Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2018

Open Access 01-12-2018 | Research article

Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model

Authors: A. B. Ahrberg, C. Horstmeier, D. Berner, W. Brehm, C. Gittel, A. Hillmann, C. Josten, G. Rossi, S. Schubert, K. Winter, J. Burk

Published in: BMC Musculoskeletal Disorders | Issue 1/2018

Login to get access

Abstract

Background

Mesenchymal stromal cells (MSC) have shown promising results in the treatment of tendinopathy in equine medicine, making this therapeutic approach seem favorable for translation to human medicine. Having demonstrated that MSC engraft within the tendon lesions after local injection in an equine model, we hypothesized that they would improve tendon healing superior to serum injection alone.

Methods

Quadrilateral tendon lesions were induced in six horses by mechanical tissue disruption combined with collagenase application 3 weeks before treatment. Adipose-derived MSC suspended in serum or serum alone were then injected intralesionally. Clinical examinations, ultrasound and magnetic resonance imaging were performed over 24 weeks. Tendon biopsies for histological assessment were taken from the hindlimbs 3 weeks after treatment. Horses were sacrificed after 24 weeks and forelimb tendons were subjected to macroscopic and histological examination as well as analysis of musculoskeletal marker expression.

Results

Tendons injected with MSC showed a transient increase in inflammation and lesion size, as indicated by clinical and imaging parameters between week 3 and 6 (p < 0.05). Thereafter, symptoms decreased in both groups and, except that in MSC-treated tendons, mean lesion signal intensity as seen in T2w magnetic resonance imaging and cellularity as seen in the histology (p < 0.05) were lower, no major differences could be found at week 24.

Conclusions

These data suggest that MSC have influenced the inflammatory reaction in a way not described in tendinopathy studies before. However, at the endpoint of the current study, 24 weeks after treatment, no distinct improvement was observed in MSC-treated tendons compared to the serum-injected controls. Future studies are necessary to elucidate whether and under which conditions MSC are beneficial for tendon healing before translation into human medicine.
Literature
1.
de Jonge S, van den Berg C, de Vos RJ, van der Heide HJL, Weir A, Verhaar JAN, et al. Incidence of midportion Achilles tendinopathy in the general population. Br J Sports Med. 2011;45:1026–8.CrossRefPubMed
2.
Alfredson H. Ultrasound and Doppler-guided mini-surgery to treat midportion Achilles tendinosis: results of a large material and a randomised study comparing two scraping techniques. Br J Sports Med. 2011;45:407–10.CrossRefPubMed
3.
de Jonge S, de Vos RJ, Weir A, van Schie HTM, Bierma-Zeinstra SMA, Verhaar JAN, et al. One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial. Am J Sports Med. 2011;39:1623–9.CrossRefPubMed
4.
Sadoghi P, Rosso C, Valderrabano V, Leithner A, Vavken P. The role of platelets in the treatment of Achilles tendon injuries. J Orthop Res Off Publ Orthop Res Soc. 2013;31:111–8.CrossRef
5.
Willberg L, Sunding K, Ohberg L, Forssblad M, Fahlström M, Alfredson H. Sclerosing injections to treat midportion Achilles tendinosis: a randomised controlled study evaluating two different concentrations of Polidocanol. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. 2008;16:859–64.CrossRef
6.
Vannini F, Di Matteo B, Filardo G, Kon E, Marcacci M, Giannini S. Platelet-rich plasma for foot and ankle pathologies: a systematic review. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2014;20:2–9.CrossRef
7.
Kearney RS, Parsons N, Metcalfe D, Costa ML. Injection therapies for Achilles tendinopathy. Cochrane Database Syst Rev. 2015;(5):CD010960.
8.
Filardo G, Di Matteo B, Kon E, Merli G, Marcacci M. Platelet-rich plasma in tendon-related disorders: results and indications. Knee Surg Sports Traumatol Arthrosc. 2018;26(7):1984–99.
9.
Avella CS, Ely ER, Verheyen KLP, Price JS, Wood JLN, Smith RKW. Ultrasonographic assessment of the superficial digital flexor tendons of National Hunt racehorses in training over two racing seasons. Equine Vet J. 2009;41:449–54.CrossRefPubMed
10.
Patterson-Kane JC, Becker DL, Rich T. The pathogenesis of tendon microdamage in athletes: the horse as a natural model for basic cellular research. J Comp Pathol. 2012;147:227–47.CrossRefPubMed
11.
Smith RKW, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS One. 2013;8:e75697.CrossRefPubMedPubMedCentral
12.
Williams RB, Harkins LS, Hammond CJ, Wood JL. Racehorse injuries, clinical problems and fatalities recorded on British racecourses from flat racing and National Hunt racing during 1996, 1997 and 1998. Equine Vet J. 2001;33:478–86.CrossRefPubMed
13.
U.S. Department of Health and Human Services; Food and Drug Administration; Center for Biologics Evaluation and Research. Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage [Internet]. 2011. Available from: https://​www.​fda.​gov/​downloads/​ucm288011.​pdf.
14.
15.
Smith RKW, Korda M, Blunn GW, Goodship AE. Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment. Equine Vet J. 2003;35:99–102.CrossRefPubMed
16.
Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RKW. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44:25–32.CrossRefPubMed
17.
Geburek F, Lietzau M, Beineke A, Rohn K, Stadler PM. Effect of a single injection of autologous conditioned serum (ACS) on tendon healing in equine naturally occurring tendinopathies. Stem Cell Res Ther. 2015;6:126.CrossRefPubMedPubMedCentral
18.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.CrossRefPubMed
19.
Richardson LE, Dudhia J, Clegg PD, Smith R. Stem cells in veterinary medicine--attempts at regenerating equine tendon after injury. Trends Biotechnol. 2007;25:409–16.CrossRefPubMed
20.
Brehm W, Burk J, Delling U, Gittel C, Ribitsch I. Stem cell-based tissue engineering in veterinary orthopaedics. Cell Tissue Res. 2012;347:677–88.CrossRefPubMed
21.
Uder C, Brückner S, Winkler S, Tautenhahn HM, Christ B. Mammalian MSC from selected species: Features and applications. Cytometry A. 2018;93(1):32–49.
22.
Burk J, Berner D, Brehm W, Hillmann A, Horstmeier C, Josten C, et al. Long-term cell tracking following local injection of mesenchymal stromal cells in the equine model of induced tendon disease. Cell Transplant. 2016;25:2199–211.CrossRefPubMed
23.
Smith RKW, McIlwraith CW. Consensus on equine tendon disease: building on the 2007 Havemeyer symposium: consensus on equine tendon disease. Equine Vet J. 2012;44:2–6.CrossRefPubMed
24.
Burk J, Ribitsch I, Gittel C, Juelke H, Kasper C, Staszyk C, et al. Growth and differentiation characteristics of equine mesenchymal stromal cells derived from different sources. Vet J. 2013;195:98–106.CrossRefPubMed
25.
Paebst F, Piehler D, Brehm W, Heller S, Schroeck C, Tárnok A, et al. Comparative immunophenotyping of equine multipotent mesenchymal stromal cells: an approach toward a standardized definition. Cytom Part J Int Soc Anal Cytol. 2014;85:678–87.CrossRef
26.
Rantanen N, Jorgensen J, Genovese R. Ultrasonographic Evaluation of the Equine Limb: Technique. Ross MW, Dyson SJ Ed Diagn Manag Lameness Horse. 2nd ed. 2011. p. 182–205.
27.
Vallance SA, Vidal MA, Whitcomb MB, Murphy BG, Spriet M, Galuppo LD. Evaluation of a diode laser for use in induction of tendinopathy in the superficial digital flexor tendon of horses. Am J Vet Res. 2012;73:1435–44.CrossRefPubMed
28.
Crovace A, Lacitignola L, Rossi G, Francioso E. Histological and Immunohistochemical Evaluation of Autologous Cultured Bone Marrow Mesenchymal Stem Cells and Bone Marrow Mononucleated Cells in Collagenase-Induced Tendinitis of Equine Superficial Digital Flexor Tendon. Vet Med Int [Internet]. 2010 [cited 2015 Dec 2]; 2010. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pmc/​articles/​PMC2859019/​
29.
Martinello T, Pascoli F, Caporale G, Perazzi A, Iacopetti I, Patruno M. Might the Masson trichrome stain be considered a useful method for categorizing experimental tendon lesions? Histol Histopathol. 2015;30:963–9.PubMed
30.
Kittler J, Illingworth J. Minimum error thresholding. Pattern Recogn. 1986;19:41–7.CrossRef
31.
Hillmann A, Ahrberg AB, Brehm W, Heller S, Josten C, Paebst F, et al. Comparative characterization of human and equine mesenchymal stromal cells: a basis for translational studies in the equine model. Cell Transplant. 2016;25:109–24.CrossRefPubMed
32.
Pfaffl MW. Transcriptional biomarkers. Methods San Diego Calif. 2013;59:1–2.CrossRef
33.
Schnabel LV, Lynch ME, van der Meulen MCH, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons. J Orthop Res Off Publ Orthop Res Soc. 2009;27:1392–8.CrossRef
34.
Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15:641–8.CrossRefPubMedPubMedCentral
35.
Conze P, van Schie HT, van WR, Staszyk C, Conrad S, Skutella T, et al. Effect of autologous adipose tissue-derived mesenchymal stem cells on neovascularization of artificial equine tendon lesions. Regen Med. 2014;9:743–57.CrossRefPubMed
36.
Carvalho A de M, Badial PR, Álvarez LEC, Yamada ALM, Borges AS, Deffune E, et al. Equine tendonitis therapy using mesenchymal stem cells and platelet concentrates: a randomized controlled trial. Stem Cell Res Ther. 2013;4:85.CrossRef
37.
Burk J, Gittel C, Heller S, Pfeiffer B, Paebst F, Ahrberg AB, et al. Gene expression of tendon markers in mesenchymal stromal cells derived from different sources. BMC Res Notes. 2014;7:826.CrossRefPubMedPubMedCentral
38.
Geburek F, Mundle K, Conrad S, Hellige M, Walliser U, van Schie HTM, et al. Tracking of autologous adipose tissue-derived mesenchymal stromal cells with in vivo magnetic resonance imaging and histology after intralesional treatment of artificial equine tendon lesions - a pilot study. Stem Cell Res Ther. 2016;7:21.CrossRefPubMedPubMedCentral
39.
Yang Y, Zhang J, Qian Y, Dong S, Huang H, Boada FE, et al. Superparamagnetic Iron oxide is suitable to label tendon stem cells and track them in vivo with MR imaging. Ann Biomed Eng. 2013;41:2109–19.CrossRefPubMedPubMedCentral
40.
Addicott B, Willman M, Rodriguez J, Padgett K, Han D, Berman D, et al. Mesenchymal stem cell labeling and in vitro MR characterization at 1.5 T of new SPIO contrast agent: Molday ION rhodamine-BTM. Contrast Media Mol Imaging. 2011;6:7–18.CrossRefPubMed
41.
Bourzac CA, Koenig JB, Link KA, Nykamp SG, Koch TG. Evaluation of ultrasmall superparamagnetic iron oxide contrast agent labeling of equine cord blood and bone marrow mesenchymal stromal cells. Am J Vet Res. 2014;75:1010–7.CrossRefPubMed
42.
Wang L, Deng J, Wang J, Xiang B, Yang T, Gruwel M, et al. Superparamagnetic iron oxide does not affect the viability and function of adipose-derived stem cells, and superparamagnetic iron oxide-enhanced magnetic resonance imaging identifies viable cells. Magn Reson Imaging. 2009;27:108–19.CrossRefPubMed
43.
Delling U, Brehm W, Metzger M, Ludewig E, Winter K, Jülke H. In vivo tracking and fate of intra-Articularly injected superparamagnetic Iron oxide particle-labeled multipotent stromal cells in an ovine model of osteoarthritis. Cell Transplant. 2015;24:2379–90.CrossRefPubMed
44.
Astanina K, Simon Y, Cavelius C, Petry S, Kraegeloh A, Kiemer AK. Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production. Acta Biomater. 2014;10:4896–911.CrossRefPubMed
45.
Schäfer R, Ayturan M, Bantleon R, Kehlbach R, Siegel G, Pintaske J, et al. The use of clinically approved small particles of iron oxide (SPIO) for labeling of mesenchymal stem cells aggravates clinical symptoms in experimental autoimmune encephalomyelitis and influences their in vivo distribution. Cell Transplant. 2008;17:923–41.CrossRefPubMed
46.
Williams IF, McCullagh KG, Goodship AE, Silver IA. Studies on the pathogenesis of equine tendonitis following collagenase injury. Res Vet Sci. 1984;36:326–38.PubMed
47.
Little D, Schramme M. Ultrasonographic and MRI evaluation of a novel tendonitis model in the horse. Vet Surg. 2006;35:E15.CrossRef
48.
Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL. Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis. Am J Vet Res. 2008;69:928–37.CrossRefPubMed
49.
De Becker A, Riet IV. Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy? World J Stem Cells. 2016;8:73–87.CrossRefPubMedPubMedCentral
50.
Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J, et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radiation-induced multi-organ failure syndrome. J Gene Med. 2003;5:1028–38.CrossRefPubMed
51.
Carvalho AM, Yamada ALM, Golim MA, Álvarez LEC, Hussni CA, Alves ALG. Evaluation of mesenchymal stem cell migration after equine tendonitis therapy. Equine Vet J. 2014;46:635–8.CrossRefPubMed
52.
Guest DJ, Smith MRW, Allen WR. Equine embryonic stem-like cells and mesenchymal stromal cells have different survival rates and migration patterns following their injection into damaged superficial digital flexor tendon. Equine Vet J. 2010;42:636–42.CrossRefPubMed
53.
Dakin SG, Dudhia J, Smith RKW. Resolving an inflammatory concept: the importance of inflammation and resolution in tendinopathy. Vet Immunol Immunopathol. 2014;158:121–7.CrossRefPubMedPubMedCentral
Metadata
Title
Effects of mesenchymal stromal cells versus serum on tendon healing in a controlled experimental trial in an equine model
Authors
A. B. Ahrberg
C. Horstmeier
D. Berner
W. Brehm
C. Gittel
A. Hillmann
C. Josten
G. Rossi
S. Schubert
K. Winter
J. Burk
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2018
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-018-2163-y

Other articles of this Issue 1/2018

BMC Musculoskeletal Disorders 1/2018 Go to the issue

Research article

Effects of deep cervical flexor training on impaired physiological functions associated with chronic neck pain: a systematic review

Research article

Quality of internet-based decision aids for shoulder arthritis: what are patients reading?

Research article

Associations among knee muscle strength, structural damage, and pain and mobility in individuals with osteoarthritis and symptomatic meniscal tear

Research article

Surface damage of bovine articular cartilage-off-bone: the effect of variations in underlying substrate and frequency

Research article

Outcomes after bone grafting in patients with and without ACL revision surgery: a retrospective study

Study protocol

Protocol for a single-centre, parallel-arm, double-blind randomised trial evaluating the effects of tourniquet use in total knee arthroplasty on intra-operative and post-operative outcomes