title: Targeted Genome Engineering to Control VEGF Expression in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells: Potential Implications for the Treatment of Myocardial Infarction.
abstract: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) exhibit potency for the regeneration of infarcted hearts. Vascular endothelial growth factor (VEGF) is capable of inducing angiogenesis and can boost stem cell-based therapeutic effects. However, high levels of VEGF can cause abnormal blood vessel growth and hemangiomas. Thus, a controllable system to induce therapeutic levels of VEGF is required for cell therapy. We generated an inducible VEGF-secreting stem cell (VEGF/hUCB-MSC) that controls the expression of VEGF and tested the therapeutic efficacy in rat myocardial infarction (MI) model to apply functional stem cells to MI. To introduce the inducible VEGF gene cassette into a safe harbor site of the hUCB-MSC chromosome, the transcription activator-like effector nucleases system was used. After confirming the integration of the cassette into the locus, VEGF secretion in physiological concentration from VEGF/hUCB-MSCs after doxycycline (Dox) induction was proved in conditioned media. VEGF secretion was detected in mice implanted with VEGF/hUCB-MSCs grown via a cell sheet system. Vessel formation was induced in mice transplanted with Matrigel containing VEGF/hUCB-MSCs treated with Dox. Moreover, seeding of the VEGF/hUCB-MSCs onto the cardiac patch significantly improved the left ventricle ejection fraction and fractional shortening in a rat MI model upon VEGF induction. Induced VEGF/hUCB-MSC patches significantly decreased the MI size and fibrosis and increased muscle thickness, suggesting improved survival of cardiomyocytes and protection from MI damage. These results suggest that our inducible VEGF-secreting stem cell system is an effective therapeutic approach for the treatment of MI. Stem Cells Translational Medicine 2017;6:1040-1051.
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Hyun-Min
authors.initials: HM
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Pyung-Hwan
authors.initials: PH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Chang
authors.affiliation: Department of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Shen
authors.affiliation: Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
authors.forename: Kwaku
authors.initials: K
authors.lastname: Bonsra
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Byung-Jae
authors.initials: BJ
authors.lastname: Kang
authors.affiliation: Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Yum
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Veterinary Pharmacology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: So-Yeong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Veterinary Radiology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, College of Medicine, Yonsei University, Seoul, South Korea.
authors.forename: Hyongbum Henry
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Goo
authors.initials: G
authors.lastname: Jang
authors.affiliation: Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Je-Yoel
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Genome editing; Myocardial infarction; Stem cells; Umbilical cord blood