Recovery of the Xenopus laevis heart from ROS‐induced stress utilizes conserved pathways of cardiac regeneration

Abstract

Urodele amphibians and some fish are capable of regenerating up to a quarter of their heart tissue after cardiac injury. While many anuran amphibians like Xenopus laevis are not capable of such feats, they are able to repair lesser levels of cardiac damage, such as that caused by oxidative stress, to a far greater degree than mammals. Using an optogenetic stress induction model that utilizes the protein KillerRed, we have investigated the extent to which mechanisms of cardiac regeneration are conserved during the restoration of normal heart morphology post oxidative stress in X. laevis tadpoles. We focused particularly on the processes of cardiomyocyte proliferation and dedifferentiation, as well as the pathways that facilitate the regulation of these processes. The cardiac response to KillerRed‐induced injury in X. laevis tadpole hearts consists of a phase dominated by indicators of cardiac stress, followed by a repair‐like phase with characteristics similar to mechanisms of cardiac regeneration in urodeles and fish. In the latter phase, we found markers associated with partial dedifferentiation and cardiomyocyte proliferation in the injured tadpole heart, which, unlike in regenerating hearts, are not dependent on Notch or retinoic acid signaling. Ultimately, the X. laevis cardiac response to KillerRed‐induced oxidative stress shares characteristics with both mammalian and urodele/fish repair mechanisms, but is nonetheless a unique form of recovery, occupying an intermediate place on the spectrum of cardiac regenerative ability. An understanding of how Xenopus repairs cardiac damage can help bridge the gap between mammals and urodeles and contribute to new methods of treating heart disease.

Advances in the Genetically Engineered KillerRed for Photodynamic Therapy Applications

“…Photo-activated mem-KR can induce changes in heart rate and contractility of zebrafish. Moreover, it can produce oxidative stress in X.laevis tadpoles and help to investigate the conserved mechanisms of cardiac repair during natural heart morphology reconstruction [ 34 , 36 ]. It can affect cell viability and function of the zebrafish embryo as well as induce apoptosis in specific organs and tissues of Xenopuslaevis for studies of ROS during embryogenesis [ 35 , 37 ].…”

Vertebrate cardiac regeneration: evolutionary and developmental perspectives

“…Furthermore, adult 1-year-old Xenopus tropicalis hearts mount a robust CM proliferative response to 10% apical resection that fully regenerates the lost myocardium nearly scar-free by 30 days after injury (Liao et al 2017 ). Conversely, other research in X. laevis indicates that while tadpoles induce CM proliferation after oxidative damage (Jewhurst and McLaughlin 2019 ) and also mount a complete regenerative response after resection, post-metamorphosis 6-month old juveniles and 5-year-old adults can only mount a partial regenerative response to comparable apical resection (Marshall et al 2019 ; Marshall et al 2017 ). While this discrepancy between X. tropicalis and X. laevis may be explained by the different ages of the resected adults, it may also be explained by ploidy differences between the two species: X. tropicalis has a diploid genome with mostly mononuclear CMs, but X. laevis has a pseudotetraploid genome with mostly tetraploid CMs (Marshall et al 2018 ).…”