Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras

J. Patrick Gonzalez, Sergii Kyrychenko, Kyrychenko Victoria, Joel S. Schneider, Celine J. Granier, Eric Himelman, Kevin C. Lahey, Qingshi Zhao, Ghassan Yehia, Yuan Xiang Tao, Mantu Bhaumik, Natalia Shirokova, Diego Fraidenraich

Research output: Contribution to journalArticle

Abstract

Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle. Inflammation, regeneration and fibrosis are observed at the whole organ level, both in dystrophin-negative and dystrophin-positive portions of the chimeric tissues. Skeletal and cardiac muscle function are also decreased to mdx levels. In contrast to mdx heterozygous carriers, which show no significant phenotypes, these effects are even observed in chimeras with low levels of mdx ESC incorporation (10%-30%). Chimeric mice lack typical compensatory utrophin upregulation, and show pathological remodeling of Connexin-43. In addition, dystrophin-negative and dystrophin-positive isolated cardiomyocytes show augmented calcium response to mechanical stress, similar to mdx cells. These global effects highlight a novel role of mdx ESCs in triggering muscular dystrophy even when only low amounts are present.

Original languageEnglish (US)
JournalStem Cells
DOIs
StateAccepted/In press - 2016
Externally publishedYes

Fingerprint

Dystrophin
Muscular Dystrophies
Embryonic Stem Cells
Myocardium
Skeletal Muscle
Duchenne Muscular Dystrophy
Mechanical Stress
Phenotype
Utrophin
Inbred mdx Mouse
Muscles
Connexin 43
Blastocyst
Cardiac Myocytes
Regeneration
Fibrosis
Up-Regulation
Pathology
Inflammation
Calcium

Keywords

  • Cardiomyopathy
  • Chimeras
  • Connexin-43
  • Dystrophin
  • Embryonic stem cells
  • Muscular dystrophy
  • Utrophin

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Gonzalez, J. P., Kyrychenko, S., Victoria, K., Schneider, J. S., Granier, C. J., Himelman, E., ... Fraidenraich, D. (Accepted/In press). Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras. Stem Cells. https://doi.org/10.1002/stem.2518

Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras. / Gonzalez, J. Patrick; Kyrychenko, Sergii; Victoria, Kyrychenko; Schneider, Joel S.; Granier, Celine J.; Himelman, Eric; Lahey, Kevin C.; Zhao, Qingshi; Yehia, Ghassan; Tao, Yuan Xiang; Bhaumik, Mantu; Shirokova, Natalia; Fraidenraich, Diego.

In: Stem Cells, 2016.

Research output: Contribution to journalArticle

Gonzalez, JP, Kyrychenko, S, Victoria, K, Schneider, JS, Granier, CJ, Himelman, E, Lahey, KC, Zhao, Q, Yehia, G, Tao, YX, Bhaumik, M, Shirokova, N & Fraidenraich, D 2016, 'Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras', Stem Cells. https://doi.org/10.1002/stem.2518
Gonzalez, J. Patrick ; Kyrychenko, Sergii ; Victoria, Kyrychenko ; Schneider, Joel S. ; Granier, Celine J. ; Himelman, Eric ; Lahey, Kevin C. ; Zhao, Qingshi ; Yehia, Ghassan ; Tao, Yuan Xiang ; Bhaumik, Mantu ; Shirokova, Natalia ; Fraidenraich, Diego. / Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras. In: Stem Cells. 2016.
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AU - Gonzalez, J. Patrick

AU - Kyrychenko, Sergii

AU - Victoria, Kyrychenko

AU - Schneider, Joel S.

AU - Granier, Celine J.

AU - Himelman, Eric

AU - Lahey, Kevin C.

AU - Zhao, Qingshi

AU - Yehia, Ghassan

AU - Tao, Yuan Xiang

AU - Bhaumik, Mantu

AU - Shirokova, Natalia

AU - Fraidenraich, Diego

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AB - Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle. Inflammation, regeneration and fibrosis are observed at the whole organ level, both in dystrophin-negative and dystrophin-positive portions of the chimeric tissues. Skeletal and cardiac muscle function are also decreased to mdx levels. In contrast to mdx heterozygous carriers, which show no significant phenotypes, these effects are even observed in chimeras with low levels of mdx ESC incorporation (10%-30%). Chimeric mice lack typical compensatory utrophin upregulation, and show pathological remodeling of Connexin-43. In addition, dystrophin-negative and dystrophin-positive isolated cardiomyocytes show augmented calcium response to mechanical stress, similar to mdx cells. These global effects highlight a novel role of mdx ESCs in triggering muscular dystrophy even when only low amounts are present.

KW - Cardiomyopathy

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