title: Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.
abstract: In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts, USA. [4] Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts, USA. [5] Boston and Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. [6].
authors.forename: Lior
authors.initials: L
authors.lastname: Zangi
authors.forename: Kathy O
authors.initials: KO
authors.lastname: Lui
authors.forename: Alexander
authors.initials: A
authors.lastname: von Gise
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.forename: Wataru
authors.initials: W
authors.lastname: Ebina
authors.forename: Leon M
authors.initials: LM
authors.lastname: Ptaszek
authors.forename: Daniela
authors.initials: D
authors.lastname: Später
authors.forename: Huansheng
authors.initials: H
authors.lastname: Xu
authors.forename: Mohammadsharif
authors.initials: M
authors.lastname: Tabebordbar
authors.forename: Rostic
authors.initials: R
authors.lastname: Gorbatov
authors.forename: Brena
authors.initials: B
authors.lastname: Sena
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Rossi
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D018014:Gene Transfer Techniques; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; D040301:Vascular Endothelial Growth Factor Receptor-2