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Therapeutic potential of exosomes in rotator cuff tendon healing

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Abstract

Rotator cuff tears are common musculoskeletal injuries that can cause significant pain and disability. While the clinical results of rotator cuff repair can be good, failure of tendon healing remains a significant problem. Molecular mechanisms underlying structural failure following surgical repair remain unclear. Histologically, enhanced inflammation, disorganization of the collagen fibers, calcification, apoptosis and tissue necrosis affect the normal healing process. Mesenchymal stem cells (MSCs) have the ability to provide improved healing following rotator cuff repair via the release of mediators from secreted 30–100 nm extracellular vesicles called exosomes. They carry regulatory proteins, mRNA and miRNA and have the ability to increase collagen synthesis and angiogenesis through increased expression of mRNA and release of proangiogenic factors and regulatory proteins that play a major role in proper tissue remodeling and preventing extracellular matrix degradation. Various studies have shown the effect of exosomes on improving outcome of cutaneous wound healing, scar tissue formation, degenerative bone disease and Duchenne Muscular Dystrophy. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and propose the novel use of exosomes alone or seeded onto biomaterial matrices to stimulate secretion of favorable cellular factors in accelerating the healing response following rotator cuff repair.

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References

  1. Zhao S, Su W, Shah V et al (2017) Biomaterials based strategies for rotator cuff repair. Colloids Surf B 157:407–416. https://doi.org/10.1016/j.colsurfb.2017.06.004

    Article  CAS  Google Scholar 

  2. Gold JE, Hallman DM, Hellström F et al (2017) Systematic review of quantitative imaging biomarkers for neck and shoulder musculoskeletal disorders. BMC Musculoskelet Disorders 18:395. https://doi.org/10.1186/s12891-017-1694-y

    Article  CAS  Google Scholar 

  3. Jain NB, Higgins LD, Losina E, Collins J, Blazar PE, Katz JN (2014) Epidemiology of musculoskeletal upper extremity ambulatory surgery in the United States. BMC Musculoskelet Disorders 15:4. https://doi.org/10.1186/1471-2474-15-4

    Article  Google Scholar 

  4. Longo UG, Berton A, Khan WS, Maffulli N, Denaro V (2011) Histopathology of rotator cuff tears. Sports Med Arthrosc Rev 19:227–236. https://doi.org/10.1097/JSA.0b013e318213bccb

    Article  PubMed  Google Scholar 

  5. Rashid MS, Cooper C, Cook J et al (2017) Increasing age and tear size reduce rotator cuff repair healing rate at 1 year. Acta Orthop 88:606–611. https://doi.org/10.1080/17453674.2017.1370844

    Article  PubMed  PubMed Central  Google Scholar 

  6. Patel S, Caldwell J‐M, Doty SB et al (2017) Integrating soft and hard tissues via interface tissue engineering. J Orthop Res. https://doi.org/10.1002/jor.23810

    Article  PubMed  Google Scholar 

  7. Ruyssen-Witrand A, Jamard B, Cantagrel A et al (2017) Relationships between ultrasound enthesitis, disease activity and axial radiographic structural changes in patients with early spondyloarthritis: data from DESIR cohort. RMD Open 3:e000482. https://doi.org/10.1136/rmdopen-2017-000482

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hideaki Takahashi, Hiroyuki Tamaki, Mineo Oyama, Noriaki Yamamoto, Hideaki Onishi (2017) Time-dependent changes in the structure of calcified fibrocartilage in the rat achilles tendon-bone interface with sciatic denervation. Anat Rec 300:2166–2174. https://doi.org/10.1002/ar.23684

    Article  CAS  Google Scholar 

  9. Hexter AT, Pendegrass C, Haddad F, Blunn G (2017) Demineralized bone matrix to augment tendon-bone healing: a systematic review. Orthop J Sports Med. https://doi.org/10.1177/2325967117734517

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nakagawa H, Morihara T, Fujiwara H et al (2017) Effect of footprint preparation on tendon-to-bone healing a histologic and biomechanical study in a rat rotator cuff repair model. Arthrosc J Arthroscopic Relat Surg 33:1482–1492. https://doi.org/10.1016/j.arthro.2017.03.031

    Article  Google Scholar 

  11. Hernigou P, Flouzat Lachaniette CH, Delambre J et al (2014) Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study. Int Orthop 38:1811–1818. https://doi.org/10.1007/s00264-014-2391-1

    Article  PubMed  Google Scholar 

  12. Zitnay JL, Reese SP, Tran G, Farhang N, Bowles RD, Weiss JA (2018) Fabrication of dense anisotropic collagen scaffolds using biaxial compression. Acta Biomater 65:76–87. https://doi.org/10.1016/j.actbio.2017.11.017

    Article  CAS  PubMed  Google Scholar 

  13. Fellows CR, Matta C, Zakany R, Khan IM, Mobasheri A (2016) Adipose, bone marrow and synovial joint-derived mesenchymal stem cells for cartilage repair. Front Genet. https://doi.org/10.3389/fgene.2016.00213

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mazzocca AD, McCarthy MBR, Chowaniec DM, Cote MP, Arciero RA, Drissi H (2010) Rapid isolation of human stem cells (connective tissue progenitor cells) from the proximal humerus during arthroscopic rotator cuff surgery. Am J Sports Med 38:1438–1447. https://doi.org/10.1177/0363546509360924

    Article  PubMed  Google Scholar 

  15. Honda H, Gotoh M, Kanazawa T et al (2017) Hyaluronic acid accelerates tendon-to-bone healing after rotator cuff repair. Am J Sports Med 45:3322–3330. https://doi.org/10.1177/0363546517720199

    Article  PubMed  Google Scholar 

  16. Sevivas N, Teixeira FG, Portugal R et al (2018) Mesenchymal stem cell secretome improves tendon cell viability in vitro and tendon-bone healing in vivo when a tissue engineering strategy is used in a rat model of chronic massive rotator cuff tear. Am J Sports Med 46:449–459. https://doi.org/10.1177/0363546517735850

    Article  PubMed  Google Scholar 

  17. Kim YS, Sung CH, Chung SH, Kwak SJ, Koh YG (2017) Does an injection of adipose-derived mesenchymal stem cells loaded in fibrin glue influence rotator cuff repair outcomes? A clinical and magnetic resonance imaging study. Am J Sports Med 45:2010–2018. https://doi.org/10.1177/0363546517702863

    Article  PubMed  Google Scholar 

  18. Bi Y, Ehirchiou D, Kilts TM et al (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13:1219–1227. https://doi.org/10.1038/nm1630

    Article  CAS  PubMed  Google Scholar 

  19. Zhang J, Pan T, Liu Y, Wang JH-C (2010) Mouse treadmill running enhances tendons by expanding the pool of tendon stem cells (TSCs) and TSC-related cellular production of collagen. J Orthop Res 28:1178–1183. https://doi.org/10.1002/jor.21123

    Article  PubMed  Google Scholar 

  20. Crescitelli R, Lässer C, Szabó TG et al (2013) Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles 2:20677. https://doi.org/10.3402/jev.v2i0.20677

    Article  CAS  Google Scholar 

  21. Zonneveld MI, Brisson AR, van Herwijnen MJC et al (2014) Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. J Extracell Vesicles 3:24215. https://doi.org/10.3402/jev.v3.24215

    Article  CAS  Google Scholar 

  22. Kida Y, Morihara T, Matsuda K-I et al (2013) Bone marrow–derived cells from the footprint infiltrate into the repaired rotator cuff. J Shoulder Elbow Surg 22:197–205. https://doi.org/10.1016/j.jse.2012.02.007

    Article  PubMed  Google Scholar 

  23. Gasperi RD, Hamidi S, Harlow LM, Ksiezak-Reding H, Bauman WA, Cardozo CP (2017) Denervation-related alterations and biological activity of miRNAs contained in exosomes released by skeletal muscle fibers. Sci Rep 7:12888. https://doi.org/10.1038/s41598-017-13105-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P (2013) Delivery of functional anti-mir-9 by mesenchymal stem cell–derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids 2:e126. https://doi.org/10.1038/mtna.2013.60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Than UTT, Guanzon D, Leavesley D, Parker T (2017) Association of extracellular membrane vesicles with cutaneous wound healing. Int J Mol Sci 18:956. https://doi.org/10.3390/ijms18050956

    Article  CAS  PubMed Central  Google Scholar 

  26. Fouda MB, Thankam FG, Dilisio MF, Agrawal DK (2017) Alterations in tendon microenvironment in response to mechanical load: potential molecular targets for treatment strategies. Am J Transl Res. 9:4341–4360

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hu L, Wang J, Zhou X et al (2016) Exosomes derived from human adipose mesenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep. https://doi.org/10.1038/srep32993

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang J, Guan J, Niu X et al (2015) Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 13:1–2. https://doi.org/10.1186/s12967-015-0417-0

    Article  CAS  Google Scholar 

  29. Choi EW, Seo MK, Woo EY, Kim SH, Park EJ, Kim S (2017) Exosomes from human adipose-derived stem cells promote proliferation and migration of skin fibroblasts. Exp Dermatol. https://doi.org/10.1111/exd.13451

    Article  PubMed  PubMed Central  Google Scholar 

  30. El-Tookhy OS, Shamaa AA, Shehab GG, Abdallah AN, Azzam OM (2017) Histological evaluation of experimentally induced critical size defect skin wounds using exosomal solution of mesenchymal stem cells derived microvesicles. Int J Stem Cells 10:144–153. https://doi.org/10.15283/ijsc17043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hocking AM (2012) Mesenchymal stem cell therapy for cutaneous wounds. Adv Wound Care (New Rochelle) 1:166–171. https://doi.org/10.1089/wound.2011.0294

    Article  Google Scholar 

  32. Wang L, Hu L, Zhou X et al (2017) Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci Rep 7:13321. https://doi.org/10.1038/s41598-017-12919-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Komaki M, Numata Y, Morioka C et al (2017) Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis. Stem Cell Res Ther. https://doi.org/10.1186/s13287-017-0660-9

    Article  PubMed  PubMed Central  Google Scholar 

  34. Phinney DG, Pittenger MF (2017) MSC-derived exosomes for cell-free therapy. Stem Cells 35:851–858

    Article  CAS  PubMed  Google Scholar 

  35. Xue M, Jackson CJ (2015) Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle). 4:119–136. https://doi.org/10.1089/wound.2013.0485

    Article  PubMed  PubMed Central  Google Scholar 

  36. Laghezza Masci V, Taddei AR, Gambellini G, Giorgi F, Fausto AM (2016) Microvesicles shed from fibroblasts act as metalloproteinase carriers in a 3-D collagen matrix. J Circ Biomark. https://doi.org/10.1177/1849454416663660

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nakamura K, Jinnin M, Harada M et al (2016) Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts. J Dermatol Sci 84:30–39. https://doi.org/10.1016/j.jdermsci.2016.06.013

    Article  CAS  PubMed  Google Scholar 

  38. Qi X, Zhang J, Yuan H et al (2016) Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci 12:836–849. https://doi.org/10.7150/ijbs.14809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang Y, Yu D, Liu Z et al (2017) Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther 8:189. https://doi.org/10.1186/s13287-017-0632-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tao S-C, Yuan T, Zhang Y-L, Yin W-J, Guo S-C, Zhang C-Q (2017) Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics 7:180–195. https://doi.org/10.7150/thno.17133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bier A, Berenstein P, Kronfeld N et al (2018) Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne Muscular Dystrophy. Biomaterials 174:67–78. https://doi.org/10.1016/j.biomaterials.2018.04.055

    Article  CAS  PubMed  Google Scholar 

  42. McNally E (2012) Chapter 81—novel targets and approaches to treating skeletal muscle disease. In: Hill JA, Olson EN (eds) Muscle. Academic Press, Boston/Waltham, pp 1095–1103. https://doi.org/10.1016/b978-0-12-381510-1.00081-8

    Chapter  Google Scholar 

  43. Feng Y, Huang W, Wani M, Yu X, Ashraf M (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9:e88685. https://doi.org/10.1371/journal.pone.0088685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ferguson SW, Wang J, Lee CJ et al (2018) The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep. https://doi.org/10.1038/s41598-018-19581-x

    Article  PubMed  PubMed Central  Google Scholar 

  45. Xu T, Xu M, Bai J et al (2019) Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-β. Cytotechnology 71:57–65. https://doi.org/10.1007/s10616-018-0264-y

    Article  CAS  PubMed  Google Scholar 

  46. Tokunaga T, Shukunami C, Okamoto N et al (2015) FGF-2 stimulates the growth of tenogenic progenitor cells to facilitate the generation of tenomodulin-positive tenocytes in a rat rotator cuff healing model. Am J Sports Med 43:2411–2422. https://doi.org/10.1177/0363546515597488

    Article  PubMed  Google Scholar 

  47. Tokunaga T, Karasugi T, Arimura H et al (2017) Enhancement of rotator cuff tendon–bone healing with fibroblast growth factor 2 impregnated in gelatin hydrogel sheets in a rabbit model. J Shoulder Elbow Surg 26:1708–1717. https://doi.org/10.1016/j.jse.2017.03.020

    Article  PubMed  Google Scholar 

  48. Cui H, He Y, Chen S, Zhang D, Yu Y, Fan C (2018) Macrophage-derived miRNA-containing exosomes induce peritendinous fibrosis after tendon injury through the miR-21-5p/Smad7 pathway. Mol Ther Nucleic Acids 14:114–130. https://doi.org/10.1016/j.omtn.2018.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gaffey AC, Chen MH, Venkataraman CM et al (2015) Injectable shear-thinning hydrogels used to deliver endothelial progenitor cells, enhance cell engraftment, and improve ischemic myocardium. J Thorac Cardiovasc Surg 150:1268–1277. https://doi.org/10.1016/j.jtcvs.2015.07.035

    Article  PubMed  PubMed Central  Google Scholar 

  50. Agrawal DK, Siddique A (2018) Rejuvenation of “broken heart” with bioengineered gel. J Thorac Cardiovasc Surg. https://doi.org/10.1016/j.jtcvs.2018.08.076

    Article  PubMed  Google Scholar 

  51. Nam HY, Pingguan-Murphy B, Abbas AA, Merican AM, Kamarul T (2015) The proliferation and tenogenic differentiation potential of bone marrow-derived mesenchymal stromal cell are influenced by specific uniaxial cyclic tensile loading conditions. Biomech Model Mechanobiol 14:649–663. https://doi.org/10.1007/s10237-014-0628-y

    Article  PubMed  Google Scholar 

  52. Miyamoto H, Aoki M, Hidaka E, Fujimiya M, Uchiyama E (2017) Measurement of strain and tensile force of the Supraspinatus tendon under conditions that simulates low angle isometric elevation of the gleno-humeral joint: influence of adduction torque and joint positioning. Clin Biomech 50:92–98. https://doi.org/10.1016/j.clinbiomech.2017.10.014

    Article  Google Scholar 

  53. Nam HY, Raghavendran HRB, Pingguan-Murphy B, Abbas AA, Merican AM, Kamarul T (2017) Fate of tenogenic differentiation potential of human bone marrow stromal cells by uniaxial stretching affected by stretch-activated calcium channel agonist gadolinium. PLoS One 12:e0178117. https://doi.org/10.1371/journal.pone.0178117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Samanta S, Rajasingh S, Drosos N, Zhou Z, Dawn B, Rajasingh J (2018) Exosomes: new molecular targets of diseases. Acta Pharmacol Sin 39:501–513. https://doi.org/10.1038/aps.2017.162

    Article  CAS  PubMed  Google Scholar 

  55. Tracy SA, Ahmed A, Tigges JC et al (2019) A comparison of clinically relevant sources of mesenchymal stem cell-derived exosomes: bone marrow and amniotic fluid. J Pediatr Surg 54:86–90. https://doi.org/10.1016/j.jpedsurg.2018.10.020

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported primarily by the State of Nebraska LB506 Grant to DKA and LB692 Grant to MFD by Creighton University. The research work of DKA is also supported by Grants R01HL120659 and R01HL144125 from the National Institutes of Health (NIH). The content of this original research article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the State of Nebraska.

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Authors and Affiliations

  1. Department of Clinical and Translational Science, The Peekie Nash Carpenter Endowed Chair in Medicine, Creighton University School of Medicine, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA

    Denton E. Connor, Jordan A. Paulus, Parinaz Jila Dabestani, Finosh K. Thankam, Matthew F. Dilisio, R. Michael Gross & Devendra K. Agrawal

  2. Department of Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Matthew F. Dilisio & R. Michael Gross

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  1. Denton E. Connor
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Correspondence to Devendra K. Agrawal.

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Connor, D.E., Paulus, J.A., Dabestani, P.J. et al. Therapeutic potential of exosomes in rotator cuff tendon healing. J Bone Miner Metab 37, 759–767 (2019). https://doi.org/10.1007/s00774-019-01013-z

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