Rotator cuff tear is a significant problem that leads to poor clinical outcomes due to muscle degeneration after injury. The objective of this study was to synergistically increase the number of proregenerative cells recruited to injure rotator cuff muscle through a novel dual treatment system, consisting of a bone marrow mobilizing agent (VPC01091), hypothesized to “push” prohealing cells into the blood, and localized delivery of stromal cell-derived factor-1α (SDF-1α), to “pull” the cells to the injury site. Immediately after rotator cuff tendon injury in rat, the mobilizing agent was delivered systemically, and SDF-1α-loaded heparin-based microparticles were injected into the supraspinatus muscle. Regenerative and degenerative changes to supraspinatus muscle and the presence of inflammatory/immune cells, mesenchymal stem cells (MSCs), and satellite cells were assessed via flow cytometry and histology for up to 21 days. After dual treatment, significantly more MSCs (31.9 ± 8.0% single cells) and T lymphocytes (6.7 ± 4.3 per 20 × field of view) were observed in supraspinatus muscle 7 days after injury and treatment compared to injury alone (14.4 ± 6.5% single cells, 1.2 ± 0.7 per 20 × field of view), in addition to an elevated M2:M1 macrophage ratio (3.0 ± 0.5), an indicator of a proregenerative environment. These proregenerative cellular changes were accompanied by increased nascent fiber formation (indicated by embryonic myosin heavy chain staining) at day 7 compared to SDF-1α treatment alone, suggesting that this method may be a promising strategy to influence the early cellular response in muscle and promote a proregenerative microenvironment to increase muscle healing after severe rotator cuff tear.
Impact statement
Rotator cuff tear is a significant problem that results in muscle degeneration. In this study, a method to improve regenerative cell recruitment to muscle via localized delivery of stromal cell-derived factor-1α (SDF-1α)-loaded heparin-based microparticles (MPs) to injured muscle in combination with simultaneous treatment with a bone marrow mobilization agent was explored. Systemic delivery of a mobilizing agent to “push” cells into circulation and local injection of SDF-1α loaded MPs to “pull” cells to the injury site resulted in early regenerative effects. Thus, this dual treatment may be a promising strategy to create a more proregenerative microenvironment and positively influence muscle healing after rotator cuff tear.
Get full access to this article
View all access options for this article.
References
1.
GigliottiD, XuMC, DavidsonMJ, et al.Fibrosis, low vascularity, and fewer slow fibers after rotator-cuff injury. Muscle Nerve, 2017; 55(5):715–726; doi: 10.1002/mus.25388
2.
YamamotoA, TakagishiK, OsawaT, et al.Prevalence and risk factors of a rotator cuff tear in the general population. J Shoulder Elbow Surg, 2010; 19(1):116–120; doi: 10.1016/j.jse.2009.04.006
3.
LiL, BokshanSL, ReadyLV, et al.The primary cost drivers of arthroscopic rotator cuff repair surgery: A cost-minimization analysis of 40,618 cases. J Shoulder Elbow Surg, 2019; 28(10):1977–1982; doi: 10.1016/j.jse.2019.03.004
4.
MatherRC, 3rd, KoenigL, AcevedoD, et al.The societal and economic value of rotator cuff repair. J Bone Joint Surg Am, 2013; 95(22):1993–2000; doi: 10.2106/JBJS.L.01495
5.
GladstoneJN, BishopJY, LoIK, et al.Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome. Am J Sports Med, 2007; 35(5):719–728; doi: 10.1177/0363546506297539
6.
GoutallierD, PostelJM, GleyzeP, et al.Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J Shoulder Elbow Surg, 2003; 12(6):550–554; doi: 10.1016/s1058-2746(03)00211-8
7.
FuMC, O'DonnellEA, TaylorSA, et al.Delay to arthroscopic rotator cuff repair is associated with increased risk of revision rotator cuff surgery. Orthopedics, 2020; 43(6):340–344; doi: 10.3928/01477447-20200923-02
8.
ShenPH, LienSB, ShenHC, et al.Long-term functional outcomes after repair of rotator cuff tears correlated with atrophy of the supraspinatus muscles on magnetic resonance images. J Shoulder Elbow Surg, 2008; 17(1 Suppl):1S–7S; doi: 10.1016/j.jse.2007.04.014
9.
FrichLH, FernandesLR, SchroderHD, et al.The inflammatory response of the supraspinatus muscle in rotator cuff tear conditions. J Shoulder Elbow Surg, 2021; 30(6):e261–e275; doi: 10.1016/j.jse.2020.08.028
10.
GumucioJP, DavisME, BradleyJR, et al.Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy. J Orthop Res, 2012; 30(12):1963–1970; doi: 10.1002/jor.22168
11.
LiuX, JoshiSK, RavishankarB, et al.Upregulation of transforming growth factor-beta signaling in a rat model of rotator cuff tears. J Shoulder Elbow Surg, 2014; 23(11):1709–1716; doi: 10.1016/j.jse.2014.02.029
12.
LundgreenK, LianOB, EngebretsenL, et al.Lower muscle regenerative potential in full-thickness supraspinatus tears compared to partial-thickness tears. Acta Orthop, 2013; 84(6):565–570; doi: 10.3109/17453674.2013.858289
13.
TellierLE, KriegerJR, BrimeyerAL, et al.Localized SDF-1alpha delivery increases pro-healing bone marrow-derived cells in the supraspinatus muscle following severe rotator cuff injury. Regen Eng Transl Med, 2018; 4(2):92–103; doi: 10.1007/s40883-018-0052-4
14.
LiuX, ManzanoG, KimHT, et al.A rat model of massive rotator cuff tears. J Orthop Res, 2011; 29(4):588–595; doi: 10.1002/jor.21266
15.
RoyS, LaiH, ZouaouiR, et al.Bioactivity screening of partially desulfated low-molecular-weight heparins: A structure/activity relationship study. Glycobiology, 2011; 21(9):1194–1205; doi: 10.1093/glycob/cwr053
16.
TellierLE, MillerT, McDevittTC, et al.Hydrolysis and sulfation pattern effects on release of bioactive bone morphogenetic protein-2 from heparin-based microparticles. J Mater Chem B, 2015; 3(40):8001–8009; doi: 10.1039/C5TB00933B
17.
KriegerJR, OgleME, McFaline-FigueroaJ, et al.Spatially localized recruitment of anti-inflammatory monocytes by SDF-1alpha-releasing hydrogels enhances microvascular network remodeling. Biomaterials, 2016; 77:280–290; doi: 10.1016/j.biomaterials.2015.10.045
18.
van de WeteringP, MettersAT, SchoenmakersRG, et al.Poly(ethylene glycol) hydrogels formed by conjugate addition with controllable swelling, degradation, and release of pharmaceutically active proteins. J Control Release, 2005; 102(3):619–627; doi: 10.1016/j.jconrel.2004.10.029
19.
AiutiA, WebbIJ, BleulC, et al.The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med, 1997; 185(1):111–120; doi: 10.1084/jem.185.1.111
MendiasCL, RocheSM, HarningJA, et al.Reduced muscle fiber force production and disrupted myofibril architecture in patients with chronic rotator cuff tears. J Shoulder Elbow Surg, 2015; 24(1):111–119; doi: 10.1016/j.jse.2014.06.037
LeeC, AghaO, LiuM, et al.Rotator Cuff Fibro-Adipogenic Progenitors Demonstrate Highest Concentration, Proliferative Capacity, and Adipogenic Potential Across Muscle Groups. J Orthop Res, 2020; 38(5):1113–1121; doi: 10.1002/jor.24550
24.
LiuT, LiX, YouS, et al.Effectiveness of AMD3100 in treatment of leukemia and solid tumors: From original discovery to use in current clinical practice. Exp Hematol Oncol, 2015; 5:19; doi: 10.1186/s40164-016-0050-5
25.
PelusLM. Peripheral blood stem cell mobilization: New regimens, new cells, where do we stand. Curr Opin Hematol, 2008; 15(4):285–292; doi: 10.1097/MOH.0b013e328302f43a
26.
ChewWS, WangW, HerrDR. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res, 2016; 113(Pt A):521–532; doi: 10.1016/j.phrs.2016.09.025
27.
OliveraA, SpiegelS. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature, 1993; 365(6446):557–560; doi: 10.1038/365557a0
28.
KongY, WangH, LinT, et al.Sphingosine-1-phosphate/S1P receptors signaling modulates cell migration in human bone marrow-derived mesenchymal stem cells. Mediators Inflamm, 2014; 2014:565369; doi: 10.1155/2014/565369
29.
MaedaY, SekiN, KataokaH, et al.IL-17-producing Vgamma4+ gammadelta T cells require sphingosine 1-phosphate receptor 1 for their egress from the lymph nodes under homeostatic and inflammatory conditions. J Immunol, 2015; 195(4):1408–1416; doi: 10.4049/jimmunol.1500599
30.
JuarezJG, HarunN, ThienM, et al.Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice. Blood, 2012; 119(3):707–716; doi: 10.1182/blood-2011-04-348904
31.
OgleME, OlingyCE, AwojooduAO, et al.Sphingosine-1-phosphate receptor-3 supports hematopoietic stem and progenitor cell residence within the bone marrow niche. Stem Cells, 2017; 35(4):1040–1052; doi: 10.1002/stem.2556
32.
InoueY, NagasawaK. Selective N-desulfation of heparin with dimethyl sulfoxide containing water or methanol. Carbohydr Res, 1976; 46(1):87–95; doi: 10.1016/s0008-6215(00)83533-8
33.
NagasawaK, InoueY, KamataT. Solvolytic desulfation of glycosaminoglycuronan sulfates with dimethyl sulfoxide containing water or methanol. Carbohydr Res, 1977; 58(1):47–55; doi: 10.1016/s0008-6215(00)83402-3
34.
SetoSP, MillerT, TemenoffJS. Effect of selective heparin desulfation on preservation of bone morphogenetic protein-2 bioactivity after thermal stress. Bioconjug Chem, 2015; 26(2):286–293; doi: 10.1021/bc500565x
35.
TellierLE, TrevinoEA, BrimeyerAL, et al.Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis. Biomater Sci, 2018; 6(5):1159–1167; doi: 10.1039/C8BM00010G
36.
AndersonLE, PearsonJJ, BrimeyerAL, et al.Injection of micronized human amnion/chorion membrane results in increased early supraspinatus muscle regeneration in a chronic model of rotator cuff tear. Ann Biomed Eng, 2021; 49(12):3698–3710; doi: 10.1007/s10439-021-02880-2
37.
TrevinoEA, McFaline-FigueroaJ, GuldbergRE, et al.Full-thickness rotator cuff tear in rat results in distinct temporal expression of multiple proteases in tendon, muscle, and cartilage. J Orthop Res, 2019; 37(2):490–502; doi: 10.1002/jor.24179
38.
SelmaJM, DasA, AwojooduAO, et al.Novel lipid signaling mediators for mesenchymal stem cell mobilization during bone repair. Cell Mol Bioeng, 2018; 11(4):241–253; doi: 10.1007/s12195-018-0532-0
39.
VantucciCE, AhnH, FultonT, et al.Development of systemic immune dysregulation in a rat trauma model of biomaterial-associated infection. Biomaterials, 2021; 264:120405; doi: 10.1016/j.biomaterials.2020.120405
40.
KolfCM, ChoE, TuanRS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: Regulation of niche, self-renewal and differentiation. Arthritis Res Ther, 2007; 9(1):204; doi: 10.1186/ar2116
41.
FengX, NazF, JuanAH, et al.Identification of skeletal muscle satellite cells by immunofluorescence with Pax7 and laminin antibodies. J Vis Exp, 2018; 2018(134); doi: 10.3791/57212
42.
SongE, OuyangN, HorbeltM, et al.Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol, 2000; 204(1):19–28; doi: 10.1006/cimm.2000.1687
43.
WitherelCE, SaoK, BrissonBK, et al.Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages. Biomaterials, 2021; 269:120667; doi: 10.1016/j.biomaterials.2021.120667
44.
MadsenDH, LeonardD, MasedunskasA, et al.M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J Cell Biol, 2013; 202(6):951–966; doi: 10.1083/jcb.201301081
45.
GraneyPL, Ben-ShaulS, LandauS, et al.Macrophages of diverse phenotypes drive vascularization of engineered tissues. Sci Adv, 2020; 6(18):eaay6391; doi: 10.1126/sciadv.aay6391
46.
JettenN, VerbruggenS, GijbelsMJ, et al.Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis, 2014; 17(1):109–118; doi: 10.1007/s10456-013-9381-6
47.
SaclierM, Yacoub-YoussefH, MackeyAL, et al.Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells, 2013; 31(2):384–396; doi: 10.1002/stem.1288
48.
NishidaY, HashimotoY, OritaK, et al.Intra-articular injection of stromal cell-derived factor 1α promotes meniscal healing via macrophage and mesenchymal stem cell accumulation in a rat meniscal defect model. Int J Mol Sci, 2020; 21(15):5454; doi: 10.3390/ijms21155454
49.
QiuX, LiuS, ZhangH, et al.Mesenchymal stem cells and extracellular matrix scaffold promote muscle regeneration by synergistically regulating macrophage polarization toward the M2 phenotype. Stem Cell Res Ther, 2018; 9(1):88; doi: 10.1186/s13287-018-0821-5
50.
SadtlerK, EstrellasK, AllenBW, et al.Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science, 2016; 352(6283):366–370; doi: 10.1126/science.aad9272
51.
HymelLA, OgleME, AndersonSE, et al.Modulating local S1P receptor signaling as a regenerative immunotherapy after volumetric muscle loss injury. J Biomed Mater Res A, 2021; 109(5):695–712; doi: 10.1002/jbm.a.37053
52.
DoronG, KlontzasME, MantalarisA, et al.Multiomics characterization of mesenchymal stromal cells cultured in monolayer and as aggregates. Biotechnol Bioeng, 2020; 117(6):1761–1778; doi: 10.1002/bit.27317
53.
NakajimaH, UchidaK, GuerreroAR, et al.Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma, 2012; 29(8):1614–1625; doi: 10.1089/neu.2011.2109
54.
SattayaprasertP, VasireddiSK, BektikE, et al.Human cardiac mesenchymal stem cells remodel in disease and can regulate arrhythmia substrates. Circ Arrhythm Electrophysiol, 2020; 13(10):e008740; doi: 10.1161/CIRCEP.120.008740
55.
WrightEJ, HodsonNW, SherrattMJ, et al.Combined MSC and GLP-1 therapy modulates collagen remodeling and apoptosis following myocardial infarction. Stem Cells Int, 2016; 2016:7357096; doi: 10.1155/2016/7357096
56.
KimSH, ChungSW, OhJH. Expression of insulin-like growth factor type 1 receptor and myosin heavy chain in rabbit's rotator cuff muscle after injection of adipose-derived stem cell. Knee Surg Sports Traumatol Arthrosc, 2014; 22(11):2867–2873; doi: 10.1007/s00167-013-2560-6
57.
CarrollTJ, HerbertRD, MunnJ, et al.Contralateral effects of unilateral strength training: Evidence and possible mechanisms. J Appl Physiol (1985), 2006; 101(5):1514–1522; doi: 10.1152/japplphysiol.00531.2006
58.
SongY, ForsgrenS, YuJ, et al.Effects on contralateral muscles after unilateral electrical muscle stimulation and exercise. PLoS One, 2012; 7(12):e52230; doi: 10.1371/journal.pone.0052230
59.
HashimotoE, OchiaiN, KenmokuT, et al.Macroscopic and histologic evaluation of a rat model of chronic rotator cuff tear. J Shoulder Elbow Surg, 2016; 25(12):2025–2033; doi: 10.1016/j.jse.2016.04.024
60.
ZhuR, SnyderAH, KharelY, et al.Asymmetric synthesis of conformationally constrained fingolimod analogues—discovery of an orally active sphingosine 1-phosphate receptor type-1 agonist and receptor type-3 antagonist. J Med Chem, 2007; 50(25):6428–6435; doi: 10.1021/jm7010172
61.
ContentoRL, MolonB, BoularanC, et al.CXCR4-CCR5: A couple modulating T cell functions. Proc Natl Acad Sci U S A, 2008; 105(29):10101–10106; doi: 10.1073/pnas.0804286105
62.
KuciaM, JankowskiK, RecaR, et al.CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol, 2004; 35(3):233–245; doi: 10.1023/b:hijo.0000032355.66152.b8
63.
FuX, XiaoJ, WeiY, et al.Combination of inflammation-related cytokines promotes long-term muscle stem cell expansion. Cell Res, 2015; 25(6):655–673; doi: 10.1038/cr.2015.58
64.
KweeBJ, BudinaE, NajibiAJ, et al.CD4 T-cells regulate angiogenesis and myogenesis. Biomaterials, 2018; 178:109–121; doi: 10.1016/j.biomaterials.2018.06.003
65.
BurzynD, KuswantoW, KolodinD, et al.A special population of regulatory T cells potentiates muscle repair. Cell, 2013; 155(6):1282–1295; doi: 10.1016/j.cell.2013.10.054
66.
RatajczakMZ, MajkaM, KuciaM, et al.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, 2003; 21(3):363–371; doi: 10.1634/stemcells.21-3-363
67.
KangJR, GuptaR. Mechanisms of fatty degeneration in massive rotator cuff tears. J Shoulder Elbow Surg, 2012; 21(2):175–180; doi: 10.1016/j.jse.2011.11.017
68.
LiuX, LaronD, NatsuharaK, et al.A mouse model of massive rotator cuff tears. J Bone Joint Surg Am, 2012; 94:e41.
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.
