Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.
Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.
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衰老间充质干细胞中色素上皮衍生因子表达增加会损害其减轻心肌梗死损伤的治疗功效
DOI：
10.1093/eurheartj/ehr131
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发表时间：
2013-06
影响因子：
39.3
通讯作者：
Yi D
中科院分区：
文献类型：
--
作者：
Liang H;Hou H;Yi W;Yang G;Gu C;Lau WB;Gao E;Ma X;Lu Z;Wei X;Pei J;Yi D
目的骨髓间充质干细胞（mesenchymal stem cells，MSCs）可改善心肌梗死（myocardial infarction，MI）损伤。然而，老年供体间充质干细胞似乎不如年轻供体的有效，其潜在机制仍不清楚。在这里，我们确定了年龄相关的色素上皮衍生因子（PEDF）的表达如何影响MSC对MI的治疗效果。方法和结果逆转录聚合酶链反应和酶联免疫吸附测定分析显示，显着增加PEDF表达的MSC从老年小鼠相比，年轻的小鼠。形态和功能实验表明，与年轻MSC相比，老年MSC在治疗MI小鼠中的治疗效果显著受损。免疫荧光染色表明，与年轻的MSC相比，老年MSC的管理导致梗死区域含有较少的内皮细胞，血管平滑肌细胞和巨噬细胞，但更多的成纤维细胞。色素上皮衍生因子在年轻的骨髓间充质干细胞过度表达损害了对心肌梗死损伤的有益作用，并诱导梗死区域的细胞分布变化，与老年骨髓间充质干细胞给药相似。敲低老年MSC中的PEDF表达改善了MSC治疗功效，并诱导了与年轻MSC施用相似的细胞特征。体外研究表明，骨髓间充质干细胞分泌的PEDF可调节心脏成纤维细胞的增殖和迁移。结论首次证明旁分泌因子PEDF在MSCs抗心肌梗死损伤的调节中起重要作用。此外，老化MSC的治疗能力受损主要是由PEDF分泌增加引起的。这些发现表明PEDF是一种有前途的新型遗传修饰靶点，可用于改善老年MSC的治疗效果。
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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影响因子：
24
作者：
Hare, Joshua M.;Traverse, Jay H.;Henry, Timothy D.;Dib, Nabil;Strumpf, Robert K.;Schulman, Steven P.;Gerstenblith, Gary;DeMaria, Anthony N.;Denktas, Ali E.;Gammon, Roger S.;Hermiller, James B., Jr.;Reisman, Mark A.;Schaer, Gary L.;Sherman, Warren
通讯作者：
Sherman, Warren
影响因子：
20.1
作者：
Hatzistergos KE;Quevedo H;Oskouei BN;Hu Q;Feigenbaum GS;Margitich IS;Mazhari R;Boyle AJ;Zambrano JP;Rodriguez JE;Dulce R;Pattany PM;Valdes D;Revilla C;Heldman AW;McNiece I;Hare JM
通讯作者：
Hare JM
影响因子：
--
作者：
Chiellini, Chiara;Cochet, Olivia;Amri, Ez-Zoubir
通讯作者：
Amri, Ez-Zoubir
影响因子：
3.6
作者：
Pina, Ana Luisa;Kubitza, Marion;Kloth, Sabine
通讯作者：
Kloth, Sabine
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ