Stage-dependent cardiac regeneration inXenopusis regulated by thyroid hormone availability

Abstract

Despite therapeutic advances, heart failure is the major cause of morbidity and mortality worldwide, but why cardiac regenerative capacity is lost in adult humans remains an enigma. Cardiac regenerative capacity widely varies across vertebrates. Zebrafish and newt hearts regenerate throughout life. In mice, this ability is lost in the first postnatal week, a period physiologically similar to thyroid hormone (TH)-regulated metamorphosis in anuran amphibians. We thus assessed heart regeneration in Xenopus laevis before, during, and after TH-dependent metamorphosis. We found that tadpoles display efficient cardiac regeneration, but this capacity is abrogated during the metamorphic larval-to-adult switch. Therefore, we examined the consequence of TH excess and deprivation on the efficiently regenerating tadpole heart. We found that either acute TH treatment or blocking TH production before resection significantly but differentially altered gene expression and kinetics of extracellular matrix components deposition, and negatively impacted myocardial wall closure, both resulting in an impeded regenerative process. However, neither treatment significantly influenced DNA synthesis or mitosis in cardiac tissue after amputation. Overall, our data highlight an unexplored role of TH availability in modulating the cardiac regenerative outcome, and present X. laevis as an alternative model to decipher the developmental switches underlying stage-dependent constraint on cardiac regeneration.

Cellular and Molecular Mechanism of Cardiac Regeneration: A Comparison of Newts, Zebrafish, and Mammals

“…Even though a causal relationship has been suggested, the molecular mechanism is yet to be elucidated. Interestingly, thyroid hormone upregulation was observed in Xenopus to drive metamorphosis, with loss of cardiac regenerative capacity, although more than 80% of the cardiomyocytes stayed mononucleated [ 31 , 119 ]. This discrepancy between mammals and amphibians suggests that cardiomyocyte polyploidy might not be the only determining factor for cardiomyocyte regeneration.…”

Model systems for regeneration: Xenopus

“…frogs (Marshall et al, 2019). Although cardiomyocyte proliferation was investigated, as is often the focus in heart regeneration studies, changes relating to the ECM were also studied.…”

“…Although cardiomyocyte proliferation was investigated, as is often the focus in heart regeneration studies, changes relating to the ECM were also studied. Specifically, it was shown that whereas R animals (injured before metamorphosis) are able to clear deposited fibronectin and collagen and successfully complete cardiac regeneration, NR animals (injured after metamorphosis) display persistent fibrotic scars and fail to complete regeneration (Marshall et al, 2019). It therefore appears that cardiac regeneration may be stage and species dependent.…”

Heart Development and Regeneration in Non-mammalian Model Organisms

“…A new study using Xenopus laevis as a model of heart regeneration showed that the tadpole hearts can regenerate until the larvae reach metamorphosis. Excessive or reduced thyroid hormones reduce the cardiac regenerative capacity, suggesting that fine-tuning the availability of thyroid hormones may be necessary for heart regeneration ( Marshall et al, 2019 ).…”