title: Epicardial FSTL1 reconstitution regenerates the adult mammalian heart.
abstract: The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Vahid
authors.initials: V
authors.lastname: Serpooshan
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hurtado
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.|Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Diez-Cuñado
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.affiliation: Imperial College London, Faculty of Medicine, Imperial Centre for Translational and Experimental Medicine, Du Cane Road, London W12 0NN, UK.
authors.forename: Michela
authors.initials: M
authors.lastname: Noseda
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, and Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Tian
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, and Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qiaozhen
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wang
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Bushway
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Savchenko
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.|Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, 1417613151 Tehran, Iran.
authors.forename: Morteza
authors.initials: M
authors.lastname: Mahmoudi
authors.affiliation: Imperial College London, Faculty of Medicine, Imperial Centre for Translational and Experimental Medicine, Du Cane Road, London W12 0NN, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Academic Medical Center. Dept Anatomy, Embryology and Physiology. Meibergdreef 15. 1105AZ Amsterdam, The Netherlands.
authors.forename: Maurice J B
authors.initials: MJ
authors.lastname: van den Hoff
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Manish J
authors.initials: MJ
authors.lastname: Butte
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, and Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92037, USA.|Sanford-Burnham-Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
authors.affiliation: Stanford Cardiovascular Institute and Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D051381:Rats; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D013552:Swine; D019076:Transgenes / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; C448799:FSTL1 protein, human