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

Takahiko Sato,Koki Higashioka,Naoki Goshima,Hidetoshi Sakurai,Takuya Yamamoto,Chie Sotozono,Morio Ueno

doi:10.1016/j.stemcr.2019.06.006

Abstract

SummaryThe 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.

Highlights

The muscular dystrophies are a group of inherited skeletal muscle disorders characterized clinically by progressive muscle weakness and wasting
Transcription Factors that Induce Pax3-Positive Myogenic Cells we investigated the expression of potential regulatory genes in Pax3-GFP-positive cells isolated from skeletal muscle of fetal, postnatal, and adult mice (Figure S1A)
We first investigated whether expression of a combination of these transcription factors could induce Pax3-GFP-positive cells derived from mouse embryonic fibroblasts of Pax3-GFP;MyoD-tdTomato embryos

Summary

Introduction

The muscular dystrophies are a group of inherited skeletal muscle disorders characterized clinically by progressive muscle weakness and wasting. DMD is caused by mutations or deletions in the Dmd gene, which lead to loss of muscle fiber integrity and continuous muscle damage This damage leads to the rapid wasting of skeletal muscles, and there is as yet no cure, a number of promising approaches are being developed to retard the progression of DMD symptoms (Guiraud et al, 2015). MuSCs are closely associated with the muscle fiber, their description as satellite cells, and are normally quiescent, but begin to proliferate in response to muscle injury or during intense exercise. They enter the myogenic differentiation program, fuse with damaged myofibers or form de novo fibers, and reconstitute the quiescent MuSC population (Collins et al, 2005). Mouse MuSCs that have no Dmd mutation, when engrafted into the damaged muscle of DMD mice, contribute to the regeneration of DMD myofibers, which are positive for functional dystrophin protein (Cerletti et al, 2008)

Results

Discussion

Conclusion