Skip to main content

Advertisement

Log in

Autologous microfragmented adipose tissue reduces inflammatory and catabolic markers in supraspinatus tendon cells derived from patients affected by rotator cuff tears

  • Original Paper
  • Published:
International Orthopaedics Aims and scope Submit manuscript

Abstract

Purpose

Rotator cuff tears are common musculoskeletal disorders, and surgical repair is characterized by a high rate of re-tear. Regenerative medicine strategies, in particular mesenchymal stem cell–based therapies, have been proposed to enhance tendon healing and reduce the re-tear rate. Autologous microfragmented adipose tissue (μFAT) allows for the clinical application of cell therapies and showed the ability to improve tenocyte proliferation and viability in previous in vitro assessments. The hypothesis of this study is that μFAT paracrine action would reduce the catabolic and inflammatory marker expression in tendon cells (TCs) derived from injured supraspinatus tendon (SST).

Methods

TCs derived from injured SST were co-cultured with autologous μFAT in transwell for 48 h. Metabolic activity, DNA content, the content of soluble mediators in the media, and the gene expression of tendon-specific, inflammatory, and catabolic markers were analyzed.

Results

μFAT-treated TCs showed a reduced expression of PTGS2 and MMP-3 with respect to untreated controls. Increased IL-1Ra, VEGF, and IL-6 content were observed in the media of μFAT-treated samples, in comparison with untreated TCs.

Conclusion

μFAT exerted an anti-inflammatory action on supraspinatus tendon cells in vitro through paracrine action, resulting in the reduction of catabolic and inflammatory marker expression. These observations potentially support the use of μFAT as adjuvant therapy in the treatment of rotator cuff disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schmidt CC, Jarrett CD, Brown BT (2015) Management of Rotator Cuff Tears. J Hand Surg Am 40:399–408. https://doi.org/10.1016/j.jhsa.2014.06.122

    Article  PubMed  Google Scholar 

  2. Svendsen SW, Frost P, Jensen LD (2012) Time trends in surgery for non-traumatic shoulder disorders and postoperative risk of permanent work disability: a nationwide cohort study. Scand J Rheumatol 41:59–65. https://doi.org/10.3109/03009742.2011.595375

    Article  CAS  PubMed  Google Scholar 

  3. Colvin AC, Egorova N, Harrison AK et al (2012) National trends in rotator cuff repair. J Bone Joint Surg Am 94:227–233. https://doi.org/10.2106/JBJS.J.00739

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen M, Xu W, Dong Q et al (2013) Outcomes of single-row versus double-row arthroscopic rotator cuff repair: a systematic review and meta-analysis of current evidence. Arthroscopy 29:1437–1449. https://doi.org/10.1016/j.arthro.2013.03.076

    Article  PubMed  Google Scholar 

  5. Rhee YG, Cho NS, Yoo JH (2014) Clinical outcome and repair integrity after rotator cuff repair in patients older than 70 years versus patients younger than 70 years. Arthroscopy 30:546–554. https://doi.org/10.1016/j.arthro.2014.02.006

    Article  PubMed  Google Scholar 

  6. McElvany MD, McGoldrick E, Gee AO et al (2015) Rotator cuff repair: published evidence on factors associated with repair integrity and clinical outcome. Am J Sports Med 43:491–500. https://doi.org/10.1177/0363546514529644

    Article  PubMed  Google Scholar 

  7. Liu C-F, Aschbacher-Smith L, Barthelery NJ et al (2011) What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective. Tissue Eng Part B Rev 17:165–176. https://doi.org/10.1089/ten.TEB.2010.0662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Evans RB (2012) Managing the injured tendon: current concepts. J Hand Ther 25:173–189; quiz 190. https://doi.org/10.1016/j.jht.2011.10.004

    Article  PubMed  Google Scholar 

  9. Hoppe S, Alini M, Benneker LM et al (2013) Tenocytes of chronic rotator cuff tendon tears can be stimulated by platelet-released growth factors. J Shoulder Elb Surg 22:340–349. https://doi.org/10.1016/j.jse.2012.01.016

    Article  Google Scholar 

  10. Weeks KD, Dines JS, Rodeo SA, Bedi A (2014) The basic science behind biologic augmentation of tendon-bone healing: a scientific review. Instr Course Lect 63:443–450

    PubMed  Google Scholar 

  11. Abtahi AM, Granger EK, Tashjian RZ (2015) Factors affecting healing after arthroscopic rotator cuff repair. World J Orthop 6:211–220. https://doi.org/10.5312/wjo.v6.i2.211

    Article  PubMed  PubMed Central  Google Scholar 

  12. Randelli P, Randelli F, Ragone V et al (2014) Regenerative medicine in rotator cuff injuries. Biomed Res Int 2014. https://doi.org/10.1155/2014/129515

  13. Murphy MB, Moncivais K, Caplan AI (2013) Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med 45:e54. https://doi.org/10.1038/emm.2013.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abat F, Alfredson H, Cucchiarini M et al (2018) Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part II: treatment options. J Exp Orthop 5. https://doi.org/10.1186/s40634-018-0145-5

  15. Canapp SO, Canapp DA, Ibrahim V et al (2016) The use of adipose-derived progenitor cells and platelet-rich plasma combination for the treatment of supraspinatus tendinopathy in 55 dogs: a retrospective study. Front Vet Sci 3:61. https://doi.org/10.3389/fvets.2016.00061

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jo CH, Chai JW, Jeong EC et al (2018) Intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of rotator cuff disease: a first-in-human trial. Stem Cells 36:1441–1450. https://doi.org/10.1002/stem.2855

    Article  CAS  PubMed  Google Scholar 

  17. Mussano F, Genova T, Corsalini M et al (2017) Cytokine, chemokine, and growth factor profile characterization of undifferentiated and osteoinduced human adipose-derived stem cells. Stem Cells Int 2017:6202783. https://doi.org/10.1155/2017/6202783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Salmikangas P, Schuessler-Lenz M, Ruiz S et al (2015) Marketing regulatory oversight of advanced therapy medicinal products (ATMPs) in Europe: the EMA/CAT perspective. Adv Exp Med Biol 871:103–130. https://doi.org/10.1007/978-3-319-18618-4_6

    Article  PubMed  Google Scholar 

  19. Guess AJ, Daneault B, Wang R et al (2017) Safety profile of good manufacturing practice manufactured interferon γ-primed mesenchymal stem/stromal cells for clinical trials. Stem Cells Transl Med 6:1868–1879. https://doi.org/10.1002/sctm.16-0485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Polancec D, Zenic L, Hudetz D et al (2019) Immunophenotyping of a stromal vascular fraction from microfragmented lipoaspirate used in osteoarthritis cartilage treatment and its lipoaspirate counterpart. Genes (Basel) 10. https://doi.org/10.3390/genes10060474

  21. Nava S, Sordi V, Pascucci L et al (2019) Long-lasting anti-inflammatory activity of human microfragmented adipose tissue. Stem Cells Int 2019:5901479. https://doi.org/10.1155/2019/5901479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Paolella F, Manferdini C, Gabusi E et al (2019) Effect of microfragmented adipose tissue on osteoarthritic synovial macrophage factors. J Cell Physiol 234:5044–5055. https://doi.org/10.1002/jcp.27307

    Article  CAS  PubMed  Google Scholar 

  23. Randelli P, Menon A, Ragone V et al (2016) Lipogems product treatment increases the proliferation rate of human tendon stem cells without affecting their stemness and differentiation capability. Stem Cells Int 2016:4373410. https://doi.org/10.1155/2016/4373410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bianchi F, Maioli M, Leonardi E et al (2013) A new nonenzymatic method and device to obtain a fat tissue derivative highly enriched in pericyte-like elements by mild mechanical forces from human lipoaspirates. Cell Transplant 22:2063–2077. https://doi.org/10.3727/096368912X657855

    Article  PubMed  Google Scholar 

  25. Shah D, Naciri M, Clee P, Al-Rubeai M (2006) NucleoCounter—an efficient technique for the determination of cell number and viability in animal cell culture processes. Cytotechnology 51:39–44. https://doi.org/10.1007/s10616-006-9012-9

    Article  PubMed  PubMed Central  Google Scholar 

  26. Stanco D, Viganò M, Perucca Orfei C et al (2015) Multidifferentiation potential of human mesenchymal stem cells from adipose tissue and hamstring tendons for musculoskeletal cell-based therapy. Regen Med 10:729–743. https://doi.org/10.2217/rme.14.92

    Article  CAS  PubMed  Google Scholar 

  27. Desjardins P, Conklin D (2010) NanoDrop microvolume quantitation of nucleic acids. J Vis Exp. https://doi.org/10.3791/2565

  28. Viganò M, Perucca Orfei C, de Girolamo L et al (2018) Housekeeping gene stability in human mesenchymal stem and tendon cells exposed to tenogenic factors. Tissue Eng Part C Methods 24:360–367. https://doi.org/10.1089/ten.TEC.2017.0518

    Article  PubMed  Google Scholar 

  29. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  CAS  Google Scholar 

  30. Bailey AJ, Robins SP, Balian G (1974) Biological significance of the intermolecular crosslinks of collagen. Nature 251:105–109

    Article  CAS  Google Scholar 

  31. Nho SJ, Yadav H, Shindle MK, Macgillivray JD (2008) Rotator cuff degeneration: etiology and pathogenesis. Am J Sports Med 36:987–993. https://doi.org/10.1177/0363546508317344

    Article  PubMed  Google Scholar 

  32. Abraham AC, Shah SA, Thomopoulos S (2017) Targeting inflammation in rotator cuff tendon degeneration and repair. Tech Shoulder Elb Surg 18:84–90. https://doi.org/10.1097/BTE.0000000000000124

    Article  PubMed  PubMed Central  Google Scholar 

  33. Thankam FG, Roesch ZK, Dilisio MF et al (2018) Association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the injured rotator cuff tendon. Sci Rep 8:8918. https://doi.org/10.1038/s41598-018-27250-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gotoh M, Hamada K, Yamakawa H et al (1997) Significance of granulation tissue in torn supraspinatus insertions: an immunohistochemical study with antibodies against interleukin-1 beta, cathepsin D, and matrix metalloprotease-1. J Orthop Res 15:33–39. https://doi.org/10.1002/jor.1100150106

    Article  CAS  PubMed  Google Scholar 

  35. Riley GP, Curry V, DeGroot J et al (2002) Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix Biol 21:185–195

    Article  CAS  Google Scholar 

  36. Zhang J, Wang JH-C (2010) Production of PGE(2) increases in tendons subjected to repetitive mechanical loading and induces differentiation of tendon stem cells into non-tenocytes. J Orthop Res 28:198–203. https://doi.org/10.1002/jor.20962

    Article  PubMed  Google Scholar 

  37. Schneider M, Angele P, Järvinen TAH, Docheva D (2018) Rescue plan for Achilles: therapeutics steering the fate and functions of stem cells in tendon wound healing. Adv Drug Deliv Rev 129:352–375. https://doi.org/10.1016/j.addr.2017.12.016

    Article  CAS  PubMed  Google Scholar 

  38. Hammerman M, Blomgran P, Ramstedt S, Aspenberg P (2015) COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage. J Appl Physiol 119:534–540. https://doi.org/10.1152/japplphysiol.00239.2015

    Article  CAS  PubMed  Google Scholar 

  39. Rundle CH, Chen S-T, Coen MJ et al (2014) Direct lentiviral-cyclooxygenase 2 application to the tendon-bone interface promotes osteointegration and enhances return of the pull-out tensile strength of the tendon graft in a rat model of biceps tenodesis. PLoS One 9:e98004. https://doi.org/10.1371/journal.pone.0098004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bergqvist F, Carr AJ, Wheway K et al (2019) Divergent roles of prostacyclin and PGE2 in human tendinopathy. Arthritis Res Ther 21. https://doi.org/10.1186/s13075-019-1855-5

  41. Millar NL, Wei AQ, Molloy TJ et al (2009) Cytokines and apoptosis in supraspinatus tendinopathy. J Bone Joint Surg (Br) 91:417–424. https://doi.org/10.1302/0301-620X.91B3.21652

    Article  CAS  Google Scholar 

  42. Ackermann PW, Domeij-Arverud E, Leclerc P et al (2013) Anti-inflammatory cytokine profile in early human tendon repair. Knee Surg Sports Traumatol Arthrosc 21:1801–1806. https://doi.org/10.1007/s00167-012-2197-x

    Article  CAS  PubMed  Google Scholar 

  43. Millar NL, Akbar M, Campbell AL et al (2016) IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci Rep 6. https://doi.org/10.1038/srep27149

  44. Yoshihara Y, Hamada K, Nakajima T et al (2001) Biochemical markers in the synovial fluid of glenohumeral joints from patients with rotator cuff tear. J Orthop Res 19:573–579. https://doi.org/10.1016/S0736-0266(00)00063-2

    Article  CAS  PubMed  Google Scholar 

  45. Lo IKY, Marchuk LL, Hollinshead R et al (2004) Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase mRNA levels are specifically altered in torn rotator cuff tendons. Am J Sports Med 32:1223–1229. https://doi.org/10.1177/0363546503262200

    Article  PubMed  Google Scholar 

  46. Assunção JH, Godoy-Santos AL, Dos Santos MCLG et al (2017) Matrix metalloproteases 1 and 3 promoter gene polymorphism is associated with rotator cuff tear. Clin Orthop Relat Res 475:1904–1910. https://doi.org/10.1007/s11999-017-5271-3

    Article  PubMed  PubMed Central  Google Scholar 

  47. Del Buono A, Oliva F, Longo UG et al (2012) Metalloproteases and rotator cuff disease. J Shoulder Elb Surg 21:200–208. https://doi.org/10.1016/j.jse.2011.10.020

    Article  Google Scholar 

  48. Costa-Almeida R, Berdecka D, Rodrigues MT et al (2018) Tendon explant cultures to study the communication between adipose stem cells and native tendon niche. J Cell Biochem 119:3653–3662. https://doi.org/10.1002/jcb.26573

    Article  CAS  PubMed  Google Scholar 

  49. Costa-Almeida R, Calejo I, Reis RL, Gomes ME (2018) Crosstalk between adipose stem cells and tendon cells reveals a temporal regulation of tenogenesis by matrix deposition and remodeling. J Cell Physiol 233:5383–5395. https://doi.org/10.1002/jcp.26363

    Article  CAS  PubMed  Google Scholar 

  50. Gotoh M, Mitsui Y, Shibata H et al (2013) Increased matrix metalloprotease-3 gene expression in ruptured rotator cuff tendons is associated with postoperative tendon retear. Knee Surg Sports Traumatol Arthrosc 21:1807–1812. https://doi.org/10.1007/s00167-012-2209-x

    Article  PubMed  Google Scholar 

  51. Shukunami C, Takimoto A, Oro M, Hiraki Y (2006) Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol 298:234–247. https://doi.org/10.1016/j.ydbio.2006.06.036

    Article  CAS  PubMed  Google Scholar 

  52. Veronesi F, Della Bella E, Torricelli P et al (2015) Effect of adipose-derived mesenchymal stromal cells on tendon healing in aging and estrogen deficiency: an in vitro co-culture model. Cytotherapy 17:1536–1544. https://doi.org/10.1016/j.jcyt.2015.07.007

    Article  CAS  PubMed  Google Scholar 

  53. Thankam FG, Evan DK, Agrawal DK, Dilisio MF (2018) Collagen type III content of the long head of the biceps tendon as an indicator of glenohumeral arthritis. Mol Cell Biochem. https://doi.org/10.1007/s11010-018-3449-y

  54. Pajala A, Melkko J, Leppilahti J et al (2009) Tenascin-C and type I and III collagen expression in total Achilles tendon rupture. An immunohistochemical study. Histol Histopathol 24:1207–1211. https://doi.org/10.14670/HH-24.1207

    Article  CAS  PubMed  Google Scholar 

  55. Dabrowski MP, Stankiewicz W, Płusa T et al (2001) Competition of IL-1 and IL-1ra determines lymphocyte response to delayed stimulation with PHA. Mediat Inflamm 10:101–107

    Article  CAS  Google Scholar 

  56. Palomo J, Dietrich D, Martin P et al (2015) The interleukin (IL)-1 cytokine family – balance between agonists and antagonists in inflammatory diseases. Cytokine 76:25–37. https://doi.org/10.1016/j.cyto.2015.06.017

    Article  CAS  PubMed  Google Scholar 

  57. Luo J, Xiong Y, Han X, Lu Y (2011) VEGF non-angiogenic functions in adult organ homeostasis: therapeutic implications. J Mol Med; New York 89:635–645. https://doi.org/10.1007/s00109-011-0739-1

    Article  CAS  PubMed  Google Scholar 

  58. Cohen T, Nahari D, Cerem LW et al (1996) Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271:736–741

    Article  CAS  Google Scholar 

  59. Legerlotz K, Jones ER, Screen HRC, Riley GP (2012) Increased expression of IL-6 family members in tendon pathology. Rheumatology (Oxford) 51:1161–1165. https://doi.org/10.1093/rheumatology/kes002

    Article  CAS  Google Scholar 

  60. Liu Z, Simpson RJ, Cheers C (1995) Interaction of interleukin-6, tumour necrosis factor and interleukin-1 during Listeria infection. Immunology 85:562–567

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen S, Deng G, Li K et al (2018) Interleukin-6 promotes proliferation but inhibits Tenogenic differentiation via the Janus kinase/signal transducers and activators of transcription 3 (JAK/STAT3) pathway in tendon-derived stem cells. Med Sci Monit 24:1567–1573. https://doi.org/10.12659/MSM.908802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lin TW, Cardenas L, Glaser DL, Soslowsky LJ (2006) Tendon healing in interleukin-4 and interleukin-6 knockout mice. J Biomech 39:61–69. https://doi.org/10.1016/j.jbiomech.2004.11.009

    Article  PubMed  Google Scholar 

  63. John T, Lodka D, Kohl B et al (2010) Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytes. J Orthop Res 28:1071–1077. https://doi.org/10.1002/jor.21079

    Article  CAS  PubMed  Google Scholar 

  64. Pauly S, Klatte-Schulz F, Stahnke K et al (2018) The effect of autologous platelet rich plasma on tenocytes of the human rotator cuff. BMC Musculoskelet Disord 19:422. https://doi.org/10.1186/s12891-018-2339-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was funded by the Italian Ministry of Health “Ricerca Corrente.”

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlotta Perucca Orfei.

Ethics declarations

Conflict of interest

L.d.G.: paid consultant for Lipogems SpA. The other authors have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Viganò, M., Lugano, G., Perucca Orfei, C. et al. Autologous microfragmented adipose tissue reduces inflammatory and catabolic markers in supraspinatus tendon cells derived from patients affected by rotator cuff tears. International Orthopaedics (SICOT) 45, 419–426 (2021). https://doi.org/10.1007/s00264-020-04693-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00264-020-04693-9

Keywords

Navigation