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Frontiers in veterinary science2015; 2; 55; doi: 10.3389/fvets.2015.00055

Equine Induced Pluripotent Stem Cells have a Reduced Tendon Differentiation Capacity Compared to Embryonic Stem Cells.

Abstract: Tendon injuries occur commonly in horses and their repair through scar tissue formation predisposes horses to a high rate of re-injury. Pluripotent stem cells may provide a cell replacement therapy to improve tendon tissue regeneration and lower the frequency of re-injury. We have previously demonstrated that equine embryonic stem cells (ESCs) differentiate into the tendon cell lineage upon injection into the damaged horse tendon and can differentiate into functional tendon cells in vitro to generate artificial tendons. Induced pluripotent stem cells (iPSCs) have now been derived from horses but, to date, there are no reports on their ability to differentiate into tendon cells. As iPSCs can be produced from adult cell types, they provide a more accessible source of cells than ESCs, which require the use of horse embryos. The aim of this study was to compare tendon differentiation by ESCs and iPSCs produced through two independent methods. In two-dimensional differentiation assays, the iPSCs expressed tendon-associated genes and proteins, which were enhanced by the presence of transforming growth factor-β3. However, in three-dimensional (3D) differentiation assays, the iPSCs failed to differentiate into functional tendon cells and generate artificial tendons. These results demonstrate the utility of the 3D in vitro tendon assay for measuring tendon differentiation and the need for more detailed studies to be performed on equine iPSCs to identify and understand their epigenetic differences from pluripotent ESCs prior to their clinical application.
Publication Date: 2015-11-16 PubMed ID: 26664982PubMed Central: PMC4672282DOI: 10.3389/fvets.2015.00055Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study investigates the viability of using induced pluripotent stem cells (iPSCs) from horses to repair tendon injuries. It showed that while these cells can show characteristics of tendon-associated genes and proteins, they were unable to successfully differentiate into functional tendon cells and create artificial tendons like their embryonic stem cell (ESCs) counterparts.

The Research Context

  • Horses frequently suffer from tendon injuries that often heal with scar tissue, making them susceptible to re-injury.
  • A potential therapeutic approach to improve tendon tissue regeneration and reduce re-injury rates might involve the use of pluripotent stem cells.
  • Previously, the study team demonstrated that equine embryonic stem cells (ESCs) could differentiate into tendon cells and form functional artificial tendons in vitro.
  • Induced pluripotent stem cells (iPSCs), which are derived from adult cells, present a more accessible source of cells than ESCs, which require horse embryos.
  • The main aim of the study was to compare the ability of ESCs and iPSCs to differentiate into tendon cells.

In-depth Study Findings

  • The researchers carried out two types of differentiation assays – two-dimensional (conventional cell culture techniques) and three-dimensional (3D).
  • In the two-dimensional assays, iPSCs indicated expression of tendon-associated genes and proteins, particularly when the growth factor transforming growth factor-β3 was present.
  • However, in the three-dimensional assays, which more fully replicated the physical and biochemical environment of a tendon, iPSCs failed to differentiate into functional tendon cells and generate artificial tendons.
  • This difference between the outcomes of 2D and 3D assays underscored the importance of a 3D in vitro tendon assay for examining tendon differentiation.

Conclusion and Future Considerations

  • The findings revealed important distinctions between iPSCs and ESCs in terms of differentiation into functional tendon cells.
  • While iPSCs did express tendon-associated genes and proteins under certain circumstances, they did not differentiate into functional tendon cells or generate artificial tendons in a three-dimensional environment.
  • This suggests a need to investigate the epigenetic differences between iPSCs and pluripotent ESCs in greater detail before iPSCs derived from horses can be effectively used in clinical application for tendon repair.

Cite This Article

APA
Bavin EP, Smith O, Baird AE, Smith LC, Guest DJ. (2015). Equine Induced Pluripotent Stem Cells have a Reduced Tendon Differentiation Capacity Compared to Embryonic Stem Cells. Front Vet Sci, 2, 55. https://doi.org/10.3389/fvets.2015.00055

Publication

ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 2
Pages: 55
PII: 55

Researcher Affiliations

Bavin, Emma P
  • Centre for Preventive Medicine, Animal Health Trust , Newmarket , UK.
Smith, Olivia
  • Département de biomédecine vétérinaire, Faculté de médecine vétérinaire, Université de Montréal , Saint-Hyacinthe, QC , Canada.
Baird, Arabella E G
  • Centre for Preventive Medicine, Animal Health Trust , Newmarket , UK.
Smith, Lawrence C
  • Département de biomédecine vétérinaire, Faculté de médecine vétérinaire, Université de Montréal , Saint-Hyacinthe, QC , Canada.
Guest, Deborah J
  • Centre for Preventive Medicine, Animal Health Trust , Newmarket , UK.

References

This article includes 37 references
  1. 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 Sep;33(5):478-86.
    doi: 10.2746/042516401776254808pubmed: 11558743google scholar: lookup
  2. Dyson SJ. Medical management of superficial digital flexor tendonitis: a comparative study in 219 horses (1992-2000).. Equine Vet J 2004 Jul;36(5):415-9.
    doi: 10.2746/0425164044868422pubmed: 15253082google scholar: lookup
  3. Singer ER, Barnes J, Saxby F, Murray JK. Injuries in the event horse: training versus competition.. Vet J 2008 Jan;175(1):76-81.
    doi: 10.1016/j.tvjl.2006.11.009pubmed: 17204438google scholar: lookup
  4. Lam KH, Parkin TD, Riggs CM, Morgan KL. Descriptive analysis of retirement of Thoroughbred racehorses due to tendon injuries at the Hong Kong Jockey Club (1992-2004).. Equine Vet J 2007 Mar;39(2):143-8.
    doi: 10.2746/042516407X159132pubmed: 17378443google scholar: lookup
  5. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. 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 Jan;44(1):25-32.
  6. Durando MM, Zarucco L, Schaer TP, Ross M, Reef VB. Pneumopericardium in a horse secondary to sternal bone marrow aspiration. Equine Vet Educ (2006) 18:75–9.
  7. Carrade DD, Lame MW, Kent MS, Clark KC, Walker NJ, Borjesson DL. Comparative Analysis of the Immunomodulatory Properties of Equine Adult-Derived Mesenchymal Stem Cells().. Cell Med 2012;4(1):1-11.
    doi: 10.3727/215517912X647217pmc: PMC3495591pubmed: 23152950google scholar: lookup
  8. Carrade Holt DD, Wood JA, Granick JL, Walker NJ, Clark KC, Borjesson DL. Equine mesenchymal stem cells inhibit T cell proliferation through different mechanisms depending on tissue source.. Stem Cells Dev 2014 Jun 1;23(11):1258-65.
    doi: 10.1089/scd.2013.0537pubmed: 24438346google scholar: lookup
  9. Paterson YZ, Rash N, Garvican ER, Paillot R, Guest DJ. Equine mesenchymal stromal cells and embryo-derived stem cells are immune privileged in vitro.. Stem Cell Res Ther 2014 Jul 30;5(4):90.
    doi: 10.1186/scrt479pmc: PMC4247727pubmed: 25080326google scholar: lookup
  10. Ranera B, Antczak D, Miller D, Doroshenkova T, Ryan A, McIlwraith CW, Barry F. Donor-derived equine mesenchymal stem cells suppress proliferation of mismatched lymphocytes.. Equine Vet J 2016 Mar;48(2):253-60.
    doi: 10.1111/evj.12414pubmed: 25582202google scholar: lookup
  11. Broeckx S, Forier R, Marien T, Suls M, Savkovic V, Franco-Obergon A. The influence of allogeneic mesenchymal stem cells on the hematological status of horses. J Stem Cell Res Ther (2013) 3:136.
    doi: 10.4172/2157-7633.1000136google scholar: lookup
  12. Carrade DD, Affolter VK, Outerbridge CA, Watson JL, Galuppo LD, Buerchler S, Kumar V, Walker NJ, Borjesson DL. Intradermal injections of equine allogeneic umbilical cord-derived mesenchymal stem cells are well tolerated and do not elicit immediate or delayed hypersensitivity reactions.. Cytotherapy 2011 Nov;13(10):1180-92.
    doi: 10.3109/14653249.2011.602338pubmed: 21899391google scholar: lookup
  13. Carrade DD, Owens SD, Galuppo LD, Vidal MA, Ferraro GL, Librach F, Buerchler S, Friedman MS, Walker NJ, Borjesson DL. Clinicopathologic findings following intra-articular injection of autologous and allogeneic placentally derived equine mesenchymal stem cells in horses.. Cytotherapy 2011 Apr;13(4):419-30.
    doi: 10.3109/14653249.2010.536213pubmed: 21105841google scholar: lookup
  14. Guest DJ, Smith MR, Allen WR. Monitoring the fate of autologous and allogeneic mesenchymal progenitor cells injected into the superficial digital flexor tendon of horses: preliminary study.. Equine Vet J 2008 Mar;40(2):178-81.
    doi: 10.2746/042516408X276942pubmed: 18267891google scholar: lookup
  15. Guest DJ, Smith MR, 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 Oct;42(7):636-42.
  16. Becerra P, Valdés Vázquez MA, Dudhia J, Fiske-Jackson AR, Neves F, Hartman NG, Smith RK. Distribution of injected technetium(99m)-labeled mesenchymal stem cells in horses with naturally occurring tendinopathy.. J Orthop Res 2013 Jul;31(7):1096-102.
    doi: 10.1002/jor.22338pubmed: 23508674google scholar: lookup
  17. Guest DJ, Allen WR. Expression of cell-surface antigens and embryonic stem cell pluripotency genes in equine blastocysts.. Stem Cells Dev 2007 Oct;16(5):789-96.
    doi: 10.1089/scd.2007.0032pubmed: 17999600google scholar: lookup
  18. Li X, Zhou SG, Imreh MP, Ahrlund-Richter L, Allen WR. Horse embryonic stem cell lines from the proliferation of inner cell mass cells.. Stem Cells Dev 2006 Aug;15(4):523-31.
    doi: 10.1089/scd.2006.15.523pubmed: 16978056google scholar: lookup
  19. Barsby T, Guest D. Transforming growth factor beta3 promotes tendon differentiation of equine embryo-derived stem cells.. Tissue Eng Part A 2013 Oct;19(19-20):2156-65.
    doi: 10.1089/ten.TEA.2012.0372pubmed: 23611525google scholar: lookup
  20. Barsby T, Bavin EP, Guest DJ. Three-dimensional culture and transforming growth factor beta3 synergistically promote tenogenic differentiation of equine embryo-derived stem cells.. Tissue Eng Part A 2014 Oct;20(19-20):2604-13.
    doi: 10.1089/ten.TEA.2013.0457pmc: PMC4195467pubmed: 24628376google scholar: lookup
  21. Nagy K, Sung HK, Zhang P, Laflamme S, Vincent P, Agha-Mohammadi S, Woltjen K, Monetti C, Michael IP, Smith LC, Nagy A. Induced pluripotent stem cell lines derived from equine fibroblasts.. Stem Cell Rev Rep 2011 Sep;7(3):693-702.
    doi: 10.1007/s12015-011-9239-5pmc: PMC3137777pubmed: 21347602google scholar: lookup
  22. Breton A, Sharma R, Diaz AC, Parham AG, Graham A, Neil C, Whitelaw CB, Milne E, Donadeu FX. Derivation and characterization of induced pluripotent stem cells from equine fibroblasts.. Stem Cells Dev 2013 Feb 15;22(4):611-21.
    doi: 10.1089/scd.2012.0052pmc: PMC3564467pubmed: 22897112google scholar: lookup
  23. Whitworth DJ, Ovchinnikov DA, Sun J, Fortuna PR, Wolvetang EJ. Generation and characterization of leukemia inhibitory factor-dependent equine induced pluripotent stem cells from adult dermal fibroblasts.. Stem Cells Dev 2014 Jul 1;23(13):1515-23.
    doi: 10.1089/scd.2013.0461pmc: PMC4066230pubmed: 24555755google scholar: lookup
  24. Aguiar C, Theoret C, Smith O, Segura M, Lemire P, Smith LC. Immune potential of allogeneic equine induced pluripotent stem cells.. Equine Vet J 2015 Nov;47(6):708-14.
    doi: 10.1111/evj.12345pubmed: 25196173google scholar: lookup
  25. Sharma R, Livesey MR, Wyllie DJ, Proudfoot C, Whitelaw CB, Hay DC, Donadeu FX. Generation of functional neurons from feeder-free, keratinocyte-derived equine induced pluripotent stem cells.. Stem Cells Dev 2014 Jul 1;23(13):1524-34.
    doi: 10.1089/scd.2013.0565pubmed: 24548115google scholar: lookup
  26. Baird A, Barsby T, Guest DJ. Derivation of Canine Induced Pluripotent Stem Cells.. Reprod Domest Anim 2015 Aug;50(4):669-76.
    doi: 10.1111/rda.12562pubmed: 26074059google scholar: lookup
  27. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.. Methods 2001 Dec;25(4):402-8.
    doi: 10.1006/meth.2001.1262pubmed: 11846609google scholar: lookup
  28. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells.. Nature 2007 Jul 19;448(7151):313-7.
    doi: 10.1038/nature05934pubmed: 17554338google scholar: lookup
  29. Rao MS, Malik N. Assessing iPSC reprogramming methods for their suitability in translational medicine.. J Cell Biochem 2012 Oct;113(10):3061-8.
    doi: 10.1002/jcb.24183pmc: PMC3552293pubmed: 22573568google scholar: lookup
  30. Hotta A, Ellis J. Retroviral vector silencing during iPS cell induction: an epigenetic beacon that signals distinct pluripotent states.. J Cell Biochem 2008 Nov 1;105(4):940-8.
    doi: 10.1002/jcb.21912pubmed: 18773452google scholar: lookup
  31. Nirmalanandhan VS, Juncosa-Melvin N, Shearn JT, Boivin GP, Galloway MT, Gooch C, Bradica G, Butler DL. Combined effects of scaffold stiffening and mechanical preconditioning cycles on construct biomechanics, gene expression, and tendon repair biomechanics.. Tissue Eng Part A 2009 Aug;15(8):2103-2111.
    doi: 10.1089/ten.tea.2008.0335pmc: PMC2792106pubmed: 19191501google scholar: lookup
  32. Bilic J, Izpisua Belmonte JC. Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart?. Stem Cells 2012 Jan;30(1):33-41.
    doi: 10.1002/stem.700pubmed: 22213481google scholar: lookup
  33. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP, Daley GQ. Epigenetic memory in induced pluripotent stem cells.. Nature 2010 Sep 16;467(7313):285-90.
    doi: 10.1038/nature09342pmc: PMC3150836pubmed: 20644535google scholar: lookup
  34. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, Apostolou E, Stadtfeld M, Li Y, Shioda T, Natesan S, Wagers AJ, Melnick A, Evans T, Hochedlinger K. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.. Nat Biotechnol 2010 Aug;28(8):848-55.
    doi: 10.1038/nbt.1667pmc: PMC3148605pubmed: 20644536google scholar: lookup
  35. Chin MH, Mason MJ, Xie W, Volinia S, Singer M, Peterson C, Ambartsumyan G, Aimiuwu O, Richter L, Zhang J, Khvorostov I, Ott V, Grunstein M, Lavon N, Benvenisty N, Croce CM, Clark AT, Baxter T, Pyle AD, Teitell MA, Pelegrini M, Plath K, Lowry WE. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures.. Cell Stem Cell 2009 Jul 2;5(1):111-23.
    doi: 10.1016/j.stem.2009.06.008pmc: PMC3448781pubmed: 19570518google scholar: lookup
  36. Ghosh Z, Wilson KD, Wu Y, Hu S, Quertermous T, Wu JC. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells.. PLoS One 2010 Feb 1;5(2):e8975.
  37. Marchetto MC, Yeo GW, Kainohana O, Marsala M, Gage FH, Muotri AR. Transcriptional signature and memory retention of human-induced pluripotent stem cells.. PLoS One 2009 Sep 18;4(9):e7076.

Citations

This article has been cited 19 times.
  1. Jiang L, Lu J, Chen Y, Lyu K, Long L, Wang X, Liu T, Li S. Mesenchymal stem cells: An efficient cell therapy for tendon repair (Review).. Int J Mol Med 2023 Aug;52(2).
    doi: 10.3892/ijmm.2023.5273pubmed: 37387410google scholar: lookup
  2. Barrachina L, Arshaghi TE, O'Brien A, Ivanovska A, Barry F. Induced pluripotent stem cells in companion animals: how can we move the field forward?. Front Vet Sci 2023;10:1176772.
    doi: 10.3389/fvets.2023.1176772pubmed: 37180067google scholar: lookup
  3. Wang T, Wang L, Zhang L, Long Y, Zhang Y, Hou Z. Single-cell RNA sequencing in orthopedic research.. Bone Res 2023 Feb 24;11(1):10.
    doi: 10.1038/s41413-023-00245-0pubmed: 36828839google scholar: lookup
  4. Zhao H, Liang T, Tang Y, Zhu D, Lin Q, Chen J, Fei J, Yu T, Zhang Y. Single-Cell Transcriptomics Analysis of the Pathogenesis of Tendon Injury.. Oxid Med Cell Longev 2022;2022:7887782.
    doi: 10.1155/2022/7887782pubmed: 36148412google scholar: lookup
  5. Yang Q, Li J, Su W, Yu L, Li T, Wang Y, Zhang K, Wu Y, Wang L. Electrospun aligned poly(ε-caprolactone) nanofiber yarns guiding 3D organization of tendon stem/progenitor cells in tenogenic differentiation and tendon repair.. Front Bioeng Biotechnol 2022;10:960694.
    doi: 10.3389/fbioe.2022.960694pubmed: 36110313google scholar: lookup
  6. Li ZJ, Yang QQ, Zhou YL. Basic Research on Tendon Repair: Strategies, Evaluation, and Development.. Front Med (Lausanne) 2021;8:664909.
    doi: 10.3389/fmed.2021.664909pubmed: 34395467google scholar: lookup
  7. Yang F, Richardson DW. Comparative Analysis of Tenogenic Gene Expression in Tenocyte-Derived Induced Pluripotent Stem Cells and Bone Marrow-Derived Mesenchymal Stem Cells in Response to Biochemical and Biomechanical Stimuli.. Stem Cells Int 2021;2021:8835576.
    doi: 10.1155/2021/8835576pubmed: 33510795google scholar: lookup
  8. Scarfone RA, Pena SM, Russell KA, Betts DH, Koch TG. The use of induced pluripotent stem cells in domestic animals: a narrative review.. BMC Vet Res 2020 Dec 8;16(1):477.
    doi: 10.1186/s12917-020-02696-7pubmed: 33292200google scholar: lookup
  9. Su Y, Zhu J, Salman S, Tang Y. Induced pluripotent stem cells from farm animals.. J Anim Sci 2020 Nov 1;98(11).
    doi: 10.1093/jas/skaa343pubmed: 33098420google scholar: lookup
  10. Wang HN, Huang YC, Ni GX. Mechanotransduction of stem cells for tendon repair.. World J Stem Cells 2020 Sep 26;12(9):952-965.
    doi: 10.4252/wjsc.v12.i9.952pubmed: 33033557google scholar: lookup
  11. Citeroni MR, Ciardulli MC, Russo V, Della Porta G, Mauro A, El Khatib M, Di Mattia M, Galesso D, Barbera C, Forsyth NR, Maffulli N, Barboni B. In Vitro Innovation of Tendon Tissue Engineering Strategies.. Int J Mol Sci 2020 Sep 14;21(18).
    doi: 10.3390/ijms21186726pubmed: 32937830google scholar: lookup
  12. Komura S, Satake T, Goto A, Aoki H, Shibata H, Ito K, Hirakawa A, Yamada Y, Akiyama H. Induced pluripotent stem cell-derived tenocyte-like cells promote the regeneration of injured tendons in mice.. Sci Rep 2020 Mar 4;10(1):3992.
    doi: 10.1038/s41598-020-61063-6pubmed: 32132649google scholar: lookup
  13. Dai GC, Li YJ, Chen MH, Lu PP, Rui YF. Tendon stem/progenitor cell ageing: Modulation and rejuvenation.. World J Stem Cells 2019 Sep 26;11(9):677-692.
    doi: 10.4252/wjsc.v11.i9.677pubmed: 31616543google scholar: lookup
  14. Pessôa LVF, Bressan FF, Freude KK. Induced pluripotent stem cells throughout the animal kingdom: Availability and applications.. World J Stem Cells 2019 Aug 26;11(8):491-505.
    doi: 10.4252/wjsc.v11.i8.491pubmed: 31523369google scholar: lookup
  15. Yang F, Zhang A, Richardson DW. Regulation of the tenogenic gene expression in equine tenocyte-derived induced pluripotent stem cells by mechanical loading and Mohawk.. Stem Cell Res 2019 Aug;39:101489.
    doi: 10.1016/j.scr.2019.101489pubmed: 31277043google scholar: lookup
  16. Shojaee A, Parham A. Strategies of tenogenic differentiation of equine stem cells for tendon repair: current status and challenges.. Stem Cell Res Ther 2019 Jun 18;10(1):181.
    doi: 10.1186/s13287-019-1291-0pubmed: 31215490google scholar: lookup
  17. McClellan A, Evans R, Sze C, Kan S, Paterson Y, Guest D. A novel mechanism for the protection of embryonic stem cell derived tenocytes from inflammatory cytokine interleukin 1 beta.. Sci Rep 2019 Feb 26;9(1):2755.
    doi: 10.1038/s41598-019-39370-4pubmed: 30808942google scholar: lookup
  18. Baird A, Lindsay T, Everett A, Iyemere V, Paterson YZ, McClellan A, Henson FMD, Guest DJ. Osteoblast differentiation of equine induced pluripotent stem cells.. Biol Open 2018 May 10;7(5).
    doi: 10.1242/bio.033514pubmed: 29685993google scholar: lookup
  19. Liu L, Hindieh J, Leong DJ, Sun HB. Advances of stem cell based-therapeutic approaches for tendon repair.. J Orthop Translat 2017 Apr;9:69-75.
    doi: 10.1016/j.jot.2017.03.007pubmed: 29662801google scholar: lookup