title: SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability.
abstract: When pluripotency factors are removed, embryonic stem cells (ESCs) undergo spontaneous differentiation, which, among other lineages, also gives rise to cardiac sublineages, including chamber cardiomyocytes and pacemaker cells. Such heterogeneity complicates the use of ESC-derived heart cells in therapeutic and diagnostic applications. We sought to direct ESCs to differentiate specifically into cardiac pacemaker cells by overexpressing a transcription factor critical for embryonic patterning of the native cardiac pacemaker (the sinoatrial node). Overexpression of SHOX2 during ESC differentiation upregulated the pacemaker gene program, resulting in enhanced automaticity in vitro and induced biological pacing upon transplantation in vivo. The accentuated automaticity is accompanied by temporally evolving changes in the effectors and regulators of Wnt signaling. Our findings provide a strategy for enriching the cardiac pacemaker cell population from ESCs.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA; Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Ionta
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liang
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Rafie
authors.affiliation: Sapienza University of Rome, Rome 00161, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giacomello
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA; Departments of Biomedical Engineering and Pediatrics, Emory University, Atlanta, GA 30322, USA. Electronic address: heecheol.cho@emory.edu.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Cho
mesh_terms: D000818:Animals; D054849:Cardiac Electrophysiology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics*; D004624:Embryo Transfer; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D059010:Single-Cell Analysis; D012849:Sinoatrial Node / Q000166:cytology* / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018398:Homeodomain Proteins; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; C484664:SHOX2 protein, human