Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy
Résumé
Key cell types including skeletal muscle have proven difficult to differentiate in
vitro from pluripotent cells. During embryonic development, skeletal muscles
arise from somites, which derive from the presomitic mesoderm (PSM). Based on
our understanding of PSM development, we established serum-free conditions
allowing efficient differentiation of monolayer cultures of mouse embryonic stem
(ES) cells into PSM-like cells without introduction of exogenous genetic material
or cell sorting. We show that primary and secondary skeletal myogenesis can be
recapitulated in vitro from these PSM-like cells. Our strategy allowed for the
production of striated contractile fibers from mouse and human pluripotent cells
in vitro with an efficiency comparing with current cardiomyocytes differentiation
protocols. We also differentiated ES cells into Pax7-positive cells with satellite
cell characteristics, including the ability to generate dystrophin-positive fibers
when grafted into muscles from dystrophin-deficient mdx mice. We show that
differentiated ES cells derived from mdx mice exhibit a striking branched
phenotype resembling that described in vivo, thus providing an attractive model
to study the origin of the pathological defects associated with Duchenne
Muscular Dystrophy.
Origine : Fichiers produits par l'(les) auteur(s)
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