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c-kit+ cells minimally contribute cardiomyocytes to the heart.

van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, Middleton RC, Marbán E, Molkentin JD - Nature (2014)

Bottom Line: Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008.By contrast, c-kit(+) cells amply generated cardiac endothelial cells.Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Department of Medicine, division of Cardiology, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA [3].

ABSTRACT
If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit(+) cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.

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Related in: MedlinePlus

Analysis of eGFP+ myocytes in the hearts of Kit+/MCM × R-GFP mice after isoproterenol infusion-induced injurya, Schematic diagram showing tamoxifen treatment of Kit+/MCM × R-GFP mice between 7 and 14 weeks of age with isoproterenol (ISO) infusion occurring between weeks 10–14. b, c, Quantitation and imaging of disassociated cardiomyocytes (separate images shown at 2 different magnifications) from the hearts of ISO injured Kit+/MCM × R-GFP mice, which showed rare but definitive cardiomyocyte labeling. *P<0.05 vs R-GFP, 31 eGFP+ cells of 395,302 counted from 2 hearts.
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Figure 11: Analysis of eGFP+ myocytes in the hearts of Kit+/MCM × R-GFP mice after isoproterenol infusion-induced injurya, Schematic diagram showing tamoxifen treatment of Kit+/MCM × R-GFP mice between 7 and 14 weeks of age with isoproterenol (ISO) infusion occurring between weeks 10–14. b, c, Quantitation and imaging of disassociated cardiomyocytes (separate images shown at 2 different magnifications) from the hearts of ISO injured Kit+/MCM × R-GFP mice, which showed rare but definitive cardiomyocyte labeling. *P<0.05 vs R-GFP, 31 eGFP+ cells of 395,302 counted from 2 hearts.

Mentions: Cardiac injury increases cellular turnover in the heart, hence we subjected Kit+/MCM × R-GFP mice to MI at 10 weeks of age during a 6 week tamoxifen labeling protocol (Fig. 3k and Extended Data Fig. 6d–f). The percentage of eGFP+ cardiomyocytes increased to 0.016% within the heart, with more being localized to the infarct border zone (Fig. 3l, m, n). c-kit+ lineage cells within the heart were also pre-labeled by giving tamoxifen only before MI injury, which again showed a very low percentage of eGFP+ cardiomyocytes (Fig. 3o, p). Percentages of eGFP+ cardiomyocytes in the heart during 4 weeks of isoproterenol infusion-induced injury were 0.007% (Extended Data Fig. 7a–c). These astonishingly low values of cardiomyocyte formation were independently verified using blinded heart histological sections from Kit+/MCM × R-GFP mice sent to an outside academic laboratory (Extended Data Fig. 8a, b, c).


c-kit+ cells minimally contribute cardiomyocytes to the heart.

van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, Middleton RC, Marbán E, Molkentin JD - Nature (2014)

Analysis of eGFP+ myocytes in the hearts of Kit+/MCM × R-GFP mice after isoproterenol infusion-induced injurya, Schematic diagram showing tamoxifen treatment of Kit+/MCM × R-GFP mice between 7 and 14 weeks of age with isoproterenol (ISO) infusion occurring between weeks 10–14. b, c, Quantitation and imaging of disassociated cardiomyocytes (separate images shown at 2 different magnifications) from the hearts of ISO injured Kit+/MCM × R-GFP mice, which showed rare but definitive cardiomyocyte labeling. *P<0.05 vs R-GFP, 31 eGFP+ cells of 395,302 counted from 2 hearts.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127035&req=5

Figure 11: Analysis of eGFP+ myocytes in the hearts of Kit+/MCM × R-GFP mice after isoproterenol infusion-induced injurya, Schematic diagram showing tamoxifen treatment of Kit+/MCM × R-GFP mice between 7 and 14 weeks of age with isoproterenol (ISO) infusion occurring between weeks 10–14. b, c, Quantitation and imaging of disassociated cardiomyocytes (separate images shown at 2 different magnifications) from the hearts of ISO injured Kit+/MCM × R-GFP mice, which showed rare but definitive cardiomyocyte labeling. *P<0.05 vs R-GFP, 31 eGFP+ cells of 395,302 counted from 2 hearts.
Mentions: Cardiac injury increases cellular turnover in the heart, hence we subjected Kit+/MCM × R-GFP mice to MI at 10 weeks of age during a 6 week tamoxifen labeling protocol (Fig. 3k and Extended Data Fig. 6d–f). The percentage of eGFP+ cardiomyocytes increased to 0.016% within the heart, with more being localized to the infarct border zone (Fig. 3l, m, n). c-kit+ lineage cells within the heart were also pre-labeled by giving tamoxifen only before MI injury, which again showed a very low percentage of eGFP+ cardiomyocytes (Fig. 3o, p). Percentages of eGFP+ cardiomyocytes in the heart during 4 weeks of isoproterenol infusion-induced injury were 0.007% (Extended Data Fig. 7a–c). These astonishingly low values of cardiomyocyte formation were independently verified using blinded heart histological sections from Kit+/MCM × R-GFP mice sent to an outside academic laboratory (Extended Data Fig. 8a, b, c).

Bottom Line: Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008.By contrast, c-kit(+) cells amply generated cardiac endothelial cells.Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Department of Medicine, division of Cardiology, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA [3].

ABSTRACT
If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit(+) cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit(+) cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit(+) cells amply generated cardiac endothelial cells. Thus, endogenous c-kit(+) cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.

Show MeSH
Related in: MedlinePlus