Thyroid hormone drives fetal cardiomyocyte maturation

Abstract

Tri-iodo-l-thyronine (T(3)) suppresses the proliferation of near-term serum-stimulated fetal ovine cardiomyocytes in vitro. Thus, we hypothesized that T(3) is a major stimulant of cardiomyocyte maturation in vivo. We studied 3 groups of sheep fetuses on gestational days 125-130 (term ∼145 d): a T(3)-infusion group, to mimic fetal term levels (plasma T(3) levels increased from ∼0.1 to ∼1.0 ng/ml; t(1/2)∼24 h); a thyroidectomized group, to produce low thyroid hormone levels; and a vehicle-infusion group, to serve as intact controls. At 130 d of gestation, sections of left ventricular freewall were harvested, and the remaining myocardium was enzymatically dissociated. Proteins involved in cell cycle regulation (p21, cyclin D1), proliferation (ERK), and hypertrophy (mTOR) were measured in left ventricular tissue. Evidence that elevated T(3) augmented the maturation rate of cardiomyocytes included 14% increased width, 31% increase in binucleation, 39% reduction in proliferation, 150% reduction in cyclin D1 protein, and 500% increase in p21 protein. Increased expression of phospho-mTOR, ANP, and SERCA2a also suggests that T(3) promotes maturation and hypertrophy of fetal cardiomyocytes. Thyroidectomized fetuses had reduced cell cycle activity and binucleation. These findings support the hypothesis that T(3) is a prime driver of prenatal cardiomyocyte maturation.

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

“…Because PPARA/PPARGC1A is known to be regulated by or interact with the thyroid hormone pathway, [32][33][34][35] which promotes the maturation of fetal VCMs and ESC-CMs, 36,37 we then examined the functional consequences of T3 treatment on contractile forces. Although shortening of single hESCCMs or their clusters has been measured as an surrogate index for contractile forces, 38,39 a multicellular 3D hvCMT system has been developed, where true dynamic tension developed by the tissue in real time can be measured.…”

Thyroid hormone action in postnatal heart development

“…Our contention that T3 triggers the postnatal CM hyperplastic response during maturational heart growth is not always, at first glance, consistent with earlier reports. For example, Chattergoon et al (2012) evaluated the effects on fetal CM maturation of T3 given to sheep by infusion on gestational days 125-130 (term~145 days). These studies suggested that T3 augments CM maturation, as evidenced by increases in cell width, binucleation and expression of the cell cycle inhibitor, p21, as well as by reductions in cyclin D1 and in cell proliferation.…”

A natural product, resveratrol, protects against high-glucose-induced developmental damage in chicken embryo

“…On the other side, regulators of the cell cycle were altered in chicken embryos following highglucose treatment, while resveratrol reversed the alteration. When chicken embryos were exposed to high-glucose environment, embryonic cells may have been arrested in the G1 phase because of the suppression of cyclin D1 and the upregulation of p21 [17], which would lead to a reduction of embryonic cell proliferation. We can suspect that the effect of resveratrol may also be related to its activity on these regulators.…”