title: Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2.
abstract: Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells (CPCs), but how the two processes are synchronized is not well understood. Here, we show that the secreted Bone Morphogenetic Protein (BMP) antagonist GREMLIN 2 (GREM2) is induced in CPCs shortly after cardiac mesoderm specification during differentiation of human pluripotent stem cells. GREM2 expression follows cardiac lineage differentiation independently of the differentiation method used, or the origin of the pluripotent stem cells, suggesting that GREM2 is linked to cardiogenesis. Addition of GREM2 protein strongly increases cardiomyocyte output compared to established procardiogenic differentiation methods. Our data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of CPCs. However, canonical BMP signaling inhibition alone is not sufficient to induce cardiac differentiation, which depends on subsequent JNK pathway activation specifically by GREM2. These findings may have broader implications in the design of approaches to orchestrate growth and differentiation of pluripotent stem cell-derived lineages that depend on precise regulation of BMP signaling.
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.|2 Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: Jeffery B
authors.initials: JB
authors.lastname: Bylund
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.
authors.forename: Linh T
authors.initials: LT
authors.lastname: Trinh
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.
authors.forename: Cassandra P
authors.initials: CP
authors.lastname: Awgulewitsch
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.|3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: David T
authors.initials: DT
authors.lastname: Paik
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.
authors.forename: Christopher
authors.initials: C
authors.lastname: Jetter
authors.affiliation: 4 Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia .
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Jha
authors.affiliation: 5 Stem Cell and Regenerative Medicine Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 6 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Kristof
authors.initials: K
authors.lastname: Nolan
authors.affiliation: 4 Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia .
authors.forename: Chunhui
authors.initials: C
authors.lastname: Xu
authors.affiliation: 6 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati , Cincinnati, Ohio.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson
authors.affiliation: 5 Stem Cell and Regenerative Medicine Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.affiliation: 1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.|3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D016207:Cytokines; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C495107:GREM2 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: BMP signaling; GREMLIN 2; cardiomyocyte differentiation; human pluripotent stem cells