The CXCR4/SDF1 axis participates in various cellular processes, including cell migration, which is essential for skeletal muscle repair. Although increasing evidence has confirmed the role of CXCR4/SDF1 in embryonic muscle development, the function of this pathway during adult myogenesis remains to be fully elucidated. In addition, a role for CXCR4 signaling in muscle maintenance and repair has only recently emerged. Here, we have demonstrated that CXCR4 and stromal cell-derived factor-1 (SDF1) are up-regulated in injured muscle, suggesting their involvement in the repair process. In addition, we found that notexin-damaged muscles showed delayed muscle regeneration on treatment with CXCR4 agonist (AMD3100). Accordingly, small-interfering RNA-mediated silencing of SDF1 or CXCR4 in injured muscles impaired muscle regeneration, whereas the addition of SDF1 ligand accelerated repair. Furthermore, we identified that CXCR4/SDF1-regulated muscle repair was dependent on matrix metalloproteinase-10 (MMP-10) activity. Thus, our findings support a model in which MMP-10 activity modulates CXCR4/SDF1 signaling, which is essential for efficient skeletal muscle regeneration.
MossFP and LeblondCP. (1971). Satellite cells as the source of nuclei in muscles of growing rats. Anat Rec, 170:421–435.
3.
CollinsCA, OlsenI, ZammitPS, HeslopL, PetrieA, PartridgeTA and MorganJE. (2005). Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell, 122:289–301.
4.
ChargeSB and RudnickiMA. (2004). Cellular and molecular regulation of muscle regeneration. Physiol Rev, 84:209–238.
5.
HughesSM and BlauHM. (1990). Migration of myoblasts across basal lamina during skeletal muscle development. Nature, 345:350–353.
6.
BroxmeyerHE. (2001). Regulation of hematopoiesis by chemokine family members. Int J Hematol, 74:9–17.
7.
NagasawaT, NakajimaT, TachibanaK, IizasaH, BleulCC, YoshieO, MatsushimaK, YoshidaN, SpringerTA and KishimotoT. (1996). Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc Natl Acad Sci U S A, 93:14726–14729.
8.
LapidotT, DarA and KolletO. (2005). How do stem cells find their way home?. Blood, 106:1901–1910.
9.
WangK, ZhaoX, KuangC, QianD, WangH, JiangH, DengM and HuangL. (2012). Overexpression of SDF-1alpha enhanced migration and engraftment of cardiac stem cells and reduced infarcted size via CXCR4/PI3K pathway. PLoS One, 7:e43922
10.
PercherancierY, BerchicheYA, SlightI, Volkmer-EngertR, TamamuraH, FujiiN, BouvierM and HevekerN. (2005). Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers. J Biol Chem, 280:9895–9903.
11.
SharmaM, AfrinF, SatijaN, TripathiRP and GangenahalliGU. (2011). Stromal-derived factor-1/CXCR4 signaling: indispensable role in homing and engraftment of hematopoietic stem cells in bone marrow. Stem Cells Dev, 20:933–946.
WongD and KorzW. (2008). Translating an antagonist of chemokine receptor CXCR4: from bench to bedside. Clin Cancer Res, 14:7975–7980.
14.
BroxmeyerHE, CooperS, KohliL, HangocG, LeeY, MantelC, ClappDW and KimCH. (2003). Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo. J Immunol, 170:421–429.
15.
LatailladeJJ, ClayD, BourinP, HerodinF, DupuyC, JasminC and Le Bousse-KerdilesMC. (2002). Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood, 99:1117–1129.
16.
KonoplyannikovM, HaiderKH, LaiVK, AhmedRP, JiangS and AshrafM. (2013). Activation of diverse signaling pathways by ex-vivo delivery of multiple cytokines for myocardial repair. Stem Cells Dev, 22:204–215.
17.
AskariAT, UnzekS, PopovicZB, GoldmanCK, ForudiF, KiedrowskiM, RovnerA, EllisSG, ThomasJD, et al. (2003). Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet, 362:697–703.
18.
HuX, DaiS, WuWJ, TanW, ZhuX, MuJ, GuoY, BolliR and RokoshG. (2007). Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation, 116:654–663.
19.
SchoberA. (2008). Chemokines in vascular dysfunction and remodeling. Arterioscler Thromb Vasc Biol, 28:1950–1959.
20.
HoTK, TsuiJ, XuS, LeoniP, AbrahamDJ and BakerDM. (2012). Angiogenic effects of stromal cell-derived factor-1 (SDF-1/CXCL12) variants in vitro and the in vivo expressions of CXCL12 variants and CXCR4 in human critical leg ischemia. J Vasc Surg, 51:689–699.
21.
ToupadakisCA, WongA, GenetosDC, ChungDJ, MurugeshD, AndersonMJ, LootsGG, ChristiansenBA, KapatkinAS and YellowleyCE. (2012). Long-term administration of AMD3100, an antagonist of SDF-1/CXCR4 signaling, alters fracture repair. J Orthop Res, 30:1853–1859.
22.
LiburaJ, DrukalaJ, MajkaM, TomescuO, NavenotJM, KuciaM, MarquezL, PeiperSC, BarrFG, Janowska-WieczorekA and RatajczakMZ. (2002). CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood, 100:2597–2606.
23.
FernandisAZ, PrasadA, BandH, KloselR and GanjuRK. (2004). Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene, 23:157–167.
24.
RatajczakMZ, MajkaM, KuciaM, DrukalaJ, PietrzkowskiZ, PeiperS and Janowska-WieczorekA. (2003). Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells, 21:363–371.
25.
VasyutinaE, SteblerJ, Brand-SaberiB, SchulzS, RazE and BirchmeierC. (2005). CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Genes Dev, 19:2187–2198.
26.
OdemisV, LampE, PezeshkiG, MoeppsB, SchillingK, GierschikP, LittmanDR and EngeleJ. (2005). Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Mol Cell Neurosci, 30:494–505.
27.
OdemisV, BoosmannK, DieterlenMT and EngeleJ. (2007). The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCzeta. J Cell Sci, 120:4050–4059.
28.
BaeGU, GaioU, YangYJ, LeeHJ, KangJS and KraussRS. (2008). Regulation of myoblast motility and fusion by the CXCR4-associated sialomucin, CD164. J Biol Chem, 283:8301–8309.
29.
MelchionnaR, Di CarloA, De MoriR, CappuzzelloC, BarberiL, MusaroA, CencioniC, FujiiN, TamamuraH, et al. (2010). Induction of myogenic differentiation by SDF-1 via CXCR4 and CXCR7 receptors. Muscle Nerve, 41:828–835.
30.
BrzoskaE, KowalewskaM, Markowska-ZagrajekA, KowalskiK, ArchackaK, ZimowskaM, GrabowskaI, CzerwinskaAM, Czarnecka-GoraM, et al. (2012). Sdf-1 (CXCL12) improves skeletal muscle regeneration via the mobilisation of Cxcr4 and CD34 expressing cells. Biol Cell, 104:722–737.
31.
GriffinCA, ApponiLH, LongKK and PavlathGK. (2010). Chemokine expression and control of muscle cell migration during myogenesis. J Cell Sci, 123:3052–3060.
32.
VincentiMP and BrinckerhoffCE. (2007). Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: can MMPs be good for you?. J Cell Physiol, 213:355–364.
33.
SchultzGS and WysockiA. (2009). Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen, 17:153–162.
34.
MottJD and WerbZ. (2004). Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol, 16:558–564.
35.
HuangW, WangT, ZhangD, ZhaoT, DaiB, AshrafA, WangX, XuM, MillardRW, et al. (2012). Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. Stem Cells Dev, 21:778–789.
36.
ChristovC, ChretienF, Abou-KhalilR, BassezG, ValletG, AuthierFJ, BassagliaY, ShininV, TajbakhshS, ChazaudB and GherardiRK. (2007). Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol Biol Cell, 18:1397–1409.
37.
MonteroI, OrbeJ, VaroN, BeloquiO, MonrealJI, RodriguezJA, DiezJ, LibbyP and ParamoJA. (2006). C-reactive protein induces matrix metalloproteinase-1 and -10 in human endothelial cells: implications for clinical and subclinical atherosclerosis. J Am Coll Cardiol, 47:1369–1378.
38.
RodriguezJA, OrbeJ, Martinez de LizarrondoS, CalvayracO, RodriguezC, Martinez-GonzalezJ and ParamoJA. (2008). Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli. Front Biosci, 13:2916–2921.
39.
GillJH, KirwanIG, SeargentJM, MartinSW, TijaniS, AnikinVA, MearnsAJ, BibbyMC, AnthoneyA and LoadmanPM. (2004). MMP-10 is overexpressed, proteolytically active, and a potential target for therapeutic intervention in human lung carcinomas. Neoplasia, 6:777–785.
40.
BobadillaM, SáinzN, RodriguezJA, AbizandaG, OrbeJ, De MartinoA, García VerdugoJM, PáramoJA, PrósperF and Pérez-RuizA. (2013). MMP-10 is required for efficient muscle regeneration in mouse models of injury and muscular dystrophy. Stem Cells, 32:447–461.
41.
De ClercqE. (2005). Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. Mini Rev Med Chem, 5:805–824.
42.
ZhangR, PanX, HuangZ, WeberGF and ZhangG. (2011). Osteopontin enhances the expression and activity of MMP-2 via the SDF-1/CXCR4 axis in hepatocellular carcinoma cell lines. PLoS One, 6:e23831
43.
GongY, FanY and Hoover-PlowJ. (2011). Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9. Arterioscler Thromb Vasc Biol, 31:2035–2043.
ZhangH, TrivediA, LeeJU, LohelaM, LeeSM, FandelTM, WerbZ and Noble-HaeussleinLJ. (2011). Matrix metalloproteinase-9 and stromal cell-derived factor-1 act synergistically to support migration of blood-borne monocytes into the injured spinal cord. J Neurosci, 31:15894–15903.
46.
HungerC, OdemisV and EngeleJ. (2012). Expression and function of the SDF-1 chemokine receptors CXCR4 and CXCR7 during mouse limb muscle development and regeneration. Exp Cell Res, 318:2178–2190.
47.
MisaoY, TakemuraG, AraiM, OhnoT, OnogiH, TakahashiT, MinatoguchiS, FujiwaraT and FujiwaraH. (2006). Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res, 71:455–465.
48.
SaxenaP, KejriwalN and NewmanMA. (2007). Use of flexible silastic drains in thoracic surgery: a word of caution. Ann Thorac Surg, 83:2258–2259; author reply 2259.
49.
AbbottJD, HuangY, LiuD, HickeyR, KrauseDS and GiordanoFJ. (2004). Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation, 110:3300–3305.
50.
DaiS, YuanF, MuJ, LiC, ChenN, GuoS, KingeryJ, PrabhuSD, BolliR and RokoshG. (2010). Chronic AMD3100 antagonism of SDF-1alpha-CXCR4 exacerbates cardiac dysfunction and remodeling after myocardial infarction. J Mol Cell Cardiol, 49:587–597.
51.
GhadgeSK, MuhlstedtS, OzcelikC and BaderM. (2010). SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther, 129:97–108.
52.
KimDS, KangSI, LeeSY, NohKT and KimEC. (2014). Involvement of SDF-1 and monocyte chemoattractant protein-1 in hydrogen peroxide-induced extracellular matrix degradation in human dental pulp cells. Int Endod J, 47:298–308.
53.
NaumannU, CameroniE, PruensterM, MahabaleshwarH, RazE, ZerwesHG, RotA and ThelenM. (2010). CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS One, 5:e9175
54.
BrinckerhoffCE and MatrisianLM. (2002). Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol, 3:207–214.
55.
SachidanandanC, SambasivanR and DhawanJ. (2002). Tristetraprolin and LPS-inducible CXC chemokine are rapidly induced in presumptive satellite cells in response to skeletal muscle injury. J Cell Sci, 115:2701–2712.
56.
PorterJD, GuoW, MerriamAP, KhannaS, ChengG, ZhouX, AndradeFH, RichmondsC and KaminskiHJ. (2003). Persistent over-expression of specific CC class chemokines correlates with macrophage and T-cell recruitment in mdx skeletal muscle. Neuromuscul Disord, 13:223–235.
57.
HirataA, MasudaS, TamuraT, KaiK, OjimaK, FukaseA, MotoyoshiK, KamakuraK, Miyagoe-SuzukiY and TakedaS. (2003). Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection: a role for osteopontin. Am J Pathol, 163:203–215.
58.
SteblerJ, SpielerD, SlanchevK, MolyneauxKA, RichterU, CojocaruV, TarabykinV, WylieC, KesselM and RazE. (2004). Primordial germ cell migration in the chick and mouse embryo: the role of the chemokine SDF-1/CXCL12. Dev Biol, 272:351–361.
59.
RucciN, SanitaP and AngelucciA. (2011). Roles of metalloproteases in metastatic niche. Curr Mol Med, 11:609–622.
60.
RaffoD, PontiggiaO and SimianM. (2011). Role of MMPs in metastatic dissemination: implications for therapeutic advances. Curr Pharm Biotechnol, 12:1937–1947.
61.
McQuibbanGA, GongJH, WongJP, WallaceJL, Clark-LewisI and OverallCM. (2002). Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood, 100:1160–1167.
62.
OverallCM, TamE, McQuibbanGA, MorrisonC, WallonUM, BiggHF, KingAE and Roberts.CR (2000). Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation. J Biol Chem, 275:39497–39506.
63.
Van LintP and LibertC. (2007). Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol, 82:1375–1381.
64.
HatfieldKJ, ReikvamH and BruserudO. (2010). The crosstalk between the matrix metalloprotease system and the chemokine network in acute myeloid leukemia. Curr Med Chem, 17:4448–4461.
65.
ChinniSR, SivaloganS, DongZ, FilhoJC, DengX, BonfilRD and CherML. (2006). CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate, 66:32–48.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
