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Sci. Adv., 31 Jul 2026 Vol 12, Issue 31 | https://doi.org/10.1126/sciadv.aei7316 TRF2 couples muscle stem cell identity to regenerative repair

Ji-Hyung Lee¹, Kiran Kumar Nakka^2,3,4, Ryan P. Calhoun^5,6, Sarah Hachmer⁷, Adity Gupta⁷, Eric Arreza^2,3, Lynn A. Megeney^2,3, Patrick Seale^5,6, Roger A. Greenberg⁸, F. Jeffrey Dilworth^2,3,7, Foteini Mourkioti^1,5,9*

¹Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²Sprott Center for Stem Cell Re-search, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
³Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, College Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
⁵Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wi53706, USA.
⁸Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹Institute for Regenerative Medicine, Musculoskeletal Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

^*Corresponding author.

Abstract

Stem cell–mediated regeneration is essential for tissue integrity. In skeletal muscle, tissue repair largely depends on muscle stem cells (MuSCs), which undergo dynamic cell-state transitions through making precise fate decisions during regeneration. However, the molecular regulators of cell-state conversion in MuSCs remain unclear. Here, we identify a previously unrecognized, noncanonical role for TRF2 in MuSC biology. TRF2 is dynamically regulated upon injury and required to preserve stem cell identity, support reparative myogenesis, and sustain self-renewal. MuSC-specific TRF2 disruption exacerbates muscular dystrophy pathology in mice, recapitulating key features of human disease. Mechanistically, TRF2 associates with regulatory regions enriched for DNA G-quadruplex–forming sequences at lineage-specific genes, sustaining their expression. These findings establish TRF2 as a pivotal regulator of adult stem cell function and tissue-specific regenerative responses.

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