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. 2013 Jan 17;493(7432):433-6.
doi: 10.1038/nature11682. Epub 2012 Dec 5.

Mammalian heart renewal by pre-existing cardiomyocytes

Samuel E Senyo  1 , Matthew L Steinhauser, Christie L Pizzimenti, Vicky K Yang, Lei Cai, Mei Wang, Ting-Di Wu, Jean-Luc Guerquin-Kern, Claude P Lechene, Richard T Lee
Affiliations

Mammalian heart renewal by pre-existing cardiomyocytes

Samuel E Senyo et al. Nature. .

Abstract

Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes. Other studies suggest that new cardiomyocytes are born at a very low rate, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse-chase approaches--genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry--that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.

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Figures

Figure 1
Figure 1. Multi-isotope imaging mass spectrometry (MIMS) to study cardiomyocyte turnover
a) Primary question: are new cardiomyocytes are derived from progenitors or from pre-existing cardiomyocytes? b) 14N mass image. Subcellular details are evident, including cardiomyocyte nuclei (white arrows). Scale bar = 20μm. c) MIMS resolves periodic sarcomeres (black arrows) in cardiomyocytes. Non-cardiomyocytes (white arrows) are seen outside cardiomyocyte borders. Scale bar = 5μm. d) Hue saturation intensity (HSI) 15N:14N image of small intestinal epithelium after 15N-thymidine. The scale ranges from blue, where the ratio is equivalent to natural ratio (0.37%, expressed as 0% above natural ratio), to red, where the ratio is 150% above natural ratio. 15N-labeling is concentrated in nuclei in a pattern resembling chromatin. Scale bar = 15μm. e) HSI 15N:14N image of heart section (left ventricle). 15N-thymidine administered for 1 wk. Rare 15N-labeled interstitial cells (asterisk). Cardiomyocyte nuclei (white arrows) are unlabeled. Scale bar = 15μm.
Figure 2
Figure 2. Cardiomyocyte DNA synthesis decreases with age
a) 15N-thymidine administered for 8 wks to mice of different ages: Neonate: starting post-natal day 4, Young adult: starting at 2 mos, Old adult: starting at 22 mos. Top: 14N mass images show histologic details. Bottom: 15N:14N HSI images show 15N-labeled nuclei. Mosaics constructed of 9 tiles, 60μm each. Scale bar = 30μm. b) High magnification analysis demonstrates cardiomyocyte from the young adult with nuclear 15N-labeling (large arrow), two labeled non-cardiomyocytes (small arrows), and an adjacent unlabeled cardiomyocyte nucleus (medium arrow). Scale bar = 10μm. c) Age-related decline in cardiomyocyte DNA synthesis. Left: neonate compared to young adult. Right: Scale reduced to compare young adult to old adult (n=3 mice per group). Mean% ± S.E.M.
Figure 3
Figure 3. New cardiomyocytes are derived from pre-existing cardiomyocytes during aging
a) Experimental strategy. MerCreMer+/ZEG+ mice (n=4) treated for 2 wks with 4OH-tamoxifen to induce cardiomyocyte-specific GFP expression. 15N-thymidine administered continuously during 10 wk chase, then cycling cells identified by 15N-labeling. New cardiomyocytes (15N+) derived from preexisting cardiomyocytes should express GFP at a rate similar to surrounding quiescent (15N−) cardiomyocytes. New cardiomyocytes (15N+) derived from progenitors should be GFP−. b) Left: 15N:14N HSI image demonstrating 15N-thymidine labeled cardiomyocyte nucleus (white asterisk) and 15N-labeled non-cardiomyocyte (white arrow). Right: Immunofluorescent image showing 15N-labeled cardiomyocyte is GFP+. Scale bar = 15μm.
Figure 4
Figure 4. Myocardial injury stimulates division of pre-existing cardiomyocytes
a) Myocardial infarction (MI) leads to extensive DNA synthesis within and adjacent to scar (arrows). MerCreMer+/ZEG+ mice were treated for 2 wks with 4OH-tamoxifen to induce cardiomyocyte-specific GFP expression before MI or sham surgery, then 15N-thymidine administered continuously for 8wks. Mosaics of 70 60×60μm MIMS tiles. Trichrome stained adjacent section (far right) shows scar. Scale bars = 90μm. b) 15N-thymidine labeled cardiomyocyte nucleus (white arrows) from MI border region. Immunofluorescent staining demonstrates that the cardiomyocyte is GFP+. Scale bars = 10 μm. c) Mean % 15N+ cardiomyocyte nuclei after MI (n=4) in the scar border region compared to sham operated mice (n=3). Mean% ± S.E.M.
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