Abstract
To identify and analyze the live proliferating cardiomyocytes is crucial for deciphering the mechanisms controlling endogenous cardiac regeneration. Traditional methods confuse cell division with multinucleation in postnatal cardiomyocytes. Recent efforts have achieved significant progress on discerning cytokinesis from only nuclear division. However, those methods were either designed to label post-cytokinesis progeny or challenging to sort the live proliferating cardiomyocytes. In this study, we highlighted an Aurora kinase B reporter–based mouse system with a tdTomato fluorescence labeling. It could efficiently identify proliferating cardiomyocytes in neonates. The analysis of sorting tdTomato+ cardiomyocytes with different ploidy indicated that mononucleated cardiomyocytes might not possess significantly higher proliferating potential than other cardiomyocytes when most cardiomyocytes have become post-mitotic. Moreover, tdTomato+ cardiomyocytes were significantly increased and enriched at injury border zone after apex resection in neonates, while there were no increased tdTomato+ cardiomyocytes after myocardial infarction in adults.
Highlights
Myocardial infarction (MI) is among the leading causes of morbidity and mortality worldwide, severely affecting human health (Waks and Buxton, 2018)
CAG-Dre mice were used to cross with Aurora kinase B (Aurkb)-rox-tdTomato mice to label all proliferating cells (Figure 1C)
As expected by the design of this recombination system, immunostaining of sections in P4 neonatal hearts showed that expression of tdTomato in CAG-Dre × Aurkb-rox-tdTomato mice but not of tdTomato was activated in the Aurkb-rox-tdTomato mice (Supplementary Figure 1A)
Summary
Myocardial infarction (MI) is among the leading causes of morbidity and mortality worldwide, severely affecting human health (Waks and Buxton, 2018). MI leads to a rapid loss of a large number of cardiomyocytes, resulting in irreversible heart failure. The fate-mapping technique has proved that the primary source of endogenous cardiac regeneration is the proliferation of pre-existing cardiomyocytes (Senyo et al, 2013; He et al, 2017; Nakada et al, 2017). To identify and analyze the live proliferating cardiomyocytes is crucial for deciphering the mechanisms controlling endogenous cardiac regeneration. The complete process of cardiomyocyte proliferation includes DNA replication, mitosis, and cytokinesis (Broughton and Sussman, 2019). The traditional methods mainly focused on the markers of DNA replication and nuclear division, such as Ki67, BrdU/EdU, and PHH3, which poorly differentiates authentic cell division from endoreduplication, cytokinetic mitosis, or DNA repair (Hesse et al, 2012; Cai et al, 2018; Wodsedalek et al, 2019)
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