title: The caspase-8 shRNA-modified mesenchymal stem cells improve the function of infarcted heart.
abstract: The beneficial effects of mesenchymal stem cells (MSCs) in cardiac cell therapy are greatly limited due to poor survival after transplantation into ischemic hearts. Here, we investigated whether caspase 8 small hairpin RNA (shRNA) modification enhance human MSCs (hMSCs) survival and improve infarcted heart function. Recombinant adenovirus encoding pre-miRNA-155-designed caspase 8 shRNA was prepared to inhibit caspase 8 expression in hMSCs. The effect of caspase 8 shRNA modification on protecting hMSCs from apoptosis under the conditions of serum deprivation and hypoxia was tested by Annexin V/PI staining and caspase 8 activity assay. The caspase 8 shRNA-modified and superparamagnetic iron oxide (SPIO)-labeled hMSCs were injected into the border zone of the infarcted region of rat heart. Echocardiography and Masson trichrome staining were performed to assess heart function and cardiac fibrosis. Our results showed that adenovirus-mediated caspase 8 shRNA could efficiently inhibit caspase 8 expression in hMSCs. Knock-down of caspase 8 expression lead to inhibition of hMSCs apoptosis, reduction of caspase 8 activity and up-regulations of HGF, IGF-1 and Bcl-2. Transplantation of caspase 8 shRNA-modified hMSCs could significantly improve infracted heart function, attenuate cardiac fibrosis. Consistently, the rate of cardiomyocyte apoptosis and caspase 8 activity were significantly decreased, and the survival rate of transplanted hMSCs was markedly elevated in the myocardium receiving caspase 8 shRNA-modified hMSCs transplantation. Together, our findings implicated the therapeutic potential of caspase 8 shRNA-modified hMSCs in improving the infarcted heart function.
authors: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China.
authors: Yeyou
authors: Y
authors: Liang
authors: Qiuxiong
authors: Q
authors: Lin
authors: Jiening
authors: J
authors: Zhu
authors: Xiaohong
authors: X
authors: Li
authors: Yongheng
authors: Y
authors: Fu
authors: Xiao
authors: X
authors: Zou
authors: Xiaoying
authors: X
authors: Liu
authors: Honghong
authors: H
authors: Tan
authors: Chunyu
authors: C
authors: Deng
authors: Xiyong
authors: X
authors: Yu
authors: Zhixin
authors: Z
authors: Shan
authors: Weiwei
authors: W
authors: Yuan
mesh_terms: D000256:Adenoviridae; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053181:Caspase 8 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C505530:CASP8 protein, human; D053181:Caspase 8