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Detection of slow-cycling and stem/progenitor cells in different regions of rat Achilles tendon: response to treadmill exercise

  • Experimental Study
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

Tendons generally exhibit poor healing capacity, probably due to slow cell regeneration potential and low vascularization. The potential to regenerate may partly be due to activation of stem/progenitor cells localized in the tendon or its vicinity. In the present study, we attempted to determine where in the rat Achilles tendon stem/progenitor cells reside and to investigate the effect of exercise on cell proliferation in the in vivo situation.

Method

We used bromodeoxyuridine (BrdU) labelling to investigate proliferation and label-retaining cells (i.e. slow-cycling cells) in non-exercised and exercised rats, in combination with immunostaining of the stem cell marker nucleostemin. Rat Achilles tendons were harvested 14, 28, 56 and 105 days after BrdU administration.

Results

We found the proportion of stem/progenitor cells to be twice as high in the distal tendon (DT) compared with the mid/proximal tendon (MPT) and that paratenon/endotenon regions appear to host a pool of existing stem/progenitor cells. Exercise increased the BrdU-stained cell population after 14 days only (DT region p = 0.032, MPT p = 0.065), indicating effect mainly on more differentiated cells, since the nucleostemin-positive cells (i.e. stem/progenitor cells) remained unaffected in the intact Achilles tendon.

Conclusion

Stem/progenitor cells exist in several areas of the rat Achilles tendon which implies a possible stem cell regeneration pool of different origins. The distal region has twice the amount of stem/progenitor cells compared with the mid/proximal region, indicating a potentially higher stem cell activity in this tissue. Daily moderate exercise (treadmill running) mainly improves in vivo cell proliferation in rapidly proliferating cells, whereas the stem/progenitor pool remains constant.

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References

  1. Ackermann PW, Salo PT, Hart DA (2009) Neuronal pathways in tendon healing. Front Biosci 14:5165–5187

    Article  PubMed  CAS  Google Scholar 

  2. Benjamin M, Evans EJ, Copp L (1986) The histology of tendon attachments to bone in man. J Anat 149:89–100

    PubMed  CAS  Google Scholar 

  3. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF (2007) Identification of tendon stem/progenitor cells and the role of extracellular matrix in their niche. Nat Med 13:1219–1227

    Article  PubMed  CAS  Google Scholar 

  4. Boushel R, Langberg H, Green S, Skovgaard D, Bulow J, Kjaer M (2000) Blood flow and oxygenation in peritendinous tissue and calf muscle during dynamic exercise in humans. J Physiol 524:305–313

    Article  PubMed  CAS  Google Scholar 

  5. Couppé C, Kongsgaard M, Aagaard P, Hansen P, Bojsen-Moller J, Kjaer M, Magnusson SP (2008) Habitual loading results in tendon hypertrophy and increased stiffness of the human patellar tendon. J Appl Physiol 105:805–810

    Article  PubMed  Google Scholar 

  6. Gineyts E, Cloos PA, Borel O, Grimaud L, Delmas PD, Garnero P (2000) Racemization and isomerization of type I collagen C-telopeptides in human bone and soft tissue: assessment of tissue turnover. Biochem J 345:481–485

    Article  PubMed  CAS  Google Scholar 

  7. Glazebrook MA, Wright JR, Langman M, Stanish WD, Lee JM (2008) Histological analysis of achilles tendons in an overuse rat model. J Orthop Res 26:840–846

    Article  PubMed  Google Scholar 

  8. Heinemeier KM, Olesen JL, Haddad F, Langberg H, Kjaer M, Baldwin KM, Schjerling P (2007) Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types. J Physiol 582:1303–1316

    Article  PubMed  CAS  Google Scholar 

  9. Henriksson H, Thornemo M, Karlsson C, Hägg O, Junevik K, Lindahl A, Brisby H (2009) Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species. Spine (Phila Pa 1976) 34:2278–2287

    Article  Google Scholar 

  10. Holm L, Reitelseder S, Pedersen TG, Doessing S, Petersen SG, Flyvbjerg A, Andersen JL, Aagaard P, Kjaer M (2008) Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity. J Appl Physiol 105:1454–1461

    Article  PubMed  CAS  Google Scholar 

  11. Hong HS, Lee J, Lee E, Kwon YS, Lee E, Ahn W, Jiang MH, Kim JC, Son Y (2009) A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 15:425–435

    Article  PubMed  CAS  Google Scholar 

  12. Karlsson C, Thornemo M, Henriksson HB, Lindahl A (2009) Identification of a stem cell niche in the zone of Ranvier within the knee joint. J Anat 215:355–363

    Article  PubMed  Google Scholar 

  13. Kim SJ, Cheung S, Hellerstein MK (2004) Isolation of nuclei from label-retaining cells and measurement of their turnover rates in rat colon. Am J Physiol Cell Physiol 286:C1464–C1473

    Article  PubMed  CAS  Google Scholar 

  14. Ksiezopolska-Orlowska K (2010) Changes in bone mechanical strength in response to physical therapy. Pol Arch Med Wewn 120:368–373

    PubMed  Google Scholar 

  15. Maffulli N, Longo U, Sharma P, Denaro V (2010) Tendon injury and repair mechanics. In: Archer C, Ralphs J (eds) Regenerative medicine and biomaterials for the repair of connective tissue. Woodhead Publishing Limited, Cambridge, pp 394–418

    Chapter  Google Scholar 

  16. Magnusson SP, Langberg H, Kjaer M (2010) The pathogenesis of tendinopathy: balancing the response to loading. Nat Rev Rheumatol 6:262–268

    Article  PubMed  Google Scholar 

  17. Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 2:115–128

    Article  Google Scholar 

  18. Potten CS, Morris RJ (1988) Epithelial stem cells in vivo. J Cell Sci Suppl 10:45–62

    Article  PubMed  CAS  Google Scholar 

  19. Sasaki N, Henriksson HB, Runesson E, Larsson K, Sekiguchi M, Kikuchi S, Konno S, Rydevik B, Brisby H (2012) Physical exercise affects cell proliferation in lumbar intervertebral disc regions in rats. Spine (Phila Pa 1976) 37:1440–1447

    Article  Google Scholar 

  20. Skovgaard D, Bayer ML, Mackey AL, Madsen J, Kjaer M, Kjaer A (2010) Increased cellular proliferation in rat skeletal muscle and tendon in response to exercise: use of FLT and PET/CT. Mol Imaging Biol 12:626–634

    Article  PubMed  Google Scholar 

  21. Szczodry M, Zhang J, Lim C, Davitt HL, Yeager T, Fu FH, Wang JH (2009) Tredmill running exercise results in the presence of numerous myofibroblasts in mouse patellar tendon. J Orthop Res 27:1373–1378

    Article  PubMed  CAS  Google Scholar 

  22. Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM (2000) Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102:451–461

    Article  PubMed  CAS  Google Scholar 

  23. Tempfer H, Wagner A, Gehwolf R, Lehner C, Tauber M, Resch H, Bauer HC (2009) Perivascular cells of the supraspinatus tendon express both tendon- and stem cell-related markers. Histochem Cell Biol 131:733–741

    Article  PubMed  CAS  Google Scholar 

  24. Tsai RY, McKay RD (2002) A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 16:2991–3003

    Article  PubMed  CAS  Google Scholar 

  25. Yang G, Crawford RC, Wang JH (2004) Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions. J Biomech 37:1543–1550

    Article  PubMed  Google Scholar 

  26. Zeichen J, van Griensven M, Bosch U (2000) The proliferative response of isolated human tendon fibroblasts to cyclic biaxial mechanical strain. Am J Sports Med 28:888–892

    PubMed  CAS  Google Scholar 

  27. Zhang J, Pan T, Im HJ, Fu FH, Wang JH (2011) Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity. BMC Med 9:68

    Article  PubMed  Google Scholar 

  28. Zhang J, Pan T, Liu Y, Wang JH (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

    Article  PubMed  Google Scholar 

  29. Zhang J, Wang JH (2010) Mechanobiological response of tendon stem cells: implications of tendon homeostasis and pathogenesis of tendinopathy. J Orthop Res 28:639–643

    Article  PubMed  Google Scholar 

  30. Zhang J, Wang JH (2010) Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet Disord 11:10

    Article  PubMed  Google Scholar 

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Acknowledgments

The study was supported by grants from Sahlgrenska University Hospital, LUA/ALF Research project: 44931, Dr. Felix Neuberghs Foundation (ER) and by the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (project nr. SLL20100168).

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Authors and Affiliations

  1. Department of Orthopaedics, Institute of Clinical Sciences, University of Göteborg, Göteborg, Sweden

    Eva Runesson, Helena Brisby, Jón Karlsson & Bengt I. Eriksson

  2. Integrative Orthopaedic Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institute, 17176, Stockholm, Sweden

    Paul Ackermann

  3. Lundberg Laboratory for Orthopaedic Research, Department of Orthopaedics, Sahlgrenska University Hospital, Gröna Stråket 12, 413 45, Göteborg, Sweden

    Eva Runesson

  4. Department of Orthopaedics, Sahlgrenska University Hospital/Mölndal, 43180, Mölndal, Sweden

    Jón Karlsson & Bengt I. Eriksson

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  1. Eva Runesson
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  2. Paul Ackermann
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  3. Helena Brisby
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  4. Jón Karlsson
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  5. Bengt I. Eriksson
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Correspondence to Eva Runesson.

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Runesson, E., Ackermann, P., Brisby, H. et al. Detection of slow-cycling and stem/progenitor cells in different regions of rat Achilles tendon: response to treadmill exercise. Knee Surg Sports Traumatol Arthrosc 21, 1694–1703 (2013). https://doi.org/10.1007/s00167-013-2446-7

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  • DOI: https://doi.org/10.1007/s00167-013-2446-7

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