A myocardial lineage derives from Tbx18 epicardial cells

Abstract

Understanding the origins and roles of cardiac progenitor cells is important for elucidating the pathogenesis of congenital and acquired heart diseases1,2. Moreover, manipulation of cardiac myocyte progenitors has potential for cell-based repair strategies for various myocardial disorders3. Here we report the identification in mouse of a previously unknown cardiac myocyte lineage that derives from the proepicardial organ. These progenitor cells, which express the T-box transcription factor Tbx18, migrate onto the outer cardiac surface to form the epicardium, and then make a substantial contribution to myocytes in the ventricular septum and the atrial and ventricular walls. Tbx18-expressing cardiac progenitors also give rise to cardiac fibroblasts and coronary smooth muscle cells. The pluripotency of Tbx18 proepicardial cells provides a theoretical framework for applying these progenitors to effect cardiac repair and regeneration.

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Figure 1: LacZ expression in Tbx18:nlacZ knock-in mice recapitulates endogenous Tbx18 expression.
Figure 2: Cells derived from Tbx18- expressing cells are observed within the heart by E10.5, and exhibit a cardiomyocyte identity.
Figure 3: Tbx18 lineage tracing in the adult heart.
Figure 4: Tbx18- expressing progenitors within proepicardium are distinct, and retain the capacity to differentiate into cardiomyocytes and smooth muscle cells in vitro.

Change history

  • 03 July 2008

    In the AOP version of this paper, Lei Yang was incorrectly affiliated to the Complex Carbohydrate Research Centre, University of Georgia, Athens, Georgia 30602, USA. The correct affiliation is Skaggs School of Pharmacy, University of California, San Diego, La Jolla, California 92093, USA. This was corrected for print on 3 July 2008.

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Acknowledgements

We thank A. Kleckner, J. Lam and M. Zamora for critical technical assistance; D. Bader for discussion; P. Soriano and F. Costantini for providing R26RlacZ and R26REYFP indicator mice; H. Kubo for providing OP9 cells; and J. Lin, D. Fischman and A. Kolodkin for providing troponin I, Pdgfrb and neuropilin 1 antibodies, respectively. We are also grateful to B. Gelb for his critical comments and revisions of the manuscript. This work was supported by AHA National Scientist Development Grant to C.-L.C. and NIH1RO1 to S.M.E.

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Correspondence to Sylvia M. Evans.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-14 with Legends in support of the paper’s conclusions. Supplementary Figure S1 depicts a working model elucidating how Tbx18-expressing proepicardial/epicardial cells contribute to heart formation. (PDF 1665 kb)

Supplementary Movie

This file contains an AVI Supplementary Movie 1 of beating cells from the single-cell clonal analysis in support of our conclusion that cells of the proepicardium have the ability to differentiate into cardiac myocytes. (AVI 76804 kb)

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Cai, C., Martin, J., Sun, Y. et al. A myocardial lineage derives from Tbx18 epicardial cells. Nature 454, 104–108 (2008) doi:10.1038/nature06969

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