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

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

doi:10.1016/j.stemcr.2019.06.006

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

Stem Cell Reports. 2019 Aug 13;13(2):352-365. doi: 10.1016/j.stemcr.2019.06.006. Epub 2019 Jul 25.

Authors

Takahiko Sato¹, Koki Higashioka², Hidetoshi Sakurai³, Takuya Yamamoto⁴, Naoki Goshima⁵, Morio Ueno⁶, Chie Sotozono⁶

Affiliations

¹ Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Anatomy, Fujita Health University, Toyoake, Aichi, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Chiyoda, Tokyo, Japan. Electronic address: takahiko@koto.kpu-m.ac.jp.
² Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
³ Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
⁴ Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; AMED-CREST, AMED, 1-7-1 Otemachi, Chiyoda, Tokyo, Japan.
⁵ Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
⁶ Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Abstract

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.

Keywords: Pax3; hiPSC; muscle stem cell; muscular dystrophy; reprogramming.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Differentiation
Disease Models, Animal
Dystrophin / deficiency
Dystrophin / genetics
Fibroblasts / cytology
Fibroblasts / metabolism
Humans
Induced Pluripotent Stem Cells / cytology*
Induced Pluripotent Stem Cells / metabolism
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Mesoderm / cytology
Mesoderm / metabolism
Mice
Mice, Inbred NOD
Mice, Knockout
Muscle Development
Muscle, Skeletal / cytology*
Muscle, Skeletal / metabolism
Muscular Dystrophy, Duchenne / therapy
MyoD Protein / genetics
MyoD Protein / metabolism
PAX3 Transcription Factor / genetics
PAX3 Transcription Factor / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Stem Cell Transplantation
Stem Cells / cytology
Stem Cells / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Dystrophin
HEYL protein, human
KLF4 protein, human
Klf4 protein, mouse
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
MyoD Protein
PAX3 Transcription Factor
Repressor Proteins