Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength

Yu Xin Wang¹, Adelaida R Palla², Andrew T V Ho², Daniel C L Robinson², Meenakshi Ravichandran², Glenn J Markov², Thach Mai², Chris Still 2nd³, Akshay Balsubramani⁴, Surag Nair⁵, Colin A Holbrook², Ann V Yang², Peggy E Kraft², Shiqi Su¹, David M Burns², Nora D Yucel², Lei S Qi⁶, Anshul Kundaje⁴, Helen M Blau⁷

Affiliations

¹ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA; Center for Genetic Disorders and Aging, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
² Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA, USA; Department of Computer Science, Stanford University, Stanford, CA, USA.
⁵ Department of Genetics, Stanford University, Stanford, CA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
⁷ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA. Electronic address: hblau@stanford.edu.

PMID: 40513560
DOI: 10.1016/j.stem.2025.05.012

Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength

Yu Xin Wang et al. Cell Stem Cell. 2025.

. 2025 Jul 3;32(7):1154-1169.e9.

doi: 10.1016/j.stem.2025.05.012. Epub 2025 Jun 12.

Authors

Affiliations

¹ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA; Center for Genetic Disorders and Aging, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
² Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA, USA; Department of Computer Science, Stanford University, Stanford, CA, USA.
⁵ Department of Genetics, Stanford University, Stanford, CA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, CA, USA; Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA; ChEM-H, Stanford University, Stanford, CA, USA.
⁷ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305-5175, USA. Electronic address: hblau@stanford.edu.

PMID: 40513560
DOI: 10.1016/j.stem.2025.05.012

Abstract

Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.

Keywords: Prostaglandin E2; aging; epigenetic remodeling; inflammaging; molecular memory; muscle stem cells; neural network analysis; regeneration; rejuvenation; sarcopenia.

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Conflict of interest statement

Declaration of interests A.R.P., A.T.V.H., and H.M.B. are named inventors on patents on PGE2 for muscle regeneration and rejuvenation licensed to Epirium Bio. A.T.V.H. and H.M.B. are consultants and H.M.B. serves on the scientific advisory board of Epirium Bio.

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Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength

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Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength

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