Mesenchymal stem cells are recruited to striated muscle by NFAT/IL-4-mediated cell fusion

Mesenchymal stem cells (MSCs) or mesenchymal adult stem cells (MASCs) that are present in the stroma of several organs have been proposed to contribute to the regeneration of different tissues including liver, blood, heart, and skeletal muscle. Yet, it remains unclear whether MSCs can be programmed to differentiate cell-autonomously into fully functional cells or whether they are recruited by surrounding cells via fusion and thereby acquire specialized cellular functions. Here, we demonstrate that Wnt signaling molecules activate the expression of distinct sets of genes characteristic for cardiac and skeletal muscle cells in MASCs. However, such cells lack morphological criteria characteristic for functional muscle cells and do not show contractile activity. In contrast, MASCs fuse efficiently with native myotubes in an IL-4-dependent manner to form functional hybrid myotubes. Injection of genetically labeled MSCs into wild-type mouse blastocysts revealed a contribution to skeletal but not cardiac muscle development. Disruption of IL-4 and NFATc2/c3 reduced or prevented a contribution of adult stem cells to the development of IL-4 and NFATc2/c3 mutant embryos, further emphasizing the apparent inability of adult stem cells to differentiate fully into striated muscle in a cell-autonomous manner.