Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

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M.P. was funded by CIRM Training Grant TG2-01161, an award from the University of Southern California's Provost Office and NHLBI NRSA 1F32HL124932. Zebrafish work was supported in part by a Doerr Family Foundation award provided to M.P. and L.B. S.R.K. was supported by K08HL121191. Purchase and husbandry of HMDP strains was supported by grants HL123295 and HL114437 to A.J.L. and grant NS083265 to T.M.

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  1. Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Michaela Patterson
    • , Lindsey Barske
    • , Ben Van Handel
    • , Peiheng Gan
    • , Avneesh Sharma
    • , Yukiko Yamaguchi
    • , Hua Shen
    • , J Gage Crump
    •  & Henry M Sucov
  2. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

    • Christoph D Rau
    •  & Aldons J Lusis
  3. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Shan Parikh
    •  & Thomas I Force
  4. Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

    • Matt Denholtz
  5. Program of Developmental Biology and Regenerative Medicine, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.

    • Ying Huang
    •  & Ching-Ling Lien
  6. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Hooman Allayee
  7. Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Ching-Ling Lien
    •  & S Ram Kumar
  8. Developmental Neuroscience Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.

    • Takako Makita
  9. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Takako Makita


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M.P., L.B., B.V.H., P.G. and A.S. conducted laboratory analyses. C.D.R. contributed bioinformatics insight and analysis, and M.D. provided FISH probes. S.P. and T.I.F. provided Tnni3k conditional mice. M.D., Y.H., Y.Y. and H.S. gave technical guidance. H.A. and A.J.L. provided insight into the use of the HMDP, and A.J.L. provided most of the HMDP mice. J.G.C., C.-L.L., T.M. and A.J.L. provided conceptual advice. S.R.K. read and interpreted echocardiographic data and provided conceptual advice. The overall project was conceived by, data were interpreted by, and the manuscript was written by M.P. and H.M.S.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Henry M Sucov.

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