Regulation of the Tenogenic Gene Expression in Equine Tenocyte-derived Induced Pluripotent Stem Cells by Mechanical Loading and Mohawk

Overview

Journal Stem Cell Res

Publisher Elsevier

Specialty Cell Biology

Date 2019 Jul 6

PMID 31277043

Citations 18

Authors

Feikun Yang

Aiwu Zhang

Dean W Richardson

Affiliations

Soon will be listed here.

Abstract

Cell-based therapeutic strategies afford major potential advantages in the repair of injured tendons. Generation of induced pluripotent stem cells (iPSCs) expands cell sources for "regenerative" therapy. However, its application in tendon repair is still limited and the effects remain unclear. In this study, equine tenocyte-derived iPSCs (teno-iPSCs) were generated by expressing four Yamanaka factors. Compared to parental tenocytes and bone marrow derived mesenchymal stem cells (BMSCs), the transcriptional activities of lineage-specific genes, including Mkx, Col1A2, Col14, DCN, ELN, FMOD, and TNC, were highly repressed in the resulting teno-iPSCs. Exposure to cyclic uniaxial mechanical loading increased the expression of Scx, Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, DCN, and TNC in BMSCs. Reintroduction of tenogenic transcription factor Mohawk (Mkx) upregulated the expression of DCN in teno-iPSCs and the expression of Scx, Col14, and FMOD in BMSCs. Mechanical loading combined with ectopic expression of equine Mkx further enhanced the expression of Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, and TNC in BMSCs. These data suggest that the repressed lineage-specific genes in the teno-iPSCs can be re-activated by mechanical loading and ectopic expression of Mkx. Our findings offer new insights into the application of iPSCs for basic and clinic research in tendon repair.

Citing Articles

Cardioprotective effects of hUCMSCs-Exosi-EGR1 MN patch in MI/RI by modulating oxidative stress and mitophagy.

Huang C, Zhang X, Wu S, Chang Q, Zheng Z, Xu J Mater Today Bio. 2025; 31:101500.

PMID: 39944530 PMC: 11815289. DOI: 10.1016/j.mtbio.2025.101500.

Recent Advances in the Use of Stem Cells in Tissue Engineering and Adjunct Therapies for Tendon Reconstruction and Future Perspectives.

Dec P, Zylka M, Burszewski P, Modrzejewski A, Pawlik A Int J Mol Sci. 2024; 25(8).

PMID: 38674084 PMC: 11050411. DOI: 10.3390/ijms25084498.

Viable tendon neotissue from adult adipose-derived multipotent stromal cells.

Taguchi T, Lopez M, Takawira C Front Bioeng Biotechnol. 2024; 11:1290693.

PMID: 38260742 PMC: 10800559. DOI: 10.3389/fbioe.2023.1290693.

Equine tendon mechanical behaviour: Prospects for repair and regeneration applications.

Shojaee A Vet Med Sci. 2023; 9(5):2053-2069.

PMID: 37471573 PMC: 10508504. DOI: 10.1002/vms3.1205.

External stimulation: A potential therapeutic strategy for tendon-bone healing.

Fu S, Lan Y, Wang G, Bao D, Qin B, Zheng Q Front Bioeng Biotechnol. 2023; 11:1150290.

PMID: 37064229 PMC: 10102526. DOI: 10.3389/fbioe.2023.1150290.

References

Nam H, Pingguan-Murphy B, Abbas A, Merican A, Kamarul T . The proliferation and tenogenic differentiation potential of bone marrow-derived mesenchymal stromal cell are influenced by specific uniaxial cyclic tensile loading conditions. Biomech Model Mechanobiol. 2014; 14(3):649-63. DOI: 10.1007/s10237-014-0628-y. View

Barsby T, Bavin E, Guest D . Three-dimensional culture and transforming growth factor beta3 synergistically promote tenogenic differentiation of equine embryo-derived stem cells. Tissue Eng Part A. 2014; 20(19-20):2604-13. PMC: 4195467. DOI: 10.1089/ten.TEA.2013.0457. View

Tan C, Lui P, Lee Y, Wong Y . Scx-transduced tendon-derived stem cells (tdscs) promoted better tendon repair compared to mock-transduced cells in a rat patellar tendon window injury model. PLoS One. 2014; 9(5):e97453. PMC: 4022525. DOI: 10.1371/journal.pone.0097453. View

Chen X, Yin Z, Chen J, Liu H, Shen W, Fang Z . Scleraxis-overexpressed human embryonic stem cell-derived mesenchymal stem cells for tendon tissue engineering with knitted silk-collagen scaffold. Tissue Eng Part A. 2013; 20(11-12):1583-92. DOI: 10.1089/ten.TEA.2012.0656. View

Docheva D, Muller S, Majewski M, Evans C . Biologics for tendon repair. Adv Drug Deliv Rev. 2014; 84:222-39. PMC: 4519231. DOI: 10.1016/j.addr.2014.11.015. View

Morita Y, Yamashita T, Toku T, Ju Y . Optimization of differentiation time of mesenchymal-stem-cell to tenocyte under a cyclic stretching with a microgrooved culture membrane and selected measurement cells. Acta Bioeng Biomech. 2018; 20(1):3-10. View

Nashun B, Hill P, Hajkova P . Reprogramming of cell fate: epigenetic memory and the erasure of memories past. EMBO J. 2015; 34(10):1296-308. PMC: 4491992. DOI: 10.15252/embj.201490649. View

Scott A, Danielson P, Abraham T, Fong G, Sampaio A, Underhill T . Mechanical force modulates scleraxis expression in bioartificial tendons. J Musculoskelet Neuronal Interact. 2011; 11(2):124-32. View

Gaspar D, Spanoudes K, Holladay C, Pandit A, Zeugolis D . Progress in cell-based therapies for tendon repair. Adv Drug Deliv Rev. 2014; 84:240-56. DOI: 10.1016/j.addr.2014.11.023. View

10.

Sommer C, Stadtfeld M, Murphy G, Hochedlinger K, Kotton D, Mostoslavsky G . Induced pluripotent stem cell generation using a single lentiviral stem cell cassette. Stem Cells. 2008; 27(3):543-9. PMC: 4848035. DOI: 10.1634/stemcells.2008-1075. View

11.

Ho J, Sawadkar P, Mudera V . A review on the use of cell therapy in the treatment of tendon disease and injuries. J Tissue Eng. 2014; 5:2041731414549678. PMC: 4221986. DOI: 10.1177/2041731414549678. View

12.

Snedeker J, Foolen J . Tendon injury and repair - A perspective on the basic mechanisms of tendon disease and future clinical therapy. Acta Biomater. 2017; 63:18-36. DOI: 10.1016/j.actbio.2017.08.032. View

13.

Qiu Y, Lei J, Koob T, Temenoff J . Cyclic tension promotes fibroblastic differentiation of human MSCs cultured on collagen-fibre scaffolds. J Tissue Eng Regen Med. 2014; 10(12):989-999. DOI: 10.1002/term.1880. View

14.

Yang G, Rothrauff B, Lin H, Yu S, Tuan R . Tendon-Derived Extracellular Matrix Enhances Transforming Growth Factor-β3-Induced Tenogenic Differentiation of Human Adipose-Derived Stem Cells. Tissue Eng Part A. 2016; 23(3-4):166-176. PMC: 5312607. DOI: 10.1089/ten.TEA.2015.0498. View

15.

Kilpinen H, Goncalves A, Leha A, Afzal V, Alasoo K, Ashford S . Common genetic variation drives molecular heterogeneity in human iPSCs. Nature. 2017; 546(7658):370-375. PMC: 5524171. DOI: 10.1038/nature22403. View

16.

Nichols A, Werre S, Dahlgren L . Transient Scleraxis Overexpression Combined with Cyclic Strain Enhances Ligament Cell Differentiation. Tissue Eng Part A. 2018; 24(19-20):1444-1455. PMC: 6198763. DOI: 10.1089/ten.TEA.2017.0481. View

17.

Yoshimoto Y, Takimoto A, Watanabe H, Hiraki Y, Kondoh G, Shukunami C . Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system. Sci Rep. 2017; 7:45010. PMC: 5361204. DOI: 10.1038/srep45010. View

18.

Hiler D, Chen X, Hazen J, Kupriyanov S, Carroll P, Qu C . Quantification of Retinogenesis in 3D Cultures Reveals Epigenetic Memory and Higher Efficiency in iPSCs Derived from Rod Photoreceptors. Cell Stem Cell. 2015; 17(1):101-15. PMC: 4547539. DOI: 10.1016/j.stem.2015.05.015. View

19.

Sun H, Schaniel C, Leong D, Wang J . Biology and mechano-response of tendon cells: Progress overview and perspectives. J Orthop Res. 2015; 33(6):785-92. PMC: 4422159. DOI: 10.1002/jor.22885. View

20.

Nourissat G, Berenbaum F, Duprez D . Tendon injury: from biology to tendon repair. Nat Rev Rheumatol. 2015; 11(4):223-33. DOI: 10.1038/nrrheum.2015.26. View