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Prostaglandin E2 Is Essential for Efficacious Skeletal Muscle Stem

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Prostaglandin E2 Is Essential for Efficacious Skeletal Muscle Stem Prostaglandin E2 is essential for efficacious skeletal INAUGURAL ARTICLE muscle stem-cell function, augmenting regeneration and strength Andrew T. V. Hoa,1, Adelaida R. Pallaa,1, Matthew R. Blakea, Nora D. Yucela, Yu Xin Wanga, Klas E. G. Magnussona,b, Colin A. Holbrooka, Peggy E. Krafta, Scott L. Delpc, and Helen M. Blaua,2 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; and cDepartment of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305 This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016. Contributed by Helen M. Blau, May 15, 2017 (sent for review April 3, 2017; reviewed by Douglas P. Millay and Fabio M. V. Rossi) Skeletal muscles harbor quiescent muscle-specific stem cells suggest that PGE2 can either promote myoblast proliferation or (MuSCs) capable of tissue regeneration throughout life. Muscle injury differentiation in culture (14–18). In the COX-2–knockout mouse precipitates a complex inflammatory response in which a multiplicity model, which lacks PGE2, regeneration is delayed. However, the of cell types, cytokines, and growth factors participate. Here we show mechanism by which PGE2 acts could not be established in these that Prostaglandin E2 (PGE2) is an inflammatory cytokine that di- studies due to the systemic constitutive loss of COX-2 and consequent rectly targets MuSCs via the EP4 receptor, leading to MuSC expansion. nonspecific effects on many cell types (15, 19). Similarly, muscle re- An acute treatment with PGE2 suffices to robustly augment muscle covery after injury was impaired in mice given a COX-2 inhibitor (15). regeneration by either endogenous or transplanted MuSCs. Loss of Additionally, mice treated with nonsteroidal anti-inflammatory drugs PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs (NSAIDs), which block the production of prostaglandins through impairs regeneration, leading to decreased muscle force. Inhibition of inhibition of COX-1 and COX-2, exhibited regeneration deficits (20, CELL BIOLOGY PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) 21). Moreover, NSAIDS lead to an attenuation of exercise-induced administration just after injury similarly hinders regeneration and expansion of human satellite cells in biopsies (20). Likewise, gluco- compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway corticoids, which reduce prostaglandin synthesis by suppressing that activates the proliferation-inducing transcription factor, Nurr1.Our phospholipase A2, COX-2, and mPGES1 expression, adversely affect findings reveal that loss of PGE2 signaling to MuSCs during recovery the recovery of muscle strength in polymyositis patients (22). How- from injury impedes muscle repair and strength. Through such gain- or ever, because the target of NSAIDs and glucocorticoids are the COX loss-of-function experiments, we found that PGE2 signaling acts as a enzymes, this effect could entail a number of prostaglandin subtypes rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC Significance function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intra- Muscle repair after injury entails an immune response that orches- muscular delivery of PGE2 suggests a previously unrecognized indica- trates efficacious regeneration. Here we identify Prostaglandin E2 tion for this therapeutic agent. (PGE2) as a crucial inflammatory mediator of muscle stem cells (MuSCs), the building blocks of muscle regeneration. PGE2 is syn- muscle stem cells | PGE2 | regeneration | NSAIDs | strength thesized and secreted into the stem-cell niche in response to injury, leading to robust MuSC proliferation, key to myofiber repair. EP4 is atellite cells, also known as muscle stem cells (MuSCs), are the receptor that mediates PGE2 signaling in MuSCs, and genetically Scrucial to muscle regeneration. They reside in a quiescent engineered mice that lack EP4 in MuSCs have impaired regenera- state in niches juxtaposed to myofibers in muscle tissues, poised to tion. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly respond to damage and repair skeletal muscles throughout life (1– used to treat pain after muscle injury, inhibit PGE2 synthesis, hinder 4). Muscle injury precipitates an inflammatory response that is muscle regeneration, and lead to weakened muscles. Importantly, a marked by the sequential infiltration of multiple cell types, including single treatment of injured muscles with PGE2 dramatically accel- neutrophils, monocytes, macrophages, T cells, and fibroadipocytes, erates muscle repair and recovery of strength. and is accompanied by MuSC activation. During this inflammatory Author contributions: A.T.V.H., A.R.P., S.L.D., and H.M.B. designed research; A.T.V.H., phase, concurrent waves of cytokines and growth factors are released, 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., including CC-chemokine ligand 2 (CCL2), IL-10, IL-1β, tumor ne- 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 crosis factor-α (TNFα), and transforming growth factor-β1(TGFβ1) H.M.B. wrote the paper. (3, 5–10). In addition, prostaglandins, potent lipid mediators of in- Reviewers: D.P.M., Cincinnati Children’s Hospital Medical Center; and F.M.V.R., The Bio- flammation, are synthesized and secreted by immune and myogenic medical Research Center. cells (6, 11). Prostaglandins derive from arachidonic acid, which is 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. released from membrane phospholipids by phospholipase A2 and Freely available online through the PNAS open access option. converted by cyclooxygenase enzymes (COX-1 and -2) into prosta- Data deposition: The data reported in this paper have been deposited in the Gene glandin H2 (PGH2) and subsequently into the different prostaglan- Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. din subtypes, PGD2, PGE2, PGF2α, PGI2, or thromboxane (TXA2). GSE97375). Specific to the generation of PGE2 are the prostaglandin synthases 1A.T.V.H. and A.R.P. contributed equally to this work. (PGES: mPGES-1, mPGES-2, and cPGES) (11–13). 2To whom correspondence should be addressed. Email: [email protected]. PGE2 has been associated with muscle regeneration, however This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. its specific mode of action remains unclear. Conflicting reports 1073/pnas.1705420114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1705420114 PNAS | June 27, 2017 | vol. 114 | no. 26 | 6675–6684 Downloaded by guest on September 26, 2021 in addition to PGE2 and therefore have pleiotropic effects. Thus, to loss-of-function experiments revealed that PGE2 signaling acts as a date, the spatiotemporal effects of PGE2 in muscle regeneration rheostat for MuSC function. Our data suggest that PGE2 profoundly remain unresolved. impacts regeneration and has therapeutic promise. In response to injury, PGE2 is transiently induced in muscle tis- sues. To establish if PGE2 acts directly on MuSCs, the building Results blocks of muscle regeneration, we generated mice in which the A Surge of PGE2 in Damaged Muscle Tissues Accelerates MuSC PGE2 receptor, EP4, could be conditionally ablated in MuSCs. In Proliferation. We sought to identify an activator of MuSC function addition, we established transgenic reporter mice that enabled spe- by capitalizing on an inflammatory response that mediates muscle cific tracking of MuSC contribution to regeneration dynamically and regeneration. Because muscle injury triggers an immediate in- sensitively over time by bioluminescence imaging (BLI) after flammatoryresponse(5,7,8,23),we hypothesized that a transiently PGE2 delivery. We coupled these models with assays of muscle force induced inflammatory modulator could regulate MuSC function and found a direct link between the ability of MuSCs to respond to and play a crucial role in regeneration. We performed qRT-PCR PGE2 and regeneration, leading to restoration of force. Gain- and and detected increased levels of the Ptger4 receptor (EP4) for A B C Notexin injury DAPI PGE2 LAMININ ∗∗∗ 8 12 ∗∗∗ ∗∗ Control 6 Injured 8 4 3d post-injury GE2/mg protein) Gapdh 4 P to 2 mRNA levels relative 0 0 PGE2 (ng Ptger4 Fresh Cultured Myoblasts Myoblasts 01234567 MuSCs MuSCs GM DM Days post-NTX injury 6d post-injury D PGE2 synthetizing enzymes E Fibers conditioned medium F AcutePGE2 6 ∗∗ ∗∗ 1.0 ∗∗ d0 d1 assay d7 Gapdh Injured Ptges ∗∗ Control Ptges 0.8 100 4 Injured Ptges2 Control Ptges2 0.6 50 2 0.4 PGE2 (ng/ml) 0.2 0 0.0 0 024616 (day 7 relative to day 0) mRNA levels relative to Vehicle Indo Vehicle PGE2 Days post-NTX injury Fold change in MuSC number GHVehicle AcutePGE2 Timelapse imaging Time (h) -24 0 38 G5 400 Vehicle PGE2 350 300 G5 G4 PGE2 250 G4 200 G3 G3 150 G2 G1 G2 G1 100 Normailzed cell count 50 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 mitosis Time (hours) Time (hours) X death IJK ∗∗∗∗ 40 (h) 40 End 600 ∗∗∗∗ Vehicle ) 30 PGE2 30 2 400 ion time s i 20 v 20 st di 200 Frequency (%) 10 10 Cell size (µm ve 1 i 0 0 Start of 0 0 5 10 15 20 25 30 35 Relat Vehicle PGE2 Timelapse Vehicle PGE2 Time to division after plating (h) Fig.
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