title: Sublethal caspase activation promotes generation of cardiomyocytes from embryonic stem cells.
abstract: Generation of new cardiomyocytes is critical for cardiac repair following myocardial injury, but which kind of stimuli is most important for cardiomyocyte regeneration is still unclear. Here we explore if apoptotic stimuli, manifested through caspase activation, influences cardiac progenitor up-regulation and cardiomyocyte differentiation. Using mouse embryonic stem cells as a cellular model, we show that sublethal activation of caspases increases the yield of cardiomyocytes while concurrently promoting the proliferation and differentiation of c-Kit+/α-actininlow cardiac progenitor cells. A broad-spectrum caspase inhibitor blocked these effects. In addition, the caspase inhibitor reversed the mRNA expression of genes expressed in cardiomyocytes and their precursors. Our study demonstrates that sublethal caspase-activation has an important role in cardiomyocyte differentiation and may have significant implications for promoting cardiac regeneration after myocardial injury involving exogenous or endogenous cell sources.
authors.affiliation: Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bulatovic
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cristian
authors.initials: C
authors.lastname: Ibarra
authors.affiliation: Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Österholm
authors.affiliation: Department of Cellular and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Beltrán-Rodríguez
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Manuel
authors.initials: M
authors.lastname: Varas-Godoy
authors.affiliation: Division of Cardiology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Månsson-Broberg
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.affiliation: Department of Cellular and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: András
authors.initials: A
authors.lastname: Simon
authors.affiliation: Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Karl-Henrik
authors.initials: KH
authors.lastname: Grinnemo
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism
chemical_list: D000185:Actinin; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3; D053453:Caspase 9