Skip to main content

Exploring Stem Cells and Inflammation in Tendon Repair and Regeneration

  • Chapter
  • First Online:
Cell Biology and Translational Medicine, Volume 2

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1089))

Abstract

Tendon injuries are frequent and are responsible for substantial morbidity both in sports and in the workplace. Despite the endogenous mechanisms of tendon repair and regeneration, tendon healing upon injury is slow and often insufficient to restore complete biomechanics functionality.

Inflammation has a pivotal role in tendon healing and failed healing responses contribute to the progression of tendinopathies. However, the molecular and cellular mechanisms involved are poorly understood requiring further insights.

During inflammation, bioactive molecules such as cytokines secreted locally at the injury site, influence resident stem cells that contribute as modulatory agents over the niche towards homeostasis, holding great promise as therapeutic agents for tendon pathological conditions associated to unresolved inflammation and failed healing.

This review overviews the role of cytokines and resident cells, focusing on the participation of tendon stem cell population in inflammation and tendon healing upon injury and their potential action in resolution of pathological conditions.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CTGF:

connective tissue growth factor

ECM:

extracelular matrix

MMPs:

matrix metalloproteinases

MSCs:

mesenchymal stem/stromal cell

NO:

nitric oxide

STAT3:

activator of transcription 3

TDSCs:

tendon-derived stem cells

References

  • Abate M, Gravare-Silbernagel K, Siljeholm C, Iorio AD, Amicis DD, Salini V, Werner S, Paganelli R (2009) Pathogenesis of tendinopathies- inflammation or degeneration? Arthritis Res Ther 11:1–15

    Article  Google Scholar 

  • Ackermann PW, Domeij-Arverud E, Leclerc P, Amoudrouz P, Nader GA (2013) Anti-inflammatory cytokine profile in early human tendon repair. Knee Surg Sports Traumatol Arthrosc 21:1801–1806

    Article  CAS  PubMed  Google Scholar 

  • Andia I, Sanchez M, Maffulli N (2010) Tendon healing and platelet-rich plasma therapies. Expert Opin Biol Ther 10:1415–1426

    Article  PubMed  Google Scholar 

  • Aparecida de Aro A, Vidal Bde C, Pimentel ER (2012) Biochemical and anisotropical properties of tendons. Micron 43:205–214

    Article  CAS  PubMed  Google Scholar 

  • Barr AE, Barbe MF (2004) Inflammation reduces physiological tissue tolerance in the development of work-related musculoskeletal disorders. J Electromyogr Kinesiol 14:77–85

    Article  PubMed  Google Scholar 

  • Bauge C, Leclercq S, Conrozier T, Boumediene K (2015) TOL19-001 reduces inflammation and MMP expression in monolayer cultures of tendon cells. BMC Complement Altern Med 15:217

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 the extracellular matrix in their niche. Nat Med 13:1219–1227

    Article  CAS  PubMed  Google Scholar 

  • Buono AD, Oliva F, Osti L, Maffulli N (2013) Metalloproteases and tendinopathy. Muscles Ligaments Tendons J 3:51–57

    PubMed  PubMed Central  Google Scholar 

  • Cadby JA, Buehler E, Godbout C, van Weeren PR, Snedeker JG (2014) Differences between the cell populations from the peritenon and the tendon core with regard to their potential implication in tendon repair. PLoS One 9(3):e92474

    Article  PubMed  PubMed Central  Google Scholar 

  • Courneya J-P, Luzina IG, Zeller CB, Rasmussen JF, Bocharov A, Schon LC, Atamas SP (2010) Interleukins 4 and 13 modulate gene expression and promote proliferation of primary human tenocytes. Fibrogenesis Tissue Repair 3:2–8

    Article  Google Scholar 

  • D’Addona A, Maffulli N, Formisano S, Rosa D (2017) Inflammation in tendinopathy. Surgeon 15(5):297–302

    Article  PubMed  Google Scholar 

  • Dakin SG, Dudhia J, Smith RK (2014) Resolving an inflammatory concept: the importance of inflammation and resolution in tendinopathy. Vet Immunol Immunopathol 158:121–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dean BJF, Dakin SG, Millar NL, Carr AJ (2017) Review- emerging concepts in the pathogenesis of tendinopathy. Surgeon J R Coll Surg Edinb Irel 15(6):349–354

    Google Scholar 

  • Docheva D, Muller SA, Majewski M, Evans CH (2015) Biologics for tendon repair. Adv Drug Deliv Rev 84:222–239

    Article  CAS  PubMed  Google Scholar 

  • Dohnert MB, Ferreira GK, Silveira PC, Zanoni ET, Dohnert LH, de Souza CT, Paula MM (2015) Inflammatory cytokines content in Achilles tendinopathy after phonophoresis treatment combined with gold nanoparticles and diclophenac diethylammonium in rats. Inflammation 38:1044–1049

    Article  CAS  PubMed  Google Scholar 

  • Durgam SS, Stewart MC (2016) Tendon-derived progenitor cells: in vitro characterization and clinical applications for tendon repair. J Stem Cell Res Med 1:8–17

    Article  Google Scholar 

  • Evans CH (1999) Cytokines and the role they play in the healing of ligaments and tendons. Sports Med 28:71–76

    Article  CAS  PubMed  Google Scholar 

  • Harrison R, Jones M, Grobbelar AO, McGrouther DA, Brown RA, Mudera V (2003) Tendon healing intrinsic or extrinsic? Direct evidence for dual mechanisms in early stages of tendon injury. Tissue Eng 9(4):852–852

    Google Scholar 

  • Ho JO, Sawadkar P, Mudera V (2014) A review on the use of cell therapy in the treatment of tendon disease and injuries. J Tissue Eng 5:204173141454967

    Article  Google Scholar 

  • James R, Kesturu G, Balian G, Chhabra AB (2008) Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options. J Hand Surg 33:102–112

    Article  Google Scholar 

  • John T, Lodka D, Kohl B, Ertel W, Jammrath J, Conrad C, Stoll C, Busch C, Schulze-Tanzil G (2010) Effect of pro-inflammatory and Immunoregulatory cytokines on human tenocytes. J Orthop Res 28:1071–1077

    CAS  PubMed  Google Scholar 

  • Killian ML, Cavinatto L, Galatz LM, Thomopoulos S (2012) The role of mechanobiology in tendon healing. J Shoulder Elb Surg 21:228–237

    Article  Google Scholar 

  • Legerlotz K, Jones ER, Screen HR, Riley GP (2012) Increased expression of IL-6 family members in tendon pathology. Rheumatology 51:1161–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin TW, Cardenas L, Glaser DL, Soslowsky LJ (2006) Tendon healing in interleukin-4 and interleukin-6 knockout mice. J Biomech 39:61–69

    Article  PubMed  Google Scholar 

  • Liu H, Zhu S, Zhang C, Lu P, Hu J, Yin Z, Ma Y, Chen X, Ouyang H (2014) Crucial transcription factors in tendon development and differentiation: their potential for tendon regeneration. Cell Tissue Res 356:287–298

    Article  PubMed  Google Scholar 

  • Lui PP (2013) Identity of tendon stem cells--how much do we know? J Cell Mol Med 17:55–64

    Article  CAS  PubMed  Google Scholar 

  • Lui PP (2015) Stem cell technology for tendon regeneration: current status, challenges, and future research directions. Stem Cells Cloning Adv Appl 2015:163

    Article  Google Scholar 

  • Lui PP, Chan KM (2011) Tendon-derived stem cells (TDSCs): from basic science to potential roles in tendon pathology and tissue engineering applications. Stem Cell Rev 7:883–897

    Article  CAS  Google Scholar 

  • Lui PPY, Wong OT, Lee YW (2016) Transplantation of tendon-derived stem cells pre-treated with connective tissue growth factor and ascorbic acid in vitro promoted better tendon repair in a patellar tendon window injury rat model. Cytotherapy 18:99–112

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Meirelles LS, Fontes AM, Covas DT, Caplan AI (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 20:419–427

    Article  CAS  Google Scholar 

  • Mienaltowski MJ, Adams SM, Birk DE (2014) Tendon proper- and peritenon-derived progenitor cells have unique tenogenic properties. Stem Cell Res Ther 5:1–15

    Article  Google Scholar 

  • Millar NL, Wei AQ, Molloy TJ, Bonar F, Murrell GAC (2009) Cytokines and apoptosis in supraspinatus tendinopathy. J Bone Joint Surg 91:417–424

    Article  CAS  Google Scholar 

  • Millar NL, Akbar M, Campbell AL, Reilly JH, Kerr SC, McLean M, Frleta-Gilchrist M, Fazzi UG, Leach WJ, Rooney BP, Crowe LAN, Murrell GAC, McInnes IB (2015) IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci Rep 6:1–11

    Google Scholar 

  • Millar NL, Murrell GA, McInnes IB (2017) Inflammatory mechanisms in tendinopathy – towards translation. Nat Rev Rheumatol 13:110–122

    Article  CAS  PubMed  Google Scholar 

  • Mobasheri A, Shakibaei M (2013) Is tendinitis an inflammatory disease initiated and driven by pro-inflammatory cytokines such as interleukin 1ß? Histol Histopathol 28:955–964

    CAS  PubMed  Google Scholar 

  • Morita W, Dakin SG, Snelling SJB, Carr AJ (2017) Cytokines in tendon disease. Bone Joint Res 6:656–664

    Article  CAS  PubMed  Google Scholar 

  • Muller SA, Todorov A, Heisterbach PE, Martin I, Majewski M (2015) Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc 23:2097–2105

    Article  PubMed  Google Scholar 

  • Ni M, Rui YF, Tan Q, Liu Y, Xu LL, Chan KM, Wang Y, Li G (2013) Engineered scaffold-free tendon tissue produced by tendon-derived stem cells. Biomaterials 34:2024–2037

    Article  CAS  PubMed  Google Scholar 

  • Prisk V, Huard J (2003) Muscle injuries and repair. Histol Histopathol 18:1243–1256

    CAS  PubMed  Google Scholar 

  • Proffen BL, Haslauer CM, Harris CE, Murray MM (2013) Mesenchymal stem cells from the retropatellar fat pad and peripheral blood stimulate ACL fibroblast migration, proliferation, and collagen gene expression. Connect Tissue Res 54:14–21

    Article  CAS  PubMed  Google Scholar 

  • Rees JD, Stride M, Scott A (2014) Tendons--time to revisit inflammation. Br J Sports Med 48:1553–1557

    Article  PubMed  Google Scholar 

  • Ren K, Torres R (2009) Role of interleukin-1beta during pain and inflammation. Brain Res Rev 60:57–64

    Article  CAS  PubMed  Google Scholar 

  • Riggin CN, Morris TR, Soslowsky LJ (2015) Tendinopathy II: etiology, pathology, and healing of tendon injury and disease. In: Reis M, Rodrigues MRT (eds) Tendon regeneration understanding tissue physiology and development to engineer functional substitutes. Elsevier, San Diego

    Google Scholar 

  • Rileya GP, Currya V, Degrootb J, Bv E, Verzijlb N, Hazlemana BL, Bankb RA (2002) Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix Biol 21:185–195

    Article  Google Scholar 

  • Rodrigues MT, Reis RL, Gomes ME (2013) Engineering tendon and ligament tissues: present developments towards successful clinical products. J Tissue Eng Regen Med 7:673–686

    Article  CAS  PubMed  Google Scholar 

  • Schulze-Tanzil G, Al-Sadi O, Wiegand E, Ertel W, Busch C, Kohl B, Pufe T (2011) The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insights. Scand J Med Sci Sports 21:337–351

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Maffulli N (2005) Basic biology of tendon injury and healing. Surgeon 3:309–316

    Article  CAS  PubMed  Google Scholar 

  • Shen W, Chen J, Yin Z, Chen X, Liu H, Heng BC, Chen W, Ouyang HW (2012) Allogenous tendon stem/progenitor cells in silk scaffold for functional shoulder repair. Cell Transplant 21:943–958

    Article  PubMed  Google Scholar 

  • Shen H, Kormpakis I, Havlioglu N, Linderman SW, Sakiyama-Elbert SE, Erickson IE, Zarembinski T, Silva MJ, Gelberman RH, Thomopoulos S (2016) The effect of mesenchymal stromal cell sheets on the inflammatory stage of flexor tendon healing. Stem Cell Res Ther 7:144

    Article  PubMed  PubMed Central  Google Scholar 

  • Snedeker JG, Foolen J (2017) Tendon injury and repair – a perspective on the basic mechanisms of tendon disease and future clinical therapy. Acta Biomater 63:18–36

    Article  PubMed  Google Scholar 

  • Speed C (2016) Metabolic influences on risk for tendon disorders. In: Ackermann PW, Hart D (eds) Metabolic influences on risk for tendon disorders, Advances in Experimental Medicine and Biology. Springer, Cham

    Google Scholar 

  • Stalman A, Bring D, Ackermann PW (2015) Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat. Knee Surg Sports Traumatol Arthrosc 23:2682–2689

    Article  CAS  PubMed  Google Scholar 

  • Subramanian A, Schilling TF (2015) Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix. Development 142:4191–4204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan SL, Selvaratnam L, Ahmad TS (2015) A mini review on the basic knowledge on tendon: revisiting the normal & injured tendon. JUMMEC 18:1–14

    Article  Google Scholar 

  • Tarafder S, Chen E, Jun Y, Kao K, Sim KH, Back J, Lee FY, Lee CH (2017) Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling. FASEB J 31:3991–3998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tempfer H, Traweger A (2015) Tendon vasculature in health and disease. Front Physiol 6:330

    Article  PubMed  PubMed Central  Google Scholar 

  • Thomopoulos S, Parks WC, Rifkin DB, Derwin KA (2015) Mechanisms of tendon injury and repair. J Orthop Res 33:832–839

    Article  PubMed  PubMed Central  Google Scholar 

  • Wojdasiewicz P, Poniatowski LA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm 2014:561459

    Article  Google Scholar 

  • Wynn TA, Vannella KM (2016) Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44:450–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang G, Im HJ, Wang JH (2005) Repetitive mechanical stretching modulates IL-1beta induced COX-2, MMP-1 expression, and PGE2 production in human patellar tendon fibroblasts. Gene 363:166–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zabrzyński J, Zabrzyńska A, Grzanka D (2016) Tendinopathy – a disease of tendons. J Orthop Trauma Surg Relat Res 3:024–030

    Google Scholar 

  • Zhang J, Wang JH-C (2010) Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet Disord 11:1–11

    Article  CAS  Google Scholar 

  • Zhang X, Lin YC, Rui YF, Xu HL, Chen H, Wang C, Teng GJ (2016) Therapeutic roles of tendon stem/progenitor cells in tendinopathy. Stem Cells Int 2016:4076578

    PubMed  PubMed Central  Google Scholar 

  • Zhou Z, Akinbiyi T, Xu L, Ramcharan M, Leong DJ, Ros SJ, Colvin AC, Schaffler MB, Majeska RJ, Flatow EL, Sun HB (2010) Tendon-derived stem/progenitor cell aging: defective self-renewal and altered fate. Aging Cell 9:911–915

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the financial support from Fundação para a Ciência e Tecnologia (FCT) for the doctoral grant PD/BD/128089/2016, the project NORTE-01-0145-FEDER-000021 supported by Norte Portugal Regional Operational Programme (NORTE 2020) and HORIZON 2020 under the TEAMING GRANT agreement No 739572 – The Discoveries CTR.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. E. Gomes .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Vinhas, A., Rodrigues, M.T., Gomes, M.E. (2018). Exploring Stem Cells and Inflammation in Tendon Repair and Regeneration. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 2. Advances in Experimental Medicine and Biology(), vol 1089. Springer, Cham. https://doi.org/10.1007/5584_2018_258

Download citation

Publish with us

Policies and ethics