paracrine actions. Thus, MSCs could be considered an “organizer” in the MI area, manipulating tissue cellular profile by secreting various growth factors and cytokines. We demonstrated that PEDF was one of the most important factors involved in MSC paracrine function. Pigment epithelium-derived factor secreted by MSCs can act upon several cell types in the infarct region (Figure 6). However, our experiments were not designed to address all discrepancies in the paracrine profile between young and older MSCs. Further experiments defining the exact alteration of the aged MSCs paracrine profile are clearly necessary. One method for increasing injury repair efficiency, and minimizing undesirable outcomes, would be directly manipulating the cell types controlling the pathological processes at work.32 Therefore, our results imply that the most efficacious aged-donor MSC utilization must focus upon optimizing paracrine profile to favorably manipulate the cellular profile in the infarct region. For such means, our study supports PEDF as a promising novel genetic modification target for augmenting aged MSC therapeutic efficacy.Figure 6

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