Telomere Length Defines the Cardiomyocyte Differentiation Potency of Mouse Induced Pluripotent Stem Cells.
Induced pluripotent stem cells (iPSCs) can be differentiated in vitro and in vivo to all cardiovascular lineages and are therefore a promising cell source for cardiac regenerative therapy. However, iPSC lines do not all differentiate into cardiomyocytes (CMs) with the same efficiency. Here, we show that telomerase-competent iPSCs with relatively long telomeres and high expression of the shelterin-complex protein TRF1 (iPSChighT) differentiate sooner and more efficiently into CMs than those with relatively short telomeres and low TRF1 expression (iPSClowT). Ascorbic acid, an enhancer of cardiomyocyte differentiation, further increases the cardiomyocyte yield from iPSChighTbut does not rescue the cardiomyogenic potential of iPSClowT. Interestingly, although iPSCslowTdifferentiate very poorly to the mesoderm and endoderm lineages, they differentiate very efficiently to the ectoderm lineage, indicating that cell fate can be determined by in vitro selection of iPSCs with different telomere content. Our findings highlight the importance of selecting iPSCs with ample telomere reserves in order to generate high numbers of CMs in a fast, reliable, and efficient way. Stem Cells 2017;35:362-373.
Regeneration and Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
Tania
T
Aguado
Pluripotent Cell Technology Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
Francisco J
FJ
Gutiérrez
Regeneration and Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
Esther
E
Aix
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Ralph P
RP
Schneider
Pluripotent Cell Technology Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
Giovanna
G
Giovinazzo
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
María A
MA
Blasco
Regeneration and Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
Ignacio
I
Flores
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000187:drug effects
D003094:Collagen; D001205:Ascorbic Acid
Ascorbic acid; Cardiomyocytes; Extracellular matrix; Induced pluripotent stem cells; Telomere length