Pluripotent stem cell-derived myogenic progenitors remodel their molecular signature upon in vivo engraftment

Tania Incitti, Alessandro Magli, Radbod Darabi, Ce Yuan, Karena Lin, Robert W. Arpke, Karim Azzag, Ami Yamamoto, Ron Stewart, James A. Thomson, Michael Kyba, Rita C.R. Perlingeiro

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Optimal cell-based therapies for the treatment of muscle degenerative disorders should not only regenerate fibers but provide a quiescent satellite cell pool ensuring long-term maintenance and regeneration. Conditional expression of Pax3/Pax7 in differentiating pluripotent stem cells (PSCs) allows the generation of myogenic progenitors endowed with enhanced regenerative capacity. To identify the molecular determinants underlying their regenerative potential, we performed transcriptome analyses of these cells along with primary myogenic cells from several developmental stages. Here we show that in vitro-generated PSC-derived myogenic progenitors possess a molecular signature similar to embryonic/fetal myoblasts. However, compared with fetal myoblasts, following transplantation they show superior myofiber engraftment and ability to seed the satellite cell niche, respond to multiple reinjuries, and contribute to long-term regeneration. Upon engraftment, the transcriptome of reisolated Pax3/Pax7–induced PSC-derived myogenic progenitors changes toward a postnatal molecular signature, particularly in genes involved in extracellular matrix remodeling. These findings demonstrate that Pax3/Pax7–induced myogenic progenitors remodel their molecular signature and functionally mature upon in vivo exposure to the adult muscle environment.

Original languageEnglish (US)
Pages (from-to)4346-4351
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number10
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. The authors are grateful to Scott Swanson for initial help with bioinformatics analyses, Juan Abrahante Lloréns for assistance with scRNA-seq analysis, and Neha Dhoke for suggestions on migration assays. This project was supported by NIH Grants R01 AR055299 (to R.C.R.P.), AR071439 (to R.C.R.P.), and AR055685 (to M.K.), U01 HL100407R01 (to R.C.R.P., M.K., and J.A.T.), MDA351022 (to M.K.), ADVault, Inc. and MyDirectives.com (R.C.R.P.), and Regenerative Medicine Minnesota (A.M.).

Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.

Keywords

  • Pax3
  • Pax7
  • Pluripotent stem cell
  • Skeletal myogenesis
  • Transcriptome analysis

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