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Inaugural Article

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Andrew T. V. Ho, Adelaida R. Palla, Matthew R. Blake, Nora D. Yucel, Yu Xin Wang, Klas E. G. Magnusson, Colin A. Holbrook, Peggy E. Kraft, Scott L. Delp, and Helen M. Blau
  1. aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
  2. bDepartment of Signal Processing, Autonomic Complex Communication Networks, Signals and Systems Linnaeus Centre, Kungliga Tekniska Högskolan Royal Institute of Technology, 100 44 Stockholm, Sweden;
  3. cDepartment of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305

See allHide authors and affiliations

PNAS June 27, 2017 114 (26) 6675-6684; first published June 12, 2017; https://doi.org/10.1073/pnas.1705420114
Andrew T. V. Ho
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Adelaida R. Palla
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Matthew R. Blake
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Nora D. Yucel
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Yu Xin Wang
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Klas E. G. Magnusson
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
bDepartment of Signal Processing, Autonomic Complex Communication Networks, Signals and Systems Linnaeus Centre, Kungliga Tekniska Högskolan Royal Institute of Technology, 100 44 Stockholm, Sweden;
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Colin A. Holbrook
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Peggy E. Kraft
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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Scott L. Delp
cDepartment of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305
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Helen M. Blau
aBaxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94305-5175;
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  • For correspondence: hblau@stanford.edu
  1. Contributed by Helen M. Blau, May 15, 2017 (sent for review April 3, 2017; reviewed by Douglas P. Millay and Fabio M. V. Rossi)

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Significance

Muscle repair after injury entails an immune response that orchestrates efficacious regeneration. Here we identify Prostaglandin E2 (PGE2) as a crucial inflammatory mediator of muscle stem cells (MuSCs), the building blocks of muscle regeneration. PGE2 is synthesized and secreted into the stem-cell niche in response to injury, leading to robust MuSC proliferation, key to myofiber repair. EP4 is the receptor that mediates PGE2 signaling in MuSCs, and genetically engineered mice that lack EP4 in MuSCs have impaired regeneration. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used to treat pain after muscle injury, inhibit PGE2 synthesis, hinder muscle regeneration, and lead to weakened muscles. Importantly, a single treatment of injured muscles with PGE2 dramatically accelerates muscle repair and recovery of strength.

Abstract

Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

  • muscle stem cells
  • PGE2
  • regeneration
  • NSAIDs
  • strength

Footnotes

  • ↵1A.T.V.H. and A.R.P. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: hblau{at}stanford.edu.
  • This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.

  • Author contributions: A.T.V.H., A.R.P., S.L.D., and H.M.B. designed research; A.T.V.H., A.R.P., M.R.B., N.D.Y., Y.X.W., C.A.H., and P.E.K. performed research; A.T.V.H., A.R.P., M.R.B., N.D.Y., K.E.G.M., C.A.H., and H.M.B. analyzed data; and A.T.V.H., A.R.P., and H.M.B. wrote the paper.

  • Reviewers: D.P.M., Cincinnati Children’s Hospital Medical Center; and F.M.V.R., The Biomedical Research Center.

  • Conflict of interest statement: A.T.V.H., A.R.P., and H.M.B. are named inventors on a patent related to the findings in this paper. H.M.B. and S.L.D. are cofounders of the company Myoforte.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE97375).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1705420114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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PGE2 targets muscle stem cells during regeneration
Andrew T. V. Ho, Adelaida R. Palla, Matthew R. Blake, Nora D. Yucel, Yu Xin Wang, Klas E. G. Magnusson, Colin A. Holbrook, Peggy E. Kraft, Scott L. Delp, Helen M. Blau
Proceedings of the National Academy of Sciences Jun 2017, 114 (26) 6675-6684; DOI: 10.1073/pnas.1705420114

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PGE2 targets muscle stem cells during regeneration
Andrew T. V. Ho, Adelaida R. Palla, Matthew R. Blake, Nora D. Yucel, Yu Xin Wang, Klas E. G. Magnusson, Colin A. Holbrook, Peggy E. Kraft, Scott L. Delp, Helen M. Blau
Proceedings of the National Academy of Sciences Jun 2017, 114 (26) 6675-6684; DOI: 10.1073/pnas.1705420114
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