Regenerating Hearts by Arresting Development With Hypothyroidism.

Mice and rats transition to mostly binucleated cardiomyocytes in the first 2 weeks after birth. Scarless myocardial repair was reported to occur before this transition. This inverse temporal relationship has spurred research into the underlying molecular and cellular mechanisms, because they are thought to be critical for understanding the decrease of heart regeneration in mice and rats and may provide molecular targets for increasing intrinsic regenerative capacity in humans. A recent article by Hirose et al brings a new perspective to this question by identifying far-reaching connections between regulation of whole-body metabolism, cardiomyocyte proliferation, and heart regeneration, all connected via thyroid hormone signaling. Increased or decreased thyroid hormone signaling has extensive effects on the development, function, and injury response of the cardiovascular system. In development, congenital hypothyroidism results in growth retardation, deafness, impaired neurogenesis, and heart failure. Although the physiological role of thyroid hormones as a stimulus for cardiomyocyte differentiation and hypertrophy is firmly established, the connection with cardiomyocyte proliferation identified by Hirose et al is new. Thyroid hormone effects have also been investigated in the context of injury and regeneration in other organs, where its actions are generally viewed as beneficial. Hirose et al began by cataloging the percentage of diploid cardiomyocytes in a wide range of species, a herculean task. It comes as no surprise that zebrafish, champions of heart regeneration, have 100% diploid cardiomyocyte nuclei, compared to mice with ≈10%. A surprising result was that humans showed 4% of mononucleated cardiomyocytes with diploid nuclei. Aficionados will note that this is significantly lower than previous reports of 35%. Hirose et al establish an intriguing correlation between the percentage of diploid cardiomyocytes and ectothermy, that is, warm-bloodedness. Indeed, there is a negative linear relationship when diploid cardiomyocyte percentages of different species are plotted against corresponding body temperatures. In other words, species with lower basal temperatures have fewer diploid cardiomyocytes. Hirose et al connect the percentage of diploid cardiomyocyte to metabolism with an elegant comparison via standard metabolic rate as per Kleiber’s law and find an inverse correlation with serum total thyroxin (T4) levels. Indeed, they measured a 4-fold increase of serum thyroid hormones (T4 and T3, the biologically more active metabolite of T4) in mouse pups between birth and 1 week of age. At the measured concentration, the occupancy of thyroid hormone receptors by T3 or T4 would be predicted to be exceedingly small. However, there is a greater rise in thyroid hormone levels that occurs in mice 2 weeks after birth, that is, after the transition to binucleated cardiomyocytes. This surge could add to the reported inhibition of postnatal cardiomyocyte proliferation by thyroid hormone receptor activation. To determine the molecular function of thyroid hormone in regulating cardiomyocyte proliferation, Hirose et al began by examining the effect of adding T3 on cell cycle activity of neonatal mouse cardiomyocytes in culture. Surprisingly, there was no effect, but the baseline percentages of EdU and Ki67 cardiomyocytes were low. This suggests that cardiomyocyte cell cycle activity was way below maximal stimulation, and the hypothesized inhibitory effect of T3 could not have been observed. However, there was increased proliferation of diploid cardiomyocytes in vivo when a specific thyroid receptor inhibitor (NH3) or the thyroid hormone synthesis blocker propylthiouracil (PTU) were administered from the embryonic to the postnatal period. The administration of PTU generated a compelling reduction in body temperature and body weight, and increased the number of cardiomyocytes 2 weeks after birth. Because PTU-induced hypothyroidism causes irreversible developmental delay in many organs, it would be of interest to know if there were any phenotypic systemic effects on these pups. Hirose et al use a dominant-negative thyroid receptor type α (ThraDN) whose transcription was activated with cre. Crosses of this mouse strain with αMHC-Cre enabled cardiomyocyte-specific disruption of thyroid hormone receptor signaling. At this point, it should be noted that Thra heterodimerizes with other nuclear hormone receptors, for example the The opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar & Ali J. Marian. From the School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, NSW, Australia (S.L.); Division of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia (S.L.); and Division of Cardiology, Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children’s Hospital of Pittsburgh, Department of Pediatrics, and McGowan Institute of Regenerative Medicine, University of Pittsburgh, PA (B.K.). Correspondence to Bernhard Kühn, MD, UPMC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Rangos 8127, Pittsburgh, PA 15224. Email bernhard.kuhn2@chp.edu Regenerating Hearts by Arresting Development With Hypothyroidism