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  • 1
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    c-kit+ cells minimally contribute cardiomyocytes to the heart (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-05-09
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127035/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van Berlo, Jop H -- Kanisicak, Onur -- Maillet, Marjorie -- Vagnozzi, Ronald J -- Karch, Jason -- Lin, Suh-Chin J -- Middleton, Ryan C -- Marban, Eduardo -- Molkentin, Jeffery D -- P01 HL108806/HL/NHLBI NIH HHS/ -- P50 HL052318/HL/NHLBI NIH HHS/ -- P50 HL077101/HL/NHLBI NIH HHS/ -- R00 HL112852/HL/NHLBI NIH HHS/ -- R01 HL105924/HL/NHLBI NIH HHS/ -- R37 HL060562/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 15;509(7500):337-41. doi: 10.1038/nature13309. Epub 2014 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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]. ; 1] Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2]. ; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Cedars-Sinai Heart Institute, 8700 Beverly Boulevard, Los Angeles, California 90048, USA. ; 1] Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA [2] Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805242" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Cell Differentiation ; Cell Fusion ; *Cell Lineage ; Endothelial Cells/cytology/metabolism ; Female ; Heart/growth & development ; Heart Injuries/*pathology ; Integrases/genetics/metabolism ; Male ; Mice ; Models, Biological ; Myoblasts, Cardiac/*cytology/*metabolism ; Myocardium/*cytology ; Myocytes, Cardiac/*cytology/metabolism ; Proto-Oncogene Proteins c-kit/*metabolism ; Regeneration/physiology ; Tamoxifen/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-24
    Description: Muscular dystrophy (MD) is associated with mutations in genes that stabilize the myofiber plasma membrane, such as through the dystrophin–glycoprotein complex (DGC). Instability of this complex or defects in membrane repair/integrity leads to calcium influx and myofiber necrosis leading to progressive dystrophic disease. MD pathogenesis is also associated with increased skeletal muscle protease levels and activity that could augment weakening of the sarcolemma through greater degradation of cellular attachment complexes. Here, we observed a compensatory increase in the serine protease inhibitor Serpina3n in mouse models of MD and after acute muscle tissue injury. Serpina3n muscle-specific transgenic mice were generated to model this increase in expression, which reduced the activity of select proteases in dystrophic skeletal muscle and protected muscle from both acute injury with cardiotoxin and from chronic muscle disease in the mdx or Sgcd –/– MD genetic backgrounds. The Serpina3n transgene mitigated muscle degeneration and fibrosis, reduced creatine kinase serum levels, restored running capacity on a treadmill and reduced muscle membrane leakiness in vivo that is characteristic of mdx and Sgcd –/– mice. Mechanistically, we show that increased Serpina3n promotes greater sarcolemma membrane integrity and stability in dystrophic mouse models in association with increased membrane residence of the integrins, the DGC/utrophin–glycoprotein complex of proteins and annexin A1. Hence, Serpina3n blocks endogenous increases in the activity of select skeletal muscle resident proteases during injury or dystrophic disease, which stabilizes the sarcolemma leading to less myofiber degeneration and increased regeneration. These results suggest the use of select protease inhibitors as a strategy for treating MD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Myofiber-specific inhibition of TGF{beta} signaling protects skeletal muscle from injury and dystrophic disease in mice (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-27
    Description: Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-β has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFβ-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGFβ signaling owing to expression of a TGFβ type II receptor dominant-negative (dnTGFβRII) truncation mutant. Expression of dnTGFβRII in myofibers mitigated the dystrophic phenotype observed in -sarcoglycan-null ( Sgcd –/– ) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGFβRII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGFβRII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGFβ directly inhibited Mt gene expression in vitro , the dnTGFβRII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGFβ signaling in MD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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