Skip to main content

Induction of chondrogenic differentiation in mesenchymal stem cells by TGF-beta cross-linked to collagen-PLLA [poly(l-lactic acid)] scaffold by transglutaminase 2

Biotechnology Letters volume 35, pages 2193–2199 (2013)Cite this article

Abstract

Transglutaminase-mediated cross-linking has been employed to optimize the mechanical properties and stability of tissue scaffolds. We have characterized tissue transglutaminase (TG2)-mediated cross-linking as a useful tool to deliver biologically-active TGF to mesenchymal stem cells (MSCs) and direct their differentiation towards a chondrogenic lineage. TGF-β3 is irreversibly cross-linked by TG2 to collagen type II-coated poly(l-lactic acid) nanofibrous scaffolds and activates Smad phosphorylation and Smad-dependent expression of a luciferase reporter. Human bone marrow-derived MSCs cultured on these scaffolds deposit cartilaginous matrix after 14 days of culture at 50 % efficiency compared to chondrogenesis in the presence of soluble TGF-β3. These findings are significant because they suggest a novel approach for the programming of MSCs in a spatially controlled manner by immobilizing biologically active TGF-β3 via cross-linking to a collagen-coated polymeric scaffold.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

References

  • Akagi A, Tajima S, Ishibashi A, Matsubara Y, Takehana M, Kobayashi S, Yamaguchi N (2002) Type XVI collagen is expressed in factor XIIIa + monocyte-derived dermal dendrocytes and constitutes a potential substrate for factor XIIIa. J Investig Dermatol 118:267–274

    PubMed  Article  CAS  Google Scholar 

  • Akimov SS, Krylov D, Fleischman LF, Belkin AM (2000) Tissue transglutaminase is an integrin-binding adhesion coreceptor for fibronectin. J Cell Biol 148:825–838

    PubMed  Article  CAS  Google Scholar 

  • Alsalameh S, Amin R, Gemba T, Lotz M (2004) Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum 50:1522–1532

    PubMed  Article  Google Scholar 

  • Arrighi I, Mark S, Alvisi M, von Rechenberg RB, Hubbell JA, Schense JC (2009) Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. Biomaterials 30:1763–1771

    PubMed  Article  CAS  Google Scholar 

  • Beazley KE, Eghtesad S, Nurminskaya MV (2012) Quercetin attenuates warfarin-induced vascular calcification in vitro independently from Matrix Gla protein. J Biol Chem 288(4):2632–2640

    PubMed  Article  Google Scholar 

  • Bowness JM, Tarr AH, Wiebe RI (1989) Transglutaminase-catalysed cross-linking: a potential mechanism for the interaction of fibrinogen, low density lipoprotein and arterial type III procollagen. Thromb Res 54:357–367

    PubMed  Article  CAS  Google Scholar 

  • Chau DY, Collighan RJ, Verderio EA, Addy VL, Griffin M (2005) The cellular response to transglutaminase-cross-linked collagen. Biomaterials 26:6518–6529

    PubMed  Article  CAS  Google Scholar 

  • Ciardelli G, Gentile P, Chiono V, Mattioli-Belmonte M, Vozzi G, Barbani N, Giusti P (2010) Enzymatically crosslinked porous composite matrices for bone tissue regeneration. J Biomed Mater Res A 92:137–151

    PubMed  Google Scholar 

  • Collighan RJ, Griffin M (2009) Transglutaminase 2 cross-linking of matrix proteins: biological significance and medical applications. Amino Acids 36:659–670

    PubMed  Article  CAS  Google Scholar 

  • Cooper AJ, Sheu KR, Burke JR, Onodera O, Strittmatter WJ, Roses AD, Blass JP (1997) Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and alpha-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length. Proc Natl Acad Sci USA 94:12604–12609

    PubMed  Article  CAS  Google Scholar 

  • Demignot S, Borge L, Adolphe M (1995) Transglutaminase activity in rabbit articular chondrocytes in culture. Biochim Biophys Acta 1266:163–170

    PubMed  Article  Google Scholar 

  • Freyria AM, Mallein-Gerin F (2012) Chondrocytes or adult stem cells for cartilage repair: the indisputable role of growth factors. Injury 43:259–265

    PubMed  Article  Google Scholar 

  • Garcia Y, Hemantkumar N, Collighan R, Griffin M, Rodriguez-Cabello JC, Pandit A (2009) In vitro characterization of a collagen scaffold enzymatically cross-linked with a tailored elastin-like polymer. Tissue Eng Part A 15:887–899

    PubMed  Article  CAS  Google Scholar 

  • Johnson K, Hashimoto S, Lotz M, Pritzker K, Terkeltaub R (2001) Interleukin-1 induces pro-mineralizing activity of cartilage tissue transglutaminase and factor XIIIa. Am J Pathol 159:149–163

    PubMed  Article  CAS  Google Scholar 

  • Johnson KA, van Etten D, Nanda N, Graham RM, Terkeltaub RA (2003) Distinct transglutaminase 2-independent and transglutaminase 2-dependent pathways mediate articular chondrocyte hypertrophy. J Biol Chem 278:18824–18832

    PubMed  Article  CAS  Google Scholar 

  • Jones ME, Messersmith PB (2007) Facile coupling of synthetic peptides and peptide-polymer conjugates to cartilage via transglutaminase enzyme. Biomaterials 28:5215–5224

    PubMed  Article  CAS  Google Scholar 

  • Jurgensen K, Aeschlimann D, Cavin V, Genge M, Hunziker EB (1997) A new biological glue for cartilage–cartilage interfaces: tissue transglutaminase. J Bone Joint Surg Am 79:185–193

    PubMed  CAS  Google Scholar 

  • Kleman JP, Aeschlimann D, Paulsson M, van der Rest M (1995) Transglutaminase-catalyzed cross-linking of fibrils of collagen V/XI in A204 rhabdomyosarcoma cells. Biochemistry 34:13768–13775

    PubMed  Article  CAS  Google Scholar 

  • Lorand L, Graham RM (2003) Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4:140–156

    PubMed  Article  CAS  Google Scholar 

  • McHale MK, Setton LA, Chilkoti A (2005) Synthesis and in vitro evaluation of enzymatically cross-linked elastin-like polypeptide gels for cartilaginous tissue repair. Tissue Eng 11:1768–1779

    PubMed  Article  CAS  Google Scholar 

  • Nurminskaya MV, Belkin AM (2012) Cellular functions of tissue transglutaminase. Int Rev Cell Mol Biol 294:1–97

    PubMed  Article  CAS  Google Scholar 

  • Nurminsky D, Shanmugasundaram S, Deasey S, Michaud C, Allen S, Hendig D, Dastjerdi A, Francis-West P, Nurminskaya M (2011) Transglutaminase 2 regulates early chondrogenesis and glycosaminoglycan synthesis. Mech Dev 128:234–245

    PubMed  Article  CAS  Google Scholar 

  • Orban JM, Wilson LB, Kofroth JA, El-Kurdi MS, Maul TM, Vorp DA (2004) Crosslinking of collagen gels by transglutaminase. J Biomed Mater Res A 68:756–762

    PubMed  Article  Google Scholar 

  • Rosenthal AK, Derfus BA, Henry LA (1997) Transglutaminase activity in aging articular chondrocytes and articular cartilage vesicles. Arthritis Rheum 40:966–970

    PubMed  Article  CAS  Google Scholar 

  • Shanmugasundaram S, Logan-Mauney S, Burgos K, Nurminskaya M (2012a) Tissue transglutaminase regulates chondrogenesis in mesenchymal stem cells on collagen type XI matrices. Amino Acids 42:1045–1053

    PubMed  Article  CAS  Google Scholar 

  • Shanmugasundaram S, Logan-Mauney S, Burgos K, Nurminskaya M (2012b) Tissue transglutaminase regulates chondrogenesis in mesenchymal stem cells on collagen type XI matrices. Amino Acids 42:1045–1053

    PubMed  Article  CAS  Google Scholar 

  • Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

    PubMed  Article  CAS  Google Scholar 

  • Spurlin TA, Bhadriraju K, Chung KH, Tona A, Plant AL (2009) The treatment of collagen fibrils by tissue transglutaminase to promote vascular smooth muscle cell contractile signaling. Biomaterials 30:5486–5496

    PubMed  Article  CAS  Google Scholar 

  • Summey BT Jr, Graff RD, Lai TS, Greenberg CS, Lee GM (2002) Tissue transglutaminase localization and activity regulation in the extracellular matrix of articular cartilage. J Orthop Res 20:76–82

    PubMed  Article  CAS  Google Scholar 

  • Williams R, Khan IM, Richardson K, Nelson L, McCarthy HE, Analbelsi T, Singhrao SK, Dowthwaite GP, Jones RE, Baird DM, Lewis H, Roberts S, Shaw HM, Dudhia J, Fairclough J, Briggs T, Archer CW (2010) Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS ONE 5:e13246

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

This study was supported by Grants from Maryland Stem Cell Research Foundation (MSCRFE-0156) and the National Institute of Health (AR057126).

Author information

Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA

    Corinne Niger, Kelly E. Beazley & Maria Nurminskaya

Authors
  1. Corinne Niger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kelly E. Beazley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Nurminskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Nurminskaya.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Niger, C., Beazley, K.E. & Nurminskaya, M. Induction of chondrogenic differentiation in mesenchymal stem cells by TGF-beta cross-linked to collagen-PLLA [poly(l-lactic acid)] scaffold by transglutaminase 2. Biotechnol Lett 35, 2193–2199 (2013). https://doi.org/10.1007/s10529-013-1301-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10529-013-1301-8

Keywords

  • Cartilage bioengineering
  • Chondrogenesis
  • Mesenchymal stem cells
  • Nanofibres
  • Poly(l-lactic acid)
  • TGF-β3
  • Tissue scaffolds
  • Transglutaminase 2