Genetic tracing and topography of spontaneous and stimulated cardiac regeneration in mice

Ilaria Secco; Ana Backovic; Mateusz Tomczyk; Antonio Mura; Gang Li; Francesca Bortolotti; Miguel Cunha Mano; Mauro Giacca

doi:10.1038/s44161-025-00623-3

Genetic tracing and topography of spontaneous and stimulated cardiac regeneration in mice

Ilaria Secco, Ana Backovic, Mateusz Tomczyk, Antonio Mura, Gang Li, Francesca Bortolotti, Miguel Cunha Mano, Mauro Giacca

Research output: Contribution to journal › Article › peer-review

Abstract

Despite recent efforts to stimulate endogenous cardiomyocyte proliferation for cardiac regeneration, the lack of reliable in vivo methods for monitoring cardiomyocyte replication has hindered our understanding of its mechanisms. Thymidine analogs, used to label proliferating cells, are unsuitable for long-term cardiac regeneration studies as their DNA incorporation elicits a damage response, leading to their elimination. Here we present CycleTrack, a genetic strategy based on the transcriptional activation of Cre recombinase from a temporally regulated cyclin B2 promoter segment, for permanent labeling of cardiomyocytes passing through the G2/M phase. Using CycleTrack, we visualized cardiomyocyte turnover in neonatal and adult mice under various conditions, including pregnancy, increased ventricular afterload, and myocardial infarction. CycleTrack also provided visual and quantitative evidence of ventricular remuscularization following treatment with pro-regenerative microRNAs. We identify the subendocardium as a key site of mitotic activity and provide a mode of cardiomyocyte division along their short axis. CycleTrack is a powerful tool to monitor cardiomyocyte renewal during regenerative interventions.

Original language	English
Article number	671
Journal	Nature
DOIs	https://doi.org/10.1038/s44161-025-00623-3
Publication status	Accepted/In press - 6 Feb 2025

Access to Document

10.1038/s44161-025-00623-3

Cite this

@article{09207308f61949029f6d97c4efbe11c1,

title = "Genetic tracing and topography of spontaneous and stimulated cardiac regeneration in mice",

abstract = "Despite recent efforts to stimulate endogenous cardiomyocyte proliferation for cardiac regeneration, the lack of reliable in vivo methods for monitoring cardiomyocyte replication has hindered our understanding of its mechanisms. Thymidine analogs, used to label proliferating cells, are unsuitable for long-term cardiac regeneration studies as their DNA incorporation elicits a damage response, leading to their elimination. Here we present CycleTrack, a genetic strategy based on the transcriptional activation of Cre recombinase from a temporally regulated cyclin B2 promoter segment, for permanent labeling of cardiomyocytes passing through the G2/M phase. Using CycleTrack, we visualized cardiomyocyte turnover in neonatal and adult mice under various conditions, including pregnancy, increased ventricular afterload, and myocardial infarction. CycleTrack also provided visual and quantitative evidence of ventricular remuscularization following treatment with pro-regenerative microRNAs. We identify the subendocardium as a key site of mitotic activity and provide a mode of cardiomyocyte division along their short axis. CycleTrack is a powerful tool to monitor cardiomyocyte renewal during regenerative interventions.",

author = "Ilaria Secco and Ana Backovic and Mateusz Tomczyk and Antonio Mura and Gang Li and Francesca Bortolotti and {Cunha Mano}, Miguel and Mauro Giacca",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = feb,

day = "6",

doi = "10.1038/s44161-025-00623-3",

language = "English",

journal = "Nature",

issn = "0028-0836",

publisher = "Springer Nature",

}

TY - JOUR

T1 - Genetic tracing and topography of spontaneous and stimulated cardiac regeneration in mice

AU - Secco, Ilaria

AU - Backovic, Ana

AU - Tomczyk, Mateusz

AU - Mura, Antonio

AU - Li, Gang

AU - Bortolotti, Francesca

AU - Cunha Mano, Miguel

AU - Giacca, Mauro

PY - 2025/2/6

Y1 - 2025/2/6

N2 - Despite recent efforts to stimulate endogenous cardiomyocyte proliferation for cardiac regeneration, the lack of reliable in vivo methods for monitoring cardiomyocyte replication has hindered our understanding of its mechanisms. Thymidine analogs, used to label proliferating cells, are unsuitable for long-term cardiac regeneration studies as their DNA incorporation elicits a damage response, leading to their elimination. Here we present CycleTrack, a genetic strategy based on the transcriptional activation of Cre recombinase from a temporally regulated cyclin B2 promoter segment, for permanent labeling of cardiomyocytes passing through the G2/M phase. Using CycleTrack, we visualized cardiomyocyte turnover in neonatal and adult mice under various conditions, including pregnancy, increased ventricular afterload, and myocardial infarction. CycleTrack also provided visual and quantitative evidence of ventricular remuscularization following treatment with pro-regenerative microRNAs. We identify the subendocardium as a key site of mitotic activity and provide a mode of cardiomyocyte division along their short axis. CycleTrack is a powerful tool to monitor cardiomyocyte renewal during regenerative interventions.

AB - Despite recent efforts to stimulate endogenous cardiomyocyte proliferation for cardiac regeneration, the lack of reliable in vivo methods for monitoring cardiomyocyte replication has hindered our understanding of its mechanisms. Thymidine analogs, used to label proliferating cells, are unsuitable for long-term cardiac regeneration studies as their DNA incorporation elicits a damage response, leading to their elimination. Here we present CycleTrack, a genetic strategy based on the transcriptional activation of Cre recombinase from a temporally regulated cyclin B2 promoter segment, for permanent labeling of cardiomyocytes passing through the G2/M phase. Using CycleTrack, we visualized cardiomyocyte turnover in neonatal and adult mice under various conditions, including pregnancy, increased ventricular afterload, and myocardial infarction. CycleTrack also provided visual and quantitative evidence of ventricular remuscularization following treatment with pro-regenerative microRNAs. We identify the subendocardium as a key site of mitotic activity and provide a mode of cardiomyocyte division along their short axis. CycleTrack is a powerful tool to monitor cardiomyocyte renewal during regenerative interventions.

UR - http://www.scopus.com/inward/record.url?scp=86000338403&partnerID=8YFLogxK

U2 - 10.1038/s44161-025-00623-3

DO - 10.1038/s44161-025-00623-3

M3 - Article

SN - 0028-0836

JO - Nature

JF - Nature

M1 - 671

ER -

Genetic tracing and topography of spontaneous and stimulated cardiac regeneration in mice

Abstract

Access to Document

Other files and links

Fingerprint

Cite this