The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unravelling steps for cardiac cell lineage formation, and their links to forms of congenital and adult cardiac diseases1,2,3. Until now there has been little evidence for native cardiac precursor cells in the postnatal heart4. Herein, we report the identification of isl1+ cardiac progenitors in postnatal rat, mouse and human myocardium. A cardiac mesenchymal feeder layer allows renewal of the isolated progenitor cells with maintenance of their capability to adopt a fully differentiated cardiomyocyte phenotype. Tamoxifen-inducible Cre/lox technology enables selective marking of this progenitor cell population including its progeny, at a defined time, and purification to relative homogeneity. Co-culture studies with neonatal myocytes indicate that isl1+ cells represent authentic, endogenous cardiac progenitors (cardioblasts) that display highly efficient conversion to a mature cardiac phenotype with stable expression of myocytic markers (25%) in the absence of cell fusion, intact Ca2+-cycling, and the generation of action potentials. The discovery of native cardioblasts represents a genetically based system to identify steps in cardiac cell lineage formation and maturation in development and disease.
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We thank W. Giles for discussions and comments on the real-time Ca2+ measurements and electrophysiology, the National Center for Microscopy and Imaging Research at UCSD for the use of the high-speed multi-photon laser-scanning microscope (Bio-Rad RTS2000) and custom plug-ins for the ImageJ software (H. Hakozaki, S. Chow and M. Ellisman), the UCSD Cancer Center Digital Imaging Shared Resource for deconvolution microscopy (S. McMullen and J. Feramisco). We would like especially to acknowledge D. Young for his expertise and help in the FACS sorting analysis (UCSD Cancer Center Flow Cytometry Laboratories). This work was supported by the NIH and the Jean Le Ducq Foundation. K.-L.L. is a Heisenberg Scholar of the German Research Foundation.
The authors declare that they have no competing financial interests.
Evaluation of human, post-natal isl1+ progenitors in atrial tissue following pediatric surgical correction of diverse congenital heart defects. (DOC 33 kb)
Comparison of isl1+ cardioblasts, cardiac sca-1+ cells and cardiac side population (SP) cells. (DOC 39 kb)
Rare subset of isl1+ cardiac progenitors in double heterozygous isl1-mER-Cre-mER/R26R hearts in 2 month old animals in the outflow tract (a) and the right atrium (b). (PDF 133 kb)
Amplification of rat isl1+ progenitors on cardiac mesenchymal cells in vitro (a, b) and their phenotypic characterization (c). (PDF 116 kb)
Video demonstrating the [Ca2+]i transients of differentiated β-Gal+ progenitors. (MOV 9207 kb)
Real time calcium imaging of FACS-sorted β-Gal+ progenitors differentiated in coculture. (DOC 21 kb)
Methods regarding flow cytometry analysis, co-culture experiments, immunocytochemistry and lacZ staining, RT-PCR, detection of [Ca2+]i transients and electrophysiological action potential recordings are described in the supplementary method section. (DOC 35 kb)
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Laugwitz, KL., Moretti, A., Lam, J. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005). https://doi.org/10.1038/nature03215
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