賀西安第四軍醫大學西京醫院應用PriCells產品/技術服務發表文章
 

Cellular repressor of E1A-stimulated gene overexpression in bone mesenchymal stem cells protects against rat myocardial infarction

 

 

Chengfei Peng^{a, b, 1}, Haifeng Peic, ¹, Feipeng Weid, ¹, Xiaoxiang Tian^b, Jie Deng^b, Chenghui Yan^b, Yang Li^b, Mingyu Sun^b, Jian Zhang^b, Dan Liu^f, Jingjing Rongf, Jie Wang^e, Erhe Gao^g, Shaohua Li^h, Yaling Han^b

 

^a Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China

^b Cardiovascular Research Institute, Department of Cardiology, General Hospital of Shenyang Military Region, Shenyang 110016, China

^c Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, China

^d Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China

^e Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China

^f  Department of Cardiology, Graduate School, Third Military Medical University, Chongqing 400038, China

^g Center for Translational Medicine, Temple University School of Medicine, Philadelphia 19104, USA

^h Department of Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick 08904, USA

 

Background

Bone mesenchymal stem cell (BMSC) therapy has modest success in ischemic heart disease but has been limited by poor survival in diseased microenvironments. Cellular repressor of E1A-stimulated genes (CREG) can prevent BMSCs from apoptosis in vitro; however, the effects of CREG-modified BMSCs on ischemic heart disease and the related mechanism remain undefined. Therefore, we designed to study the cardioprotective effects of CREG overexpression in BMSCs (^CREGBMSCs) after transplantation into infarcted heart of rats.

 

Methods

In vivo studies, 50 μl PBS or 1.5 × 10^6NormBMSCs, ^GFPBMSCs or ^CREGBMSCs were implanted intramyocardially in myocardial infarction rat models. 3 or 14 days later, cardiac function, fibrosis, apoptosis and angiogenesis were analyzed by echocardiography, masson, western blot and immunofluorescence staining, respectively. ELISA, western blot and matrigel assay were used in vitro to detect vascular endothelial growth factor (VEGF) secretion, signaling molecule expression, and angiogenic tube formation.

 

Results

In vivo, prolonged cardiac function (14d LVEF: 50.87 ± 0.94%; LVFS: 23.41 ± 1.12%), decreased fibrosis (14d Fibrotic area: 27.37 ± 1.03%) and apoptosis and increased angiogenesis were observed in CREGBMSCs, compared with other groups. In vivo and in vitro, VEGF secretion from ^CREGBMSCs was markedly enhanced. In vitro, angiogenic tube formation in ^CREGBMSC supernatants significantly increased. Moreover, CREG activated hypoxia-inducible factor-1α (HIF-1α), but not HIF-1β. Knockdown of HIF-1α with siRNA decreased VEGF secretion and angiogenic tube formation. Notably, CREG did not influence HIF-1α mRNA synthesis but inhibited the expression of Von Hippel–Lindau (VHL), a key protein that regulates HIF-1α degradation.

 

Conclusions

The ^CREGBMSC transplantation, directly or indirectly, may promote VEGF's anti-apoptosis and angiogenesis via the inhibition of VHL-mediated HIF-1α degradation, consequently protecting against myocardial infarction.

 

Keywords

 

HUM-CELL-0020；PriCells