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Sarcomere Function Inhibits Cardiomyocyte Replication and Promotes Polyploidization Through a DNA Damage Response that Limits In vivo Cell Engraftment

69 Pages Posted: 27 Jul 2020 Publication Status: Review Complete

See all articles by Anthony M. Pettinato

Anthony M. Pettinato

UConn Health - Department of Genetics and Genome Sciences

Dasom Yoo

University of Washington - Department of Bioengineering

Jennifer VanOudenhove

UConn Health - Department of Genetics and Genome Sciences

Yu-Sheng Chen

Jackson Laboratory for Genomic Medicine

Rachel Cohn

Jackson Laboratory for Genomic Medicine

Feria A. Ladha

UConn Health - Department of Genetics and Genome Sciences

Xiulan Yang

University of Washington - Institute for Stem Cell and Regenerative Medicine

Ketan Thakar

Jackson Laboratory for Genomic Medicine

Robert Romano

Jackson Laboratory for Genomic Medicine

Nicolas Legere

Jackson Laboratory for Genomic Medicine

Emily Meredith

Jackson Laboratory for Genomic Medicine

Paul Robson

The Jackson Laboratory - Jackson Laboratory for Genomic Medicine

Michael Regnier

University of Washington - Department of Bioengineering

Justin Cotney

University of Connecticut - Graduate Program in Genetics and Developmental Biology; University of Connecticut - Department of Genetics and Genome Sciences; University of Connecticut - Institute for Systems Genomics

Charles E. Murry

University of Washington - Department of Bioengineering

J. Travis Hinson

UConn Health - Department of Genetics and Genome Sciences

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Abstract

Human cardiac regeneration is limited by low cardiomyocyte replicative rates and progressive polyploidization by unclear mechanisms. To study this process, we engineered a human cardiomyocyte model to track replication and polyploidization using fluorescently tagged cyclin B1 and cardiac troponin T. Using time-lapse imaging, in vitro cardiomyocyte replication patterns recapitulated the progressive mononuclear polyploidization and replicative arrest observed in vivo. Single-cell transcriptomics and epigenetic analyses revealed that polyploidization was preceded by sarcomere formation, enhanced oxidative metabolism, a DNA damage response, and p53 activation. CRISPR knockout screening revealed p53 as a driver of cell cycle arrest and polyploidization. Inhibiting contractile function with troponin knockout, or scavenging ROS, inhibited cell cycle arrest and polypoloidization. Finally, we showed that cardiomyocyte engraftment in infarcted rat hearts could be enhanced 4-fold by the increased proliferation of troponin-knockout cardiomyocytes. Thus, sarcomere assembly inhibits cell division through a DNA damage response that can be targeted to improve cardiomyocyte replacement strategies.

Suggested Citation

Pettinato, Anthony M. and Yoo, Dasom and VanOudenhove, Jennifer and Chen, Yu-Sheng and Cohn, Rachel and Ladha, Feria A. and Yang, Xiulan and Thakar, Ketan and Romano, Robert and Legere, Nicolas and Meredith, Emily and Robson, Paul and Regnier, Michael and Cotney, Justin and Murry, Charles E. and Hinson, J. Travis, Sarcomere Function Inhibits Cardiomyocyte Replication and Promotes Polyploidization Through a DNA Damage Response that Limits In vivo Cell Engraftment. Available at SSRN: https://ssrn.com/abstract=3640833 or http://dx.doi.org/10.2139/ssrn.3640833
This version of the paper has not been formally peer reviewed.

Anthony M. Pettinato

UConn Health - Department of Genetics and Genome Sciences ( email )

Storrs, CT 06269-1063
United States

Dasom Yoo

University of Washington - Department of Bioengineering ( email )

Seattle, WA
United States

Jennifer VanOudenhove

UConn Health - Department of Genetics and Genome Sciences ( email )

Storrs, CT 06269-1063
United States

Yu-Sheng Chen

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Rachel Cohn

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Feria A. Ladha

UConn Health - Department of Genetics and Genome Sciences ( email )

Storrs, CT 06269-1063
United States

Xiulan Yang

University of Washington - Institute for Stem Cell and Regenerative Medicine ( email )

Seattle, WA
United States

Ketan Thakar

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Robert Romano

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Nicolas Legere

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Emily Meredith

Jackson Laboratory for Genomic Medicine ( email )

10 Discovery Dr
Farmington, CT 06032
United States

Paul Robson

The Jackson Laboratory - Jackson Laboratory for Genomic Medicine

10 Discovery Dr
Farmington, CT 06032
United States

Michael Regnier

University of Washington - Department of Bioengineering ( email )

Seattle, WA
United States

Justin Cotney

University of Connecticut - Graduate Program in Genetics and Developmental Biology ( email )

Storrs, CT 06269-1063
United States

University of Connecticut - Department of Genetics and Genome Sciences ( email )

Storrs, CT 06269-1063
United States

University of Connecticut - Institute for Systems Genomics ( email )

Storrs, CT 06269-1063
United States

Charles E. Murry

University of Washington - Department of Bioengineering ( email )

Seattle, WA
United States

J. Travis Hinson (Contact Author)

UConn Health - Department of Genetics and Genome Sciences ( email )

Storrs, CT 06269-1063
United States

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