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Characterization of Tendon-Specific Markers in Various Human Tissues, Tenocytes and Mesenchymal Stem Cells

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Unlike bone, cartilage, or muscle, tendon-specific markers are not well established. The purpose of the study was to investigate expression pattern and level of 6 well-known tendon-specific markers, in various human musculoskeletal tissues, tenocytes, and mesenchymal stem cells (MSCs).

Methods:

Musculoskeletal tissue samples of tendon, bone, cartilage, nerve, muscle, and fat were obtained from patients undergoing orthopedic surgery. Tenocytes, MSCs from bone marrow, adipose tissue, and umbilical cord were isolated from each tissue and cultured. Six tendon-specific markers, scleraxis (Scx), tenomodulin (TNMD), thrombospondin-4 (TSP-4), tenascin-C (TNC), type I collagen (Col I), and type III collagen (Col III) were investigated in tendon tissue, tenocytes, and MSCs.

Results:

mRNA levels of 6 tendon-specific markers were significantly higher in tendon tissue that in other connective tissues levels of Scx, TNMD, TSP-4, and Col III immediately decreased after plating tenocytes in culture dishes whereas those of TNC and Col I did not. In comparison with tendon tissue, mRNA levels pattern of Scx, TNMD, and TSP-4 in tenocytes were significantly higher than that in MSCs, but lower than in tendon tissue whereas expression pattern of TNC, Col I and III showed different pattern with each other.

Conclusion:

This study demonstrated that 6 commonly used tendon-specific markers were mainly expressed in tendon tissue, but that expression level and pattern of the tendon-specific markers with respect to kinds of tissues, culture duration of tenocytes and sources of MSCs.

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References

  1. Maffulli N, Wong J, Almekinders LC. Types and epidemiology of tendinopathy. Clin Sports Med. 2003;22:675–92.

    Article  PubMed  Google Scholar 

  2. Pennisi E. Tending tender tendons. Science. 2002;295:1011.

    Article  CAS  PubMed  Google Scholar 

  3. Battaglia TC, Clark RT, Chhabra A, Gaschen V, Hunziker EB, Mikic B. Ultrastructural determinants of murine achilles tendon strength during healing. Connect Tissue Res. 2003;44:218–24.

    Article  PubMed  Google Scholar 

  4. Uhthoff HK, Trudel G, Himori K. Relevance of pathology and basic research to the surgeon treating rotator cuff disease. J Orthop Sci. 2003;8:449–56.

    Article  PubMed  Google Scholar 

  5. Heinemeier KM, Schjerling P, Heinemeier J, Magnusson SP, Kjaer M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb (14)C. FASEB J. 2013;27:2074–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lui PP, Rui YF, Ni M, Chan KM. Tenogenic differentiation of stem cells for tendon repair-what is the current evidence? J Tissue Eng Regen Med. 2011;5:e144–63.

    Article  CAS  PubMed  Google Scholar 

  7. Miyashita H, Ochi M, Ikuta Y. Histological and biomechanical observations of the rabbit patellar tendon after removal of its central one-third. Arch Orthop Trauma Surg. 1997;116:454–62.

    Article  CAS  PubMed  Google Scholar 

  8. Docheva D, Müller SA, Majewski M, Evans CH. Biologics for tendon repair. Adv Drug Deliv Rev. 2015;84:222–39.

    Article  CAS  PubMed  Google Scholar 

  9. Chen WH, Lai MT, Wu AT, Wu CC, Gelovani JG, Lin CT, et al. In vitro stage-specific chondrogenesis of mesenchymal stem cells committed to chondrocytes. Arthritis Rheum. 2009;60:450–9.

    Article  CAS  PubMed  Google Scholar 

  10. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. 2007;13:1219–27.

    Article  CAS  PubMed  Google Scholar 

  11. Kuemmerle JM, Theiss F, Okoniewski MJ, Weber FA, Hemmi S, Mirsaidi A, et al. Identification of novel equine (Equus caballus) tendon markers using RNA sequencing. Genes (Basel). 2016;7:E97.

    Article  CAS  Google Scholar 

  12. Lee JY, Zhou Z, Taub PJ, Ramcharan M, Li Y, Akinbiyi T, et al. BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo. PLoS One. 2011;6:e17531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brandau O, Meindl A, Fässler R, Aszódi A. A novel gene, tendin, is strongly expressed in tendons and ligaments and shows high homology with chondromodulin-I. Dev Dyn. 2001;221:72–80.

    Article  CAS  PubMed  Google Scholar 

  14. Edom-Vovard F, Duprez D. Signals regulating tendon formation during chick embryonic development. Dev Dyn. 2004;229:449–57.

    Article  CAS  PubMed  Google Scholar 

  15. Wolfman NM, Hattersley G, Cox K, Celeste AJ, Nelson R, Yamaji N, et al. Ectopic induction of tendon and ligament in rats by growth and differentiation factors 5, 6, and 7, members of the TGF-beta gene family. J Clin Invest. 1997;100:321–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Taylor SE, Vaughan-Thomas A, Clements DN, Pinchbeck G, Macrory LC, Smith RK, et al. Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems. BMC Musculoskelet Disord. 2009;10:27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shukunami C, Takimoto A, Oro M, Hiraki Y. Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol. 2006;298:234–47.

    Article  CAS  PubMed  Google Scholar 

  18. Jelinsky SA, Archambault J, Li L, Seeherman H. Tendon-selective genes identified from rat and human musculoskeletal tissues. J Orthop Res. 2010;28:289–97.

    CAS  PubMed  Google Scholar 

  19. Mazzocca AD, McCarthy MB, Chowaniec D, Cote MP, Judson CH, Apostolakos J, et al. Bone marrow-derived mesenchymal stem cells obtained during arthroscopic rotator cuff repair surgery show potential for tendon cell differentiation after treatment with insulin. Arthroscopy. 2011;27:1459–71.

    Article  PubMed  Google Scholar 

  20. Shi Y, Xiong Y, Jiang Y, Zhang Z, Zhou G, Zhang W, et al. Conditional tenomodulin overexpression favors tenogenic lineage differentiation of transgenic mouse derived cells. Gene. 2017;598:9–19.

    Article  CAS  PubMed  Google Scholar 

  21. Brown JP, Galassi TV, Stoppato M, Schiele NR, Kuo CK. Comparative analysis of mesenchymal stem cell and embryonic tendon progenitor cell response to embryonic tendon biochemical and mechanical factors. Stem Cell Res Ther. 2015;6:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jo CH, Kim JE, Yoon KS, Shin S. Platelet-rich plasma stimulates cell proliferation and enhances matrix gene expression and synthesis in tenocytes from human rotator cuff tendons with degenerative tears. Am J Sports Med. 2012;40:1035–45.

    Article  PubMed  Google Scholar 

  23. Yoon JY, Lee SY, Shin S, Yoon KS, Jo CH. Comparative analysis of platelet-rich plasma effect on tenocytes from normal human rotator cuff tendon and human rotator cuff tendon with degenerative tears. Clin Shoulder Elbow. 2018;21:3–14.

    Google Scholar 

  24. Jo CH, Kim OS, Park EY, Kim BJ, Lee JH, Kang SB, et al. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res. 2008;334:423–33.

    Article  PubMed  Google Scholar 

  25. Jo CH, Yoon PW, Kim H, Kang KS, Yoon KS. Comparative evaluation of in vivo osteogenic differentiation of fetal and adult mesenchymal stem cell in rat critical-sized femoral defect model. Cell Tissue Res. 2013;353:41–52.

    Article  CAS  PubMed  Google Scholar 

  26. Saiki A, Olsson M, Jernås M, Gummesson A, McTernan PG, Andersson J, et al. Tenomodulin is highly expressed in adipose tissue, increased in obesity, and down-regulated during diet-induced weight loss. J Clin Endocrinol Metab. 2009;94:3987–94.

    Article  CAS  PubMed  Google Scholar 

  27. Lee CH, Shah B, Moioli EK, Mao JJ. CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. J Clin Investig. 2010;120:3340–9.

    Article  CAS  PubMed  Google Scholar 

  28. Tan SL, Ahmad RE, Ahmad TS, Merican AM, Abbas AA, Ng WM, et al. Effect of growth differentiation factor 5 on the proliferation and tenogenic differentiation potential of human mesenchymal stem cells in vitro. Cells Tissues Organs. 2012;196:325–38.

    Article  CAS  PubMed  Google Scholar 

  29. Haddad-Weber M, Prager P, Kunz M, Seefried L, Jakob F, Murray MM, et al. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anterior cruciate ligament cells. Cytotherapy. 2010;12:505–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Güngörmüş C, Kolankaya D. Gene expression of tendon collagens and tenocyte markers in long-term monolayer and high-density cultures of rat tenocytes. Connect Tissue Res. 2012;53:485–91.

    Article  CAS  PubMed  Google Scholar 

  31. Almarza AJ, Augustine SM, Woo SL. Changes in gene expression of matrix constituents with respect to passage of ligament and tendon fibroblasts. Ann Biomed Eng. 2008;36:1927–33.

    Article  PubMed  Google Scholar 

  32. Yao L, Bestwick CS, Bestwick LA, Maffulli N, Aspden RM. Phenotypic drift in human tenocyte culture. Tissue Eng. 2006;12:1843–9.

    Article  CAS  PubMed  Google Scholar 

  33. Mazzocca AD, Chowaniec D, McCarthy MB, Beitzel K, Cote MP, McKinnon W, et al. In vitro changes in human tenocyte cultures obtained from proximal biceps tendon: multiple passages result in changes in routine cell markers. Knee Surg Sports Traumatol Arthrosc. 2012;20:1666–72.

    Article  PubMed  Google Scholar 

  34. Yin Z, Guo J, Wu TY, Chen X, Xu LL, Lin SE, et al. Stepwise differentiation of mesenchymal stem cells augments tendon-like tissue formation and defect repair in vivo. Stem Cells Transl Med. 2016;5:1106–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang W, He A, Zhang Z, Zhang W, Zhou G, Cao Y, et al. Induction of transient tenogenic phenotype of high-density cultured human dermal fibroblasts. Connect Tissue Res. 2015;56:288–99.

    Article  CAS  PubMed  Google Scholar 

  36. Stoll C, John T, Endres M, Rosen C, Kaps C, Kohl B, et al. Extracellular matrix expression of human tenocytes in three-dimensional air–liquid and PLGA cultures compared with tendon tissue: implications for tendon tissue engineering. J Orthop Res. 2010;28:1170–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Basic Science Research Program and the Bio and Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (NRF-2015M3A9E6028412 and NRF-2017R1A2B2010995).

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Correspondence to Chris Hyunchul Jo.

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The study protocol was approved by the institutional review board at our institution, and was conducted in accordance with the approved guidelines (Seoul National University Boramae Medical Center Institutional Review Board No. 20120405/06-2012-78/118). All patients from whom tissue specimens were harvested provided informed consent.

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Jo, C.H., Lim, HJ. & Yoon, K.S. Characterization of Tendon-Specific Markers in Various Human Tissues, Tenocytes and Mesenchymal Stem Cells. Tissue Eng Regen Med 16, 151–159 (2019). https://doi.org/10.1007/s13770-019-00182-2

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  • DOI: https://doi.org/10.1007/s13770-019-00182-2

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