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Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice
Shah R Ali1, Simon Hippenmeyer2, Lily V Saadat3
1Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; shah.ali@gmail.com irv@stanford.edu rardehali@mednet.ucla.edu.
Insights
The adult mammalian heart generates new cardiomyocytes through rare, symmetric cell divisions originating from differentiated cells. This process significantly decreases after the first month of life and is not increased by myocardial infarction.
Area of Science:
- Cardiology
- Developmental Biology
- Cell Biology
Background:
- The mammalian heart was historically considered a postmitotic organ with a fixed number of cardiomyocytes set at birth.
- Cardiomyocyte binucleation complicates traditional cell turnover assays, limiting understanding of postnatal cardiomyocyte generation.
- Previous studies using advanced techniques indicated a low rate of cardiomyocyte generation, but cellular origins remained unclear.
Purpose of the Study:
- To investigate the cell of origin for postnatal cardiomyogenesis in mammals.
- To characterize the division patterns and frequency of cardiomyocytes after birth.
- To determine if myocardial infarction influences cardiomyocyte division rates.
Main Methods:
- Utilized the "mosaic analysis with double markers" mouse model for clonal analysis of cardiomyocytes.
- Tracked cardiomyocyte division events from in utero development through postnatal life.
- Induced myocardial infarction via left anterior descending coronary artery ligation to assess cardiomyocyte response.
Main Results:
- Differentiated α-myosin heavy chain-expressing cardiomyocytes were identified as the source of postnatal cardiomyogenesis.
- Symmetric cardiomyocyte division is a rare, life-long event that diminishes significantly after the first month of life.
- Cardiomyocyte division rates did not increase following myocardial infarction up to 4 weeks post-injury.
Conclusions:
- Provides direct clonal evidence for postnatal mammalian cardiomyogenesis.
- Demonstrates that cardiomyocyte proliferation is a rare event with limited contribution to the cardiomyocyte pool after early life.
- Suggests that the adult heart has a very limited capacity for cardiomyocyte regeneration, even after injury.
Abstract:
The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326-335; Bergmann O, et al. (2009) Science 324(5923):98-102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433-436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the "mosaic analysis with double markers" mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.
