Skip to main content

Advertisement

SpringerLink
Log in

Role of Yes-associated protein (YAP) in regulation of mesenchymal stem cell tenogenic differentiation

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

The Yes-associated protein (YAP) transcription co-activator is recognized as a key mediator and has been implicated in the regulation of stem cell fate; however, the role of YAP in the tenogenic differentiation of mesenchymal stem cells (MSCs) is not well understood. In the present study, we characterized tenogenic differentiation of C3H10T1/2 cells induced by BMP-12 and evaluated the function of YAP in the regulation of the BMP-12-induced tenogenesis. We found that the tendon-related proteins Scleraxis, Tenascin C, and Tenomodulin were significantly increased after induction by 10 ng/ml BMP-12 for 48 h in C3H10T1/2 cells. In addition, the expression of YAP was significantly enhanced and transferred from the cytoplasm to the nucleus during tenogenic differentiation. In contrast, downregulation of YAP suppressed the cells’ tenogenic differentiation, and the expression of YAP transferred from the nucleus to the cytoplasm. These results indicate that YAP is required for the expression of tenogenic markers in the tenocytic differentiation process of C3H10T1/2 cells. Collectively, we demonstrate that YAP transcription co-activator is a novel regulator in the process of BMP-12-induced MSCs tenogenesis and has a correlation with the other tenogenic regulators and markers. These results shed new light on the function of YAP in tendon healing and regeneration.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  • Alarcon C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massague J (2009) Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell 139(4):757–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandao AS, Bensimon-Brito A, Lourenco R, Borbinha J, Soares AR, Mateus R, Jacinto A (2019) Yap induces osteoblast differentiation by modulating Bmp signalling during zebrafish caudal fin regeneration. J Cell Sci. https://doi.org/10.1242/jcs.231993

    Article  PubMed  Google Scholar 

  • Chamberlain CS, Lee JS, Leiferman EM, Maassen NX, Baer GS, Vanderby R, Murphy WL (2015) Effects of BMP-12-releasing sutures on Achilles tendon healing. Tissue Eng A 21(5–6):916–927

    Article  CAS  Google Scholar 

  • Chen X, Song XH, Yin Z, Zou XH, Wang LL, Hu H, Cao T, Zheng M, Ouyang HW (2009) Stepwise differentiation of human embryonic stem cells promotes tendon regeneration by secreting fetal tendon matrix and differentiation factors. Stem Cells 27(6):1276–1287

    Article  CAS  PubMed  Google Scholar 

  • Dai L, Hu X, Zhang X, Zhu J, Zhang J, Fu X, Duan X, Ao Y, Zhou C (2015) Different tenogenic differentiation capacities of different mesenchymal stem cells in the presence of BMP-12. J Transl Med 13:200

    Article  PubMed  PubMed Central  Google Scholar 

  • Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183

    Article  CAS  PubMed  Google Scholar 

  • Fu L, Hu Y, Song M, Liu Z, Zhang W, Yu FX, Wu J, Wang S, Izpisua Belmonte JC, Chan P, Qu J, Tang F, Liu GH (2019) Up-regulation of FOXD1 by YAP alleviates senescence and osteoarthritis. PLoS Biol 17(4):e3000201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galli GG, Carrara M, Yuan WC, Valdes-Quezada C, Gurung B, Pepe-Mooney B, Zhang T, Geeven G, Gray NS, de Laat W, Calogero RA, Camargo FD (2015) YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol Cell 60(2):328–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Pan M, Shu H, He B, Zhang F, Sun L (2020) Vascular endothelial growth factor enhances tendon-bone healing by activating Yes-associated protein for angiogenesis induction and rotator cuff reconstruction in rats. J Cell Biochem 121(3):2343–2353

    Article  CAS  PubMed  Google Scholar 

  • Ishihara E, Nishina H (2016) Role of hippo-YAP/TAZ signaling pathway in mechanotransduction. Clin Calcium 26(12):1751–1756

    CAS  PubMed  Google Scholar 

  • Karystinou A, Roelofs AJ, Neve A, Cantatore FP, Wackerhage H, De Bari C (2015) Yes-associated protein (YAP) is a negative regulator of chondrogenesis in mesenchymal stem cells. Arthritis Res Ther 17:147

    Article  PubMed  PubMed Central  Google Scholar 

  • Kayama T, Mori M, Ito Y, Matsushima T, Nakamichi R, Suzuki H, Ichinose S, Saito M, Marumo K, Asahara H (2016) Gtf2ird1-dependent Mohawk expression regulates Mechanosensing properties of the tendon. Mol Cell Biol 36(8):1297–1309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kishore V, Bullock W, Sun X, Van Dyke WS, Akkus O (2012) Tenogenic differentiation of human MSCs induced by the topography of electrochemically aligned collagen threads. Biomaterials 33(7):2137–2144

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Zhou Z, Taub PJ, Ramcharan M, Li Y, Akinbiyi T, Maharam ER, Leong DJ, Laudier DM, Ruike T, Torina PJ, Zaidi M, Majeska RJ, Schaffler MB, Flatow EL, Sun HB (2011) BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo. PLoS ONE 6(3):e17531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Ramcharan M, Zhou Z, Leong DJ, Akinbiyi T, Majeska RJ, Sun HB (2015) The role of scleraxis in fate determination of mesenchymal stem cells for tenocyte differentiation. Sci Rep 5:13149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lian I, Kim J, Okazawa H, Zhao J, Zhao B, Yu J, Chinnaiyan A, Israel MA, Goldstein LS, Abujarour R, Ding S, Guan KL (2010) The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev 24(11):1106–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Zhang M, Shi M, Zhang T, Lu W, Yang S, Cui Q, Li Z (2021) Adipose-derived mesenchymal stromal cell-derived exosomes promote tendon healing by activating both SMAD1/5/9 and SMAD2/3. Stem Cell Res Ther 12(1):338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mo JS, Park HW, Guan KL (2014) The hippo signaling pathway in stem cell biology and cancer. EMBO Rep 15(6):642–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narimatsu M, Samavarchi-Tehrani P, Varelas X, Wrana JL (2015) Distinct polarity cues direct Taz/Yap and TGFbeta receptor localization to differentially control TGFbeta-induced Smad signaling. Dev Cell 32(5):652–656

    Article  CAS  PubMed  Google Scholar 

  • Otabe K, Nakahara H, Hasegawa A, Matsukawa T, Ayabe F, Onizuka N, Inui M, Takada S, Ito Y, Sekiya I, Muneta T, Lotz M, Asahara H (2015) Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. J Orthop Res 33(1):1–8

    Article  CAS  PubMed  Google Scholar 

  • Piccolo S, Dupont S, Cordenonsi M (2014) The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 94(4):1287–1312

    Article  CAS  PubMed  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    Article  CAS  PubMed  Google Scholar 

  • Ramdass B, Koka PS (2015) Ligament and tendon repair through regeneration using mesenchymal stem cells. Curr Stem Cell Res Ther 10(1):84–88

    Article  CAS  PubMed  Google Scholar 

  • Rehmann MS, Luna JI, Maverakis E, Kloxin AM (2016) Tuning microenvironment modulus and biochemical composition promotes human mesenchymal stem cell tenogenic differentiation. J Biomed Mater Res A 104(5):1162–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ (2001) Analysis of the tendon cell fate using scleraxis, a specific marker for tendons and ligaments. Development 128(19):3855–3866

    Article  CAS  PubMed  Google Scholar 

  • Shen H, Gelberman RH, Silva MJ, Sakiyama-Elbert SE, Thomopoulos S (2013) BMP12 induces tenogenic differentiation of adipose-derived stromal cells. PLoS ONE 8(10):e77613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukunami C, Takimoto A, Oro M, Hiraki Y (2006) Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol 298(1):234–247

    Article  CAS  PubMed  Google Scholar 

  • Song N, Armstrong AD, Li F, Ouyang H, Niyibizi C (2014) Multipotent mesenchymal stem cells from human subacromial bursa: potential for cell based tendon tissue engineering. Tissue Eng Part A 20(1–2):239–249

    Article  CAS  PubMed  Google Scholar 

  • Szeto SG, Narimatsu M, Lu M, He X, Sidiqi AM, Tolosa MF, Chan L, De Freitas K, Bialik JF, Majumder S, Boo S, Hinz B, Dan Q, Advani A, John R, Wrana JL, Kapus A, Yuen DA (2016) YAP/TAZ Are mechanoregulators of TGF-beta-smad signaling and renal fibrogenesis. J Am Soc Nephrol 27(10):3117–3128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan SL, Ahmad TS, Ng WM, Azlina AA, Azhar MM, Selvaratnam L, Kamarul T (2015) Identification of pathways mediating growth differentiation factor5-induced tenogenic differentiation in human bone marrow stromal cells. PLoS ONE 10(11):e0140869

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang Y, Rowe RG, Botvinick EL, Kurup A, Putnam AJ, Seiki M, Weaver VM, Keller ET, Goldstein S, Dai J, Begun D, Saunders T, Weiss SJ (2013) MT1-MMP-dependent control of skeletal stem cell commitment via a beta1-integrin/YAP/TAZ signaling axis. Dev Cell 25(4):402–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tao SC, Huang JY, Li ZX, Zhan S, Guo SC (2021) Small extracellular vesicles with LncRNA H19 “overload”: YAP regulation as a tendon repair therapeutic tactic. iScience 24(3):102200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uemura M, Nagasawa A, Terai K (2016) Yap/Taz transcriptional activity in endothelial cells promotes intramembranous ossification via the BMP pathway. Sci Rep 6:27473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varelas X (2014) The hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 141(8):1614–1626

    Article  CAS  PubMed  Google Scholar 

  • Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL (2008) TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10(7):837–848

    Article  CAS  PubMed  Google Scholar 

  • Weiss A, Attisano L (2013) The TGFbeta superfamily signaling pathway. Wiley Interdiscip Rev Dev Biol 2(1):47–63

    Article  CAS  PubMed  Google Scholar 

  • Xu T, Xu M, Bai J, Lin J, Yu B, Liu Y, Guo X, Shen J, Sun H, Hao Y, Geng D (2019) Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-beta. Cytotechnology 71(1):57–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zarychta-Wisniewska W, Burdzinska A, Kulesza A, Gala K, Kaleta B, Zielniok K, Siennicka K, Sabat M, Paczek L (2017) Bmp-12 activates tenogenic pathway in human adipose stem cells and affects their immunomodulatory and secretory properties. BMC Cell Biol 18(1):13

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 21(21):2747–2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong W, Li Y, Li L, Zhang W, Wang S, Zheng X (2013a) YAP-mediated regulation of the chondrogenic phenotype in response to matrix elasticity. J Mol Histol 44(5):587–595

    Article  CAS  PubMed  Google Scholar 

  • Zhong W, Tian K, Zheng X, Li L, Zhang W, Wang S, Qin J (2013b) Mesenchymal stem cell and chondrocyte fates in a multishear microdevice are regulated by Yes-associated protein. Stem Cells Dev 22(14):2083–2093

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81601619), the Program Funded by Liaoning Province Education Administration (Grant No. LZ2019008) and the Natural Science Foundation of Liaoning Province (Grant No. 2019-BS-079).

Author information

Author notes

  1. Ying Li, Chenyang Xiao, Ruihua Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedics Surgery, First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China

    Chenyang Xiao, Weiliang Zhong & Weiguo Zhang

  2. Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopaedic Diseases, Liaoning, 116011, China

    Weiliang Zhong, Gang Xu & Weiguo Zhang

  3. Department of Clinical Laboratory, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China

    Ying Li, Chenyang Xiao & Ruihua Li

Authors
  1. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chenyang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruihua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weiliang Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiguo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YL—Methodology, conceptualization, investigation, validation, writing—original draft, visualization; CX—Methodology, conceptualization, investigation, validation, writing—original draft; RL—Methodology, conceptualization, investigation, validation, writing—review & editing; WZ—Conceptualization, methodology, supervision, project administration, funding acquisition, writing—review & editing, resources; GX—Methodology, investigation, validation, funding acquisition; WZ—Validation, formal analysis, investigation, funding acquisition, resources.

Corresponding author

Correspondence to Weiliang Zhong.

Ethics declarations

Conflict of interest

The authors indicated no potential conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Xiao, C., Li, R. et al. Role of Yes-associated protein (YAP) in regulation of mesenchymal stem cell tenogenic differentiation. J Mol Histol 53, 273–283 (2022). https://doi.org/10.1007/s10735-022-10059-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-022-10059-9

Keywords

Search

Navigation