title: Cardiomyocyte--specific expression of the nuclear matrix protein, CIZ1, stimulates production of mono-nucleated cells with an extended window of proliferation in the postnatal mouse heart.
abstract: Myocardial injury in mammals leads to heart failure through pathological cardiac remodelling that includes hypertrophy, fibrosis and ventricular dilatation. Central to this is inability of the mammalian cardiomyocyte to self-renew due to entering a quiescent state after birth. Modulation of the cardiomyocyte cell-cycle after injury is therefore a target mechanism to limit damage and potentiate repair and regeneration. Here, we show that cardiomyocyte-specific over-expression of the nuclear-matrix--associated DNA replication protein, CIZ1, extends their window of proliferation during cardiac development, delaying onset of terminal differentiation without compromising function. CIZ1-expressing hearts are enlarged, but the cardiomyocytes are smaller with an overall increase in number, correlating with increased DNA replication after birth and retention of an increased proportion of mono-nucleated cardiomyocytes into adulthood. Furthermore, these CIZ1 induced changes in the heart reduce the impact of myocardial injury, identifying CIZ1 as a putative therapeutic target for cardiac repair.
authors.affiliation: LICAMM, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Sumia A
authors.initials: SA
authors.lastname: Bageghni
authors.affiliation: LICAMM, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Georgia A
authors.initials: GA
authors.lastname: Frentzou
authors.affiliation: LICAMM, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Drinkhill
authors.affiliation: Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: William
authors.initials: W
authors.lastname: Mansfield
authors.affiliation: Biology Department, University of York, York YO10 5DD, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Coverley
authors.affiliation: LICAMM, University of Leeds, Leeds LS2 9JT, UK justin.ainscough@york.ac.uk.|Biology Department, University of York, York YO10 5DD, UK.
authors.forename: Justin F X
authors.identifier: http://orcid.org/0000-0003-0231-433X
authors.initials: JF
authors.lastname: Ainscough
keywords: CIZ1; Cardiac function; Cardiomyocyte; DNA replication; Nuclear-matrix protein