Ectopic expression of Msx2 in mammalian myotubes recapitulates aspects of amphibian muscle dedifferentiation
Abstract
In contrast to urodele amphibians and teleost fish, mammals lack the regenerative responses to replace large body parts. Amphibian and fish regeneration uses dedifferentiation, i.e., reversal of differentiated state, as a means to produce progenitor cells to eventually replace damaged tissues. Therefore, induced activation of dedif- ferentiation responses in mammalian tissues holds an immense promise for regenerative medicine. Here we demonstrate that ectopic expression of Msx2 in cultured mouse myotubes recapitulates several aspects of am- phibian muscle dedifferentiation. We found that MSX2, but not MSX1, leads to cellularization of myotubes and downregulates the expression of myotube markers, such as MHC, MRF4 and myogenin. RNA sequencing of myotubes ectopically expressing Msx2 showed downregulation of over 500 myotube-enriched transcripts and upregulation of over 300 myoblast-enriched transcripts. MSX2 selectively downregulated expression of Ptgs2 and Ptger4, two members of the prostaglandin pathway with important roles in myoblast fusion during muscle differentiation. Ectopic expression of Msx2, as well as Msx1, induced partial cell cycle re-entry of myotubes by up- regulating CyclinD1 expression but failed to initiate S-phase. Finally, MSX2-induced dedifferentiation in mouse myotubes could be recapitulated by a pharmacological treatment with trichostatin A (TSA), bone morphogenetic protein 4 (BMP4) and fibroblast growth factor 1 (FGF1). Together, these observations indicate that MSX2 is a major driver of dedifferentiation in mammalian muscle cells. Mehr anzeigen
Persistenter Link
https://doi.org/10.3929/ethz-b-000105335Publikationsstatus
publishedExterne Links
Zeitschrift / Serie
Stem Cell ResearchBand
Seiten / Artikelnummer
Verlag
ElsevierThema
Homeobox genes; Muscle stem cells; Reprogramming; Skeletal muscle; Tissue regeneration; Transcription factorsOrganisationseinheit
03992 - Schroeder, Timm / Schroeder, Timm
03748 - Paro, Renato (emeritus) / Paro, Renato (emeritus)
03790 - Beerenwinkel, Niko / Beerenwinkel, Niko