title: Systemic injection of AAV9 carrying a periostin promoter targets gene expression to a myofibroblast-like lineage in mouse hearts after reperfused myocardial infarction.
abstract: Adeno-associated virus (AAV) has been used to direct gene transfer to a variety of tissues, including heart, liver, skeletal muscle, brain, kidney and lung, but it has not previously been shown to effectively target fibroblasts in vivo, including cardiac fibroblasts. We constructed expression cassettes using a modified periostin promoter to drive gene expression in a cardiac myofibroblast-like lineage, with only occasional spillover into cardiomyocyte-like cells. We compared AAV serotypes 6 and 9 and found robust gene expression when the vectors were delivered by systemic injection after myocardial infarction (MI), with little expression in healthy, non-infarcted mice. AAV9 provided expression in a greater number of cells than AAV6, with reporter gene expression visible in the cardiac infarct and border zones from 5 to 62 days post MI, as assessed by luciferase and Cre-activated green fluorescent protein expression. Although common myofibroblast markers were expressed in low abundance, most of the targeted cells expressed myosin IIb, an embryonic form of smooth muscle myosin heavy chain that has previously been associated with myofibroblasts after reperfused MI. This study is the first to demonstrate AAV-mediated expression in a potentially novel myofibroblast-like lineage in mouse hearts post MI and may open new avenues of gene therapy to treat patients surviving MI.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Piras
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Thomas
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: O'Connor
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.|Department of Radiology, University of Virginia, Charlottesville, VA, USA.|Department of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: French
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000627:therapeutic use; D019070:Cell Lineage / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006321:Heart / Q000503:physiopathology; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D058628:Myofibroblasts / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D015815:Cell Adhesion Molecules; C512835:POSTN protein, human