title: Neuregulin-1β induces mature ventricular cardiac differentiation from induced pluripotent stem cells contributing to cardiac tissue repair.
abstract: Stem cell-derived cardiomyocytes (CMs) are often electrophysiologically immature and heterogeneous, which represents a major barrier to their in vitro and in vivo application. Therefore, the purpose of this study was to examine whether Neuregulin-1β (NRG-1β) treatment could enhance in vitro generation of mature "working-type" CMs from induced pluripotent stem (iPS) cells and assess the regenerative effects of these CMs on cardiac tissue after acute myocardial infarction (AMI). With that purpose, adult mouse fibroblast-derived iPS from α-MHC-GFP mice were derived and differentiated into CMs through NRG-1β and/or dimethyl sulfoxide (DMSO) treatment. Cardiac specification and maturation of the iPS was analyzed by gene expression array, quantitative real-time polymerase chain reaction, immunofluorescence, electron microscopy, and patch-clamp techniques. In vivo, the iPS-derived CMs or culture medium control were injected into the peri-infarct region of hearts after coronary artery ligation, and functional and histology changes were assessed from 1 to 8 weeks post-transplantation. On differentiation, the iPS displayed early and robust in vitro cardiogenesis, expressing cardiac-specific genes and proteins. More importantly, electrophysiological studies demonstrated that a more mature ventricular-like cardiac phenotype was achieved when cells were treated with NRG-1β and DMSO compared with DMSO alone. Furthermore, in vivo studies demonstrated that iPS-derived CMs were able to engraft and electromechanically couple to heart tissue, ultimately preserving cardiac function and inducing adequate heart tissue remodeling. In conclusion, we have demonstrated that combined treatment with NRG-1β and DMSO leads to efficient differentiation of iPS into ventricular-like cardiac cells with a higher degree of maturation, which are capable of preserving cardiac function and tissue viability when transplanted into a mouse model of AMI.
authors.affiliation: 1 Area of Cell Therapy, Center for Applied Medical Research, University of Navarra , Pamplona, Spain .
authors.forename: Olalla
authors.initials: O
authors.lastname: Iglesias-García
authors.forename: Sven
authors.initials: S
authors.lastname: Baumgartner
authors.forename: Laura
authors.initials: L
authors.lastname: Macrí-Pellizzeri
authors.forename: Juan Roberto
authors.initials: JR
authors.lastname: Rodriguez-Madoz
authors.forename: Gloria
authors.initials: G
authors.lastname: Abizanda
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guruceaga
authors.forename: Edurne
authors.initials: E
authors.lastname: Albiasu
authors.forename: David
authors.initials: D
authors.lastname: Corbacho
authors.forename: Carolina
authors.initials: C
authors.lastname: Benavides-Vallve
authors.forename: Mario
authors.initials: M
authors.lastname: Soriano-Navarro
authors.forename: Susana
authors.initials: S
authors.lastname: González-Granero
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Gavira
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krausgrill
authors.forename: Moises
authors.initials: M
authors.lastname: Rodriguez-Mañero
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortiz-de-Solorzano
authors.forename: Marcel
authors.initials: M
authors.lastname: Halbach
authors.forename: Juergen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelacho
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D006352:Heart Ventricles / Q000166:cytology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020890:Neuregulin-1 / Q000494:pharmacology*; D012038:Regeneration; D033581:Stem Cell Transplantation; D016276:Ventricular Function
chemical_list: D020890:Neuregulin-1; C117467:neuregulin beta; D004121:Dimethyl Sulfoxide