https://doi.org/10.4081/ejh.2021.3297
Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling
Submitted: 28 June 2021
Accepted: 24 July 2021
Published: 7 September 2021
Accepted: 24 July 2021
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Rotator cuff tear (RCT) is a common tendon injury, but the mechanisms of tendon healing remain incompletely understood. Elucidating the molecular mechanisms of tenogenic differentiation is essential to develop novel therapeutic strategies in clinical treatment of RCT. The long noncoding RNA H19 plays a regulatory role in tenogenic differentiation and tendon healing, but its detailed mechanism of action remains unknown. To elucidate the role of H19 in tenogenic differentiation and tendon healing, tendon-derived stem cells were harvested from the Achilles tendons of Sprague Dawley rats and a rat model of cuff tear was established for the exploration of the function of H19 in promoting tenogenic differentiation. The results showed that H19 overexpression promoted, while H19 silencing suppressed, tenogenic differentiation of tendon-derived stem cells (TDSCs). Furthermore, bioinformatic analyses and a luciferase reporter gene assay showed that H19 directly targeted and inhibited miR-140-5p to promote tenogenic differentiation. Further, inhibiting miR-140-5p directly increased VEGFA expression, revealing a novel regulatory axis between H19, miR-140-5p, and VEGFA in modulating tenogenic differentiation. In rats with RTC, implantation of H19-overexpressing TDSCs at the lesion promoted tendon healing and functional recovery. In general, the data suggest that H19 promotes tenogenic differentiation and tendon-bone healing by targeting miR-140-5p and increasing VEGFA levels. Modulation of the H19/miR-140-5p/VEGFA axis in TDSCs is a new potential strategy for clinical treatment of tendon injury.
Chakravarty K, Webley M. Shoulder joint movement and its relationship to disability in the elderly. J Rheumatol 1993;20:1359-61.
Minagawa H, Yamamoto N, Abe H, Fukuda M, Seki N, Kikuchi K, et al. Prevalence of symptomatic and asymptomatic rotator cuff tears in the general population: From mass-screening in one village. J Orthop 2013;10:8-12.
DOI: https://doi.org/10.1016/j.jor.2013.01.008
Abate M, Schiavone C, Di Carlo L, Salini V. Prevalence of and risk factors for asymptomatic rotator cuff tears in postmenopausal women. Menopause 2014;21:275-80.
DOI: https://doi.org/10.1097/GME.0b013e31829638e3
Mather RC 3rd, Koenig L, Acevedo D, Dall TM, Gallo P, Romeo A, et al. The societal and economic value of rotator cuff repair. J Bone Joint Surg Am 2013;95:1993-2000.
DOI: https://doi.org/10.2106/JBJS.L.01495
Longo UG, Salvatore G, Rizzello G, Berton A, Ciuffreda M, Candela V, et al. The burden of rotator cuff surgery in Italy: a nationwide registry study. Arch Orthop Trauma Surg 2017;137:217-24.
DOI: https://doi.org/10.1007/s00402-016-2610-x
Boileau P, Brassart N, Watkinson DJ, Carles M, Hatzidakis AM, Krishnan SG. Arthroscopic repair of full-thickness tears of the supraspinatus: does the tendon really heal? J Bone Joint Surg Am 2005;87:1229-40.
DOI: https://doi.org/10.2106/00004623-200506000-00007
Giombini A, Di Cesare A, Safran MR, Ciatti R, Maffulli N. Short-term effectiveness of hyperthermia for supraspinatus tendinopathy in athletes: a short-term randomized controlled study. Am J Sports Med 2006;34:1247-53.
DOI: https://doi.org/10.1177/0363546506287827
Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 2007;13:1219-27.
DOI: https://doi.org/10.1038/nm1630
Zhang J, Wang JH. Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet Disord 2010;11:10.
DOI: https://doi.org/10.1186/1471-2474-11-10
Salingcarnboriboon R, Yoshitake H, Tsuji K, Obinata M, Amagasa T, Nifuji A, et al. Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Exp Cell Res 2003;287:289-300.
DOI: https://doi.org/10.1016/S0014-4827(03)00107-1
Lui PP. Identity of tendon stem cells--how much do we know? J Cell Mol Med 2013;17:55-64.
DOI: https://doi.org/10.1111/jcmm.12007
Lui PP, Chan KM. Tendon-derived stem cells (TDSCs): from basic science to potential roles in tendon pathology and tissue engineering applications. Stem Cell Rev Rep 2011;7:883-97.
DOI: https://doi.org/10.1007/s12015-011-9276-0
Cai X, Cai M, Lou L. Identification of differentially expressed genes and small molecule drugs for the treatment of tendinopathy using microarray analysis. Mol Med Rep 2015;11:3047-54.
DOI: https://doi.org/10.3892/mmr.2014.3081
Plachel F, Heuberer P, Gehwolf R, Frank J, Tempfer H, Lehner C, et al. MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies. J Orthop Res 2020;38:202-11.
DOI: https://doi.org/10.1002/jor.24473
Chen L, Liu J, Tao X, Wang G, Wang Q, Liu X. The role of Pin1 protein in aging of human tendon stem/progenitor cells. Biochem Biophys Res Commun 2015;464:487-92.
DOI: https://doi.org/10.1016/j.bbrc.2015.06.163
Zheng W, Chen C, Chen S, Fan C, Ruan H. Integrated analysis of long non-coding RNAs and mRNAs associated with peritendinous fibrosis. J Adv Res 2019;15:49-58.
DOI: https://doi.org/10.1016/j.jare.2018.08.001
Yu Y, Chen Y, Zhang X, Lu X, Hong J, Guo X, et al. Knockdown of lncRNA KCNQ1OT1 suppresses the adipogenic and osteogenic differentiation of tendon stem cell via downregulating miR-138 target genes PPARgamma and RUNX2. Cell Cycle 2018;17:2374-85.
DOI: https://doi.org/10.1080/15384101.2018.1534510
Lu YF, Liu Y, Fu WM, Xu J, Wang B, Sun YX, et al. Long noncoding RNA H19 accelerates tenogenic differentiation and promotes tendon healing through targeting miR-29b-3p and activating TGF-beta1 signaling. FASEB J 2017;31:954-64.
DOI: https://doi.org/10.1096/fj.201600722R
Wang L, Gao W, Xiong K, Hu K, Liu X, He H. VEGF and BFGF expression and histological characteristics of the bone-tendon junction during acute injury healing. J Sports Sci Med 2014;13:15-21.
Asai S, Otsuru S, Candela ME, Cantley L, Uchibe K, Hofmann TJ, et al. Tendon progenitor cells in injured tendons have strong chondrogenic potential: the CD105-negative subpopulation induces chondrogenic degeneration. Stem Cells 2014;32:3266-77.
DOI: https://doi.org/10.1002/stem.1847
Han CL, Ge M, Liu YP, Zhao XM, Wang KL, Chen N, et al. Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy. Cell Death Dis 2018;9:617.
DOI: https://doi.org/10.1038/s41419-018-0496-y
Shin MJ, Shim IK, Kim DM, Choi JH, Lee YN, Jeon IH, et al. Engineered cell sheets for the effective delivery of adipose-derived stem cells for tendon-to-bone healing. Am J Sports Med 2020;48:3347-58.
DOI: https://doi.org/10.1177/0363546520964445
Pryce BA, Watson SS, Murchison ND, Staverosky JA, Dunker N, Schweitzer R. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development 2009;136:1351-61.
DOI: https://doi.org/10.1242/dev.027342
Yin Z, Guo J, Wu TY, Chen X, Xu LL, Lin SE, et al. Stepwise differentiation of mesenchymal stem cells augments tendon-like tissue formation and defect repair in vivo. Stem Cells Transl Med 2016;5:1106-16.
DOI: https://doi.org/10.5966/sctm.2015-0215
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 2014;42:D92-7.
DOI: https://doi.org/10.1093/nar/gkt1248
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife 2015;4:e05005.
DOI: https://doi.org/10.7554/eLife.05005
Yoshikawa T, Tohyama H, Enomoto H, Matsumoto H, Toyama Y, Yasuda K. Expression of vascular endothelial growth factor and angiogenesis in patellar tendon grafts in the early phase after anterior cruciate ligament reconstruction. Knee Surg Sports Traumatol Arthrosc 2006;14:804-10.
DOI: https://doi.org/10.1007/s00167-006-0051-8
Boyer MI, Watson JT, Lou J, Manske PR, Gelberman RH, Cai SR. Quantitative variation in vascular endothelial growth factor mRNA expression during early flexor tendon healing: an investigation in a canine model. J Orthop Res 2001;19:869-72.
DOI: https://doi.org/10.1016/S0736-0266(01)00017-1
Xu Q, Sun WX, Zhang ZF. High expression of VEGFA in MSCs promotes tendon-bone healing of rotator cuff tear via microRNA-205-5p. Eur Rev Med Pharmacol Sci 2019;23:4081-8.
Zhou YL, Yang QQ, Yan YY, Zhang L, Wang QH, Ju F, et al. Gene-loaded nanoparticle-coated sutures provide effective gene delivery to enhance tendon healing. Mol Ther 2019;27:1534-46.
DOI: https://doi.org/10.1016/j.ymthe.2019.05.024
Xing SG, Zhou YL, Yang QQ, Ju F, Zhang L, Tang JB. Effects of nanoparticle-mediated growth factor gene transfer to the injured microenvironment on the tendon-to-bone healing strength. Biomater Sci 2020;8:6611-24.
DOI: https://doi.org/10.1039/D0BM01222J
Lahteenmaki HE, Virolainen P, Hiltunen A, Heikkila J, Nelimarkka OI. Results of early operative treatment of rotator cuff tears with acute symptoms. J Shoulder Elbow Surg 2006;15:148-53.
DOI: https://doi.org/10.1016/j.jse.2005.07.006
Qian L, Yu S, Chen Z, Meng Z, Huang S, Wang P. The emerging role of circRNAs and their clinical significance in human cancers. Biochim Biophys Acta Rev Cancer 2018;1870:247-60.
DOI: https://doi.org/10.1016/j.bbcan.2018.06.002
Dubin JA, Greenberg DR, Iglinski-Benjamin KC, Abrams GD. Effect of micro-RNA on tenocytes and tendon-related gene expression: A systematic review. J Orthop Res 2018;36:2823-9.
DOI: https://doi.org/10.1002/jor.24064
Zhu C, Chen T, Liu B. Inhibitory effects of miR-25 targeting HMGB1 on macrophage secretion of inflammatory cytokines in sepsis. Oncol Lett 2018;16:5027-33.
DOI: https://doi.org/10.3892/ol.2018.9308
Best KT, Lee FK, Knapp E, Awad HA, Loiselle AE. Deletion of NFKB1 enhances canonical NF-kappaB signaling and increases macrophage and myofibroblast content during tendon healing. Sci Rep 2019;9:10926.
DOI: https://doi.org/10.1038/s41598-019-47461-5
Abraham AC, Shah SA, Golman M, Song L, Li X, Kurtaliaj I, et al. Targeting the NF-kappaB signaling pathway in chronic tendon disease. Sci Transl Med 2019;11.
DOI: https://doi.org/10.1126/scitranslmed.aav4319
Takata A, Otsuka M, Kojima K, Yoshikawa T, Kishikawa T, Yoshida H, et al. MicroRNA-22 and microRNA-140 suppress NF-kappaB activity by regulating the expression of NF-kappaB coactivators. Biochem Biophys Res Commun 2011;411:826-31.
DOI: https://doi.org/10.1016/j.bbrc.2011.07.048
Ge Z, Tang H, Lyu J, Zhou B, Yang M, Tang K, et al. Conjoint analysis of lncRNA and mRNA expression in rotator cuff tendinopathy. Ann Transl Med 2020;8:335.
DOI: https://doi.org/10.21037/atm.2020.02.149
Ilaltdinov AW, Gong Y, Leong DJ, Gruson KI, Zheng D, Fung DT, et al. Advances in the development of gene therapy, noncoding RNA, and exosome-based treatments for tendinopathy. Ann N Y Acad Sci 2021;1490:3-12.
DOI: https://doi.org/10.1111/nyas.14382
Peffers MJ, Fang Y, Cheung K, Wei TK, Clegg PD, Birch HL. Transcriptome analysis of ageing in uninjured human Achilles tendon. Arthritis Res Ther 2015;17:33.
DOI: https://doi.org/10.1186/s13075-015-0544-2
Pease LI, Clegg PD, Proctor CJ, Shanley DJ, Cockell SJ, Peffers MJ. Cross platform analysis of transcriptomic data identifies ageing has distinct and opposite effects on tendon in males and females. Sci Rep 2017;7:14443.
DOI: https://doi.org/10.1038/s41598-017-14650-z
Yu Y, Chen Y, Zheng YJ, Weng QH, Zhu SP, Zhou DS. LncRNA TUG1 promoted osteogenic differentiation through promoting bFGF ubiquitination. In Vitro Cell Dev Biol Anim 2020;56:42-8.
DOI: https://doi.org/10.1007/s11626-019-00410-y
Qin CY, Cai H, Qing HR, Li L, Zhang HP. Recent advances on the role of long non-coding RNA H19 in regulating mammalian muscle growth and development. Yi Chuan 2017;39:1150-7.
Supporting Agencies
Traditional Chinese Medicine of Guangdong Province of China, Fundamental Research Funds for the Central Universities, National Natural Science Foundation of ChinaHow to Cite
Liu, Y.-J., Wang, H.-J., Xue, Z.-W., Cheang, L.-H. ., Tam, M.-S. ., Li, R.-W., Li, J.-R., Hou, H.-G., & Zheng, X.-F. (2021). Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling. European Journal of Histochemistry, 65(3). https://doi.org/10.4081/ejh.2021.3297
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