title: Nanovector-based prolyl hydroxylase domain 2 silencing system enhances the efficiency of stem cell transplantation for infarcted myocardium repair.
abstract: Mesenchymal stem cell (MSC) transplantation has attracted much attention in myocardial infarction therapy. One of the limitations is the poor survival of grafted cells in the ischemic microenvironment. Small interfering RNA-mediated prolyl hydroxylase domain protein 2 (PHD2) silencing in MSCs holds tremendous potential to enhance their survival and paracrine effect after transplantation. However, an efficient and biocompatible PHD2 silencing system for clinical application is lacking. Herein, we developed a novel PHD2 silencing system based on arginine-terminated generation 4 poly(amidoamine) (Arg-G4) nanoparticles. The system exhibited effective and biocompatible small interfering RNA delivery and PHD2 silencing in MSCs in vitro. After genetically modified MSC transplantation in myocardial infarction models, MSC survival and paracrine function of IGF-1 were enhanced significantly in vivo. As a result, we observed decreased cardiomyocyte apoptosis, scar size, and interstitial fibrosis, and increased angiogenesis in the diseased myocardium, which ultimately attenuated ventricular remodeling and improved heart function. This work demonstrated that an Arg-G4 nanovector-based PHD2 silencing system could enhance the efficiency of MSC transplantation for infarcted myocardium repair.
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Lai
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Changfa
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China ; Shanghai Institute of Cardiovascular Disease, Shanghai, People's Republic of China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D020868:Gene Silencing; D006321:Heart / Q000502:physiology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics
chemical_list: C531249:Poly(amidoamine); D011073:Polyamines; D034741:RNA, Small Interfering; D001120:Arginine; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: PHD2; mesenchymal stem cells; myocardial infarction; nanoparticles; siRNA delivery