title: MSC-based VEGF gene therapy in rat myocardial infarction model using facial amphipathic bile acid-conjugated polyethyleneimine.
abstract: Mesenchymal stem cells (MSCs) have attracted much attention in regenerative medicine owing to their apparent usefulness as multi-potent replacement cells. The potential of MSC therapy can be further improved by transforming MSCs with therapeutic genes that maximize the efficacy of gene therapy and their own therapeutic ability. Since most conventional transfection methodologies have shown marginal success in delivering exogenous genes into primary cultured cells, efficient gene transfer into primary MSCs is a prerequisite for the development of MSC-based gene therapy strategies to achieve repair and regeneration of damaged tissues. Herein, facially amphipathic bile acid-modified polyethyleneimine (BA-PEI) conjugates were synthesized and used to transfer hypoxia-inducible vascular endothelial growth factor gene (pHI-VEGF) in MSCs for the treatment of rat myocardial infarction. Under the optimized transfection conditions, the BA-PEI conjugates significantly increased the VEGF protein expression levels in rat MSCs, compared with traditional transfection methods such as Lipofectamine™ and branched-PEI (25 kDa). Furthermore, the prepared pHI-VEGF-engineered MSCs (VEGF-MSCs) resulted in improved cell viability, particularly during severe hypoxic exposure in vitro. The transplantation of MSCs genetically modified to overexpress VEGF by BA-PEI enhanced the capillary formation in the infarction region and eventually attenuated left ventricular remodeling after myocardial infarction in rats. This study demonstrates the applicability of the BA-PEI conjugates for the efficient transfection of therapeutic genes into MSCs and the feasibility of using the genetically engineered MSCs in regenerative medicine for myocardial infarction.
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Moon
authors.affiliation: Center for Theragnosis, Biomedical Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Joo
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangji-gu, Seoul 143-701, South Korea.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Mok
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, South Korea.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea. Electronic address: cdhlyj@yuhs.ac.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Choi
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea; Center for Theragnosis, Biomedical Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea. Electronic address: sunkim@kist.re.kr.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D004195:Disease Models, Animal; D015316:Genetic Therapy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000628:therapy*; D011094:Polyethyleneimine / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D042461:Vascular Endothelial Growth Factor A; D011094:Polyethyleneimine
keywords: Cell-based gene therapy; Facial amphipathic bile acid; Mesenchymal stem cells; Myocardial infarction; Vascular endothelial growth factor