Muscle xenografts reproduce key molecular features of facioscapulohumeral muscular dystrophy

Amber L. Mueller, Andrea O'Neill, Takako I. Jones, Anna Llach, Luis Alejandro Rojas, Paraskevi Sakellariou, Guido Stadler, Woodring E Wright, David Eyerman, Peter L. Jones, Robert J. Bloch

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Aberrant expression of DUX4, a gene unique to humans and primates, causes Facioscapulohumeral Muscular Dystrophy-1 (FSHD), yet the pathogenic mechanism is unknown. As transgenic overexpression models have largely failed to replicate the genetic changes seen in FSHD, many studies of endogenously expressed DUX4 have been limited to patient biopsies and myogenic cell cultures, which never fully differentiate into mature muscle fibers. We have developed a method to xenograft immortalized human muscle precursor cells from patients with FSHD and first-degree relative controls into the tibialis anterior muscle compartment of immunodeficient mice, generating human muscle xenografts. We report that FSHD cells mature into organized and innervated human muscle fibers with minimal contamination of murine myonuclei. They also reconstitute the satellite cell niche within the xenografts. FSHD xenografts express DUX4 and DUX4 downstream targets, retain the 4q35 epigenetic signature of their original donors, and express a novel protein biomarker of FSHD, SLC34A2. Ours is the first scalable, mature in vivo human model of FSHD. It should be useful for studies of the pathogenic mechanism of the disease as well as for testing therapeutic strategies targeting DUX4 expression.

Original languageEnglish (US)
Article number113011
JournalExperimental Neurology
Volume320
DOIs
StatePublished - Oct 1 2019

Keywords

  • Biomarkers
  • DUX4
  • Facioscapulohumeral muscular dystrophy
  • FSHD
  • hMPCs
  • Hypomethylation
  • Satellite cells
  • Xenograft

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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  • Cite this

    Mueller, A. L., O'Neill, A., Jones, T. I., Llach, A., Rojas, L. A., Sakellariou, P., Stadler, G., Wright, W. E., Eyerman, D., Jones, P. L., & Bloch, R. J. (2019). Muscle xenografts reproduce key molecular features of facioscapulohumeral muscular dystrophy. Experimental Neurology, 320, [113011]. https://doi.org/10.1016/j.expneurol.2019.113011