title: Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines.
abstract: Efficient differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to a variety of lineages requires step-wise approaches replicating the key commitment stages found during embryonic development. Here we show that expression of PdgfR-α segregates mouse ESC-derived Flk-1 mesoderm into Flk-1(+)PdgfR-α(+) cardiac and Flk-1(+)PdgfR-α(-) hematopoietic subpopulations. By monitoring Flk-1 and PdgfR-α expression, we found that specification of cardiac mesoderm and cardiomyocytes is determined by remarkably small changes in levels of Activin/Nodal and BMP signaling. Translation to human ESCs and iPSCs revealed that the emergence of cardiac mesoderm could also be monitored by coexpression of KDR and PDGFR-α and that this process was similarly dependent on optimal levels of Activin/Nodal and BMP signaling. Importantly, we found that individual mouse and human pluripotent stem cell lines require optimization of these signaling pathways for efficient cardiac differentiation, illustrating a principle that may well apply in other contexts.
authors.affiliation: McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kattman
authors.forename: Alec D
authors.initials: AD
authors.lastname: Witty
authors.forename: Mark
authors.initials: M
authors.lastname: Gagliardi
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Dubois
authors.forename: Maryam
authors.initials: M
authors.lastname: Niapour
authors.forename: Akitsu
authors.initials: A
authors.lastname: Hotta
authors.forename: James
authors.initials: J
authors.lastname: Ellis
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D055457:Nodal Protein / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019485:Bone Morphogenetic Proteins; D055457:Nodal Protein; D028341:Activins