Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells

Abstract

Background Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have great potential as a cell source for therapeutic applications such as regenerative medicine, disease modeling, drug screening, and toxicity testing. This potential is limited, however, by the immature state of the cardiomyocytes acquired using current protocols. Tri-iodo-L-thyronine (T3) is a growth hormone that is essential for optimal heart growth. In this study, we investigated the effect of T3 on hiPSC-CM maturation. Methods and Results A one-week treatment with T3 increased cardiomyocyte size, anisotropy, and sarcomere length. T3 treatment was associated with reduced cell cycle activity, manifest as reduced DNA synthesis and increased expression of the cyclin-dependent kinase inhibitor p21. Contractile force analyses were performed on individual cardiomyocytes using arrays of microposts, revealing an almost two-fold higher force per-beat after T3 treatment and also an enhancement in contractile kinetics. This improvement in force generation was accompanied by an increase in rates of calcium release and reuptake, along with a significant increase in sarcoendoplasmic reticulum ATPase expression. Finally, although mitochondrial genomes were not numerically increased, extracellular flux analysis showed a significant increase in maximal mitochondrial respiratory capacity and respiratory reserve capability after T3 treatment. Conclusions Using a broad spectrum of morphological, molecular, and functional parameters, we conclude that T3 is a driver for hiPSC-CM maturation. T3 treatment may enhance the utility of hiPSC-CMs for therapy, disease modeling, or drug/toxicity screens.

Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro – Correlation between contraction force and electrophysiology

“…hESC-CM and hiPS-CM in MM displayed a higher level of sarcomeric organization and increased their contraction stress by 140% and 170% respectively when compared to CMs cultured in BPEL and by 43% and 41% in comparison to CMs in CA. These results are in accordance with previously reported findings that T3 hormone increased contractile maturation in hiPS-CM [33]. Interestingly, both hESC-CM and hiPS-CM in MM generated significantly higher contraction stress than hFetal-CM.…”

“…1). Recent studies have shown that T3 thyroid hormone has the potential to stimulate different characteristics of cardiomyocyte maturation [33]. Both hESC-CMs and hiPS-CMs cultured in MM showed an increase of 140% and 170% in contraction stress, respectively, compared to CMs cultured in BPEL or a 43% and 41% increase compared to CMs in CA media on day 33 (hESC-CM -BPEL 0.21 ± 0.07 mN/mm 2 , CA 0.36 ± 0.02 mN/mm 2 , MM 0.52 ± 0.04 mN/mm 2 P < 0.0001) and (hiPS-CM -BPEL 0.18 ± 0.02 mN/mm 2 , CA 0.36 ± 0.02 mN/mm 2 , MM 0.51 ± 0.04 mN/mm 2 P < 0.0001) (Fig.…”

“…Moreover, triiodothyronine (T3) has been described as promoting electrophysiological and calcium handling maturation in mouse embryonic stem cell derived cardiomyocytes [32] and contraction maturation hiPS-CM [33].…”

Thyroid Hormones and the Heart; a Paradigm of Exquisite Fine Tuning, Combining Ancient Hellenic and Oriental Wisdom

“…Thus, Yang et al [29] have shown that T3 promotes the modulation of human cardiomyocytes derived from induced pluripotent stem cells.…”

Defined MicroRNAs Induce Aspects of Maturation in Mouse and Human Embryonic-Stem-Cell-Derived Cardiomyocytes

“…Given that previously undetected cardiac toxicity is one of the leading causes of drug development failure, the problem appears to be significant (Navarrete et al, 2013). Thus, the need for mature ESC/iPSC-CMs is clearly recognized, and many groups have attempted to improve ESC/iPSC-CM maturation by a variety of methods (Kim et al, 2010;Kuppusamy et al, 2015;Nunes et al, 2013;Yang et al, 2014b).…”