Core Transcription Factors Promote Induction of PAX3-Positive Skeletal Muscle Stem Cells

Highlights

• Persistent single MyoD can induce myogenic cells, not muscle stem cells

• The combination of Heyl, Klf4, Pax3, and transient MyoD can induce muscle stem cells

• Induced PAX3⁺ cells revealed incorporation into regenerating myofibers of DMD mice

Summary

The use of adult skeletal muscle stem cells (MuSCs) for cell therapy has been attempted for decades, but still encounters considerable difficulties. MuSCs derived from human induced pluripotent stem cells (hiPSCs) are promising candidates for stem cell therapy to treat Duchenne muscular dystrophy (DMD). Here we report that four transcription factors, HEYL, KLF4, MYOD, and PAX3, selected by comprehensive screening of different MuSC populations, enhance the derivation of PAX3-positive myogenic progenitors from fibroblasts and hiPSCs, using medium that promotes the formation of presomitic mesoderm. These induced PAX3-positive cells contribute efficiently to the repair of DMD-damaged myofibers and also reconstitute the MuSC population. These studies demonstrate how a combination of core transcription factors can fine-tune the derivation of MuSCs capable of contributing to the repair of adult skeletal muscle.