title: Acquisition of a quantitative, stoichiometrically conserved ratiometric marker of maturation status in stem cell-derived cardiac myocytes.
abstract: There is no consensus in the stem cell field as to what constitutes the mature cardiac myocyte. Thus, helping formalize a molecular signature for cardiac myocyte maturation would advance the field. In the mammalian heart, inactivation of the "fetal" TNNI gene, TNNI1 (ssTnI), together in temporal concert with its stoichiometric replacement by the adult TNNI gene product, TNNI3 (cTnI), represents a quantifiable ratiometric maturation signature. We examined the TNNI isoform transition in human induced pluripotent stem cell (iPSC) cardiac myocytes (hiPSC-CMs) and found the fetal TNNI signature, even during long-term culture. Rodent stem cell-derived and primary myocytes, however, transitioned to the adult TnI profile. Acute genetic engineering of hiPSC-CMs enabled a rapid conversion toward the mature TnI profile. While there is no single marker to denote the mature cardiac myocyte, we propose that tracking the cTnI:ssTnI protein isoform ratio provides a valuable maturation signature to quantify myocyte maturation status across laboratories.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Fikru B
authors.initials: FB
authors.lastname: Bedada
authors.affiliation: Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Sunny S-K
authors.initials: SS
authors.lastname: Chan
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Stefania K
authors.initials: SK
authors.lastname: Metzger
authors.affiliation: Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garry
authors.affiliation: Department of Medicine, Stem Cell and Regenerative Medicine Center, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kamp
authors.affiliation: Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address: metzgerj@umn.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D019210:Troponin I