title: Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration.
abstract: Heart attack is a global health problem that leads to significant morbidity, mortality, and health care burden. Adult human hearts have very limited regenerative capability after injury. However, evolutionarily primitive species generally have higher regenerative capacity than mammals. The extracellular matrix (ECM) may contribute to this difference. Mammalian cardiac ECM may not be optimally inductive for cardiac regeneration because of the fibrotic, instead of regenerative, responses in injured adult mammalian hearts. Given the high regenerative capacity of adult zebrafish hearts, we hypothesize that decellularized zebrafish cardiac ECM (zECM) made from normal or healing hearts can induce mammalian heart regeneration. Using zebrafish and mice as representative species of lower vertebrates and mammals, we show that a single administration of zECM, particularly the healing variety, enables cardiac functional recovery and regeneration of adult mouse heart tissues after acute myocardial infarction. zECM-treated groups exhibit proliferation of the remaining cardiomyocytes and multiple cardiac precursor cell populations and reactivation of ErbB2 expression in cardiomyocytes. Furthermore, zECM exhibits pro-proliferative and chemotactic effects on human cardiac precursor cell populations in vitro. These contribute to the structural preservation and correlate with significantly higher cardiac contractile function, notably less left ventricular dilatation, and substantially more elastic myocardium in zECM-treated hearts than control animals treated with saline or decellularized adult mouse cardiac ECM. Inhibition of ErbB2 activity abrogates beneficial effects of zECM administration, indicating the possible involvement of ErbB2 signaling in zECM-mediated regeneration. This study departs from conventional focuses on mammalian ECM and introduces a new approach for cardiac tissue regeneration.
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: William C W
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Zhouguang
authors.identifier: 0000-0003-0612-1519
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Maria Azzurra
authors.initials: MA
authors.lastname: Missinato
authors.affiliation: Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Dae Woo
authors.initials: DW
authors.lastname: Park
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Daniel Ward
authors.identifier: 0000-0001-7423-4908
authors.initials: DW
authors.lastname: Long
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.; Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Heng-Jui
authors.identifier: 0000-0001-6402-4667
authors.initials: HJ
authors.lastname: Liu
authors.affiliation: Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA 15213, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Biomedical Mass Spectrometry Center, University of Pittsburgh Schools of the Health Sciences, Pittsburgh, PA 15213, USA.; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.; University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Yates
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.; Center for Ultrasound Molecular Imaging and Therapeutics, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.; Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15260, USA.; Department of Chemical and Petroleum Engineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA.; Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, PA 15261, USA.; Clinical Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000737:chemistry / Q000637:transplantation; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000737:chemistry*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012038:Regeneration; D015027:Zebrafish
keywords: Extracellular matrix; cardiac repair; cardiomyogenesis; decellularization; heart regeneration; ischemic heart disease; myocardial infarction; zebrafish