Skip to main content
SpringerLink
Log in

Understanding strain-induced collagen matrix development in engineered cardiovascular tissues from gene expression profiles

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Mechanical conditioning is often used to enhance collagen synthesis, remodeling and maturation and, hence, the structural and mechanical properties of engineered cardiovascular tissues. Intermittent straining, i.e., alternating periods of cyclic and static strain, has previously been shown to result in more mature tissue compared with continuous cyclic straining. Nevertheless, the underlying mechanism is unknown. We have determined the short-term effects of continuous cyclic strain and of cyclic strain followed by static strain at the gene expression level to improve insight into the mechano-regulatory mechanism of intermittent conditioning on collagen synthesis, remodeling and maturation. Tissue-engineered constructs, consisting of human vascular-derived cells seeded onto rapidly degrading PGA/P4HB scaffolds, were conditioned with 4% strain at 1 Hz for 3 h in order to study the immediate effects of cyclic strain (n=18). Next, the constructs were either subjected to ongoing cyclic strain (4% at 1 Hz; n=9) or to static strain (n=9). Expression levels of genes involved in collagen synthesis, remodeling and maturation were studied at various time points up to 24 h within each straining protocol. The results indicate that a period of static strain following cyclic strain favors collagen synthesis and remodeling, whereas ongoing cyclic strain shifts this balance toward collagen remodeling and maturation. The data suggest that, with prolonged culture, the conditioning protocol should be changed from intermittent straining to continuous cyclic straining to improve collagen maturation after its synthesis and, hence, the tissue (mechanical) properties.

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

Similar content being viewed by others

References

  • Aikawa E, Whittaker P, Farber M, Mendelson K, Padera RF, Aikawa M, Schoen FJ (2006) Human semilunar cardiac valve remodeling by activated cells from fetus to adult: implications for postnatal adaptation, pathology, and tissue engineering. Circulation 113:1344–1352

    Article  PubMed  Google Scholar 

  • Balachandran K, Sucosky P, Jo H, Yoganathan AP (2009) Elevated cyclic stretch alters matrix remodeling in aortic valve cusps: implications for degenerative aortic valve disease. Am J Physiol Heart Circ Physiol 296:H756–H764

    Article  PubMed  CAS  Google Scholar 

  • Balachandran K, Sucosky P, Jo H, Yoganathan AP (2010) Elevated cyclic stretch induces aortic valve calcification in a bone morphogenic protein-dependent manner. Am J Pathol 177:49–57

    Article  PubMed  CAS  Google Scholar 

  • Balguid A, Rubbens MP, Mol A, Bank RA, Bogers AJ, van Kats JP, de Mol BA, Baaijens FP, Bouten CV (2007) The role of collagen cross-links in biomechanical behavior of human aortic heart valve leaflets—relevance for tissue engineering. Tissue Eng 13:1501–1511

    Article  PubMed  CAS  Google Scholar 

  • Bank RA, van Hinsbergh V (2002) Lysyl oxidase: new looks on LOX. Arterioscler Thromb Vasc Biol 22:1365–1366

    Article  PubMed  CAS  Google Scholar 

  • Bishop JE, Lindahl G (1999) Regulation of cardiovascular collagen synthesis by mechanical load. Cardiovasc Res 42:27–44

    Article  PubMed  CAS  Google Scholar 

  • Boerboom RA, Rubbens MP, Driessen NJ, Bouten CV, Baaijens FP (2008) Effect of strain magnitude on the tissue properties of engineered cardiovascular constructs. Ann Biomed Eng 36:244–253

    Article  PubMed  Google Scholar 

  • Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microb Infect 1:1349–1365

    Article  CAS  Google Scholar 

  • Butcher JT, Markwald RR (2007) Valvulogenesis: the moving target. Philos Trans R Soc Lond B Biol Sci 362:1489–1503

    Article  PubMed  CAS  Google Scholar 

  • Butcher JT, Simmons CA, Warnock JN (2008) Mechanobiology of the aortic heart valve. J Heart Valve Dis 17:62–73

    PubMed  Google Scholar 

  • Chiquet M (1999) Regulation of extracellular matrix gene expression by mechanical stress. Matrix Biol 18:417–426

    Article  PubMed  CAS  Google Scholar 

  • Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G (1993) Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 122:103–111

    Article  PubMed  CAS  Google Scholar 

  • Elbjeirami WM, Yonter EO, Starcher BC, West JL (2003) Enhancing mechanical properties of tissue-engineered constructs via lysyl oxidase crosslinking activity. J Biomed Mater Res 66A:513–521

    Article  CAS  Google Scholar 

  • Eyden B (2008) The myofibroblasts: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J Cell Mol Med 12:22–37

    Article  PubMed  CAS  Google Scholar 

  • Foolen J, Deshpande VS, Kanters FM, Baaijens FP (2012) The influence of matrix integrity on stress-fiber remodeling in 3D. Biomaterials 33:7508–7518

    Article  PubMed  CAS  Google Scholar 

  • Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst GR (1996) Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 107:404–411

    Article  PubMed  CAS  Google Scholar 

  • Freed LE, Guilak F, Guo XE, Gray ML, Tranquillo R, Holmes JW, Radisic M, Sefton MV, Kaplan D, Vunjak-Novakovic G (2006) Advanced tools for tissue engineering: scaffolds, bioreactors, and signaling. Tissue Eng 12:3285–3305

    Article  PubMed  CAS  Google Scholar 

  • van Geemen D Driessen-Mol A, Grootzwagers LG, Soekhradj-Soechit RS, Riem Vis PW, Baaijens FP, Bouten CV (2012) Variation in tissue outcome of ovine and human engineered heart valve constructs: relevance for tissue engineering. Regen Med 7:59–70

    Article  PubMed  Google Scholar 

  • Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C (2001) Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell 12:2730–2741

    PubMed  CAS  Google Scholar 

  • Hoerstrup SP, Sodian R, Daebritz S, Wang J, Bacha EA, Martin DP, Moran AM, Guleserian KJ, Sperling JS, Kaushal S, Vacanti JP, Schoen FJ, Mayer JE Jr (2000) Functional living trileaflet heart valves grown in vitro. Circulation 102:III44–III49

    Article  PubMed  CAS  Google Scholar 

  • Isenberg BC, Tranquillo RT (2003) Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents. Ann Biomed Eng 31:937–949

    Article  PubMed  Google Scholar 

  • Kagan HM (2000) Intra- and extracellular enzymes of collagen biosynthesis as biological and chemical targets in the control of fibrosis. Acta Trop 77:147–152

    Article  PubMed  CAS  Google Scholar 

  • Ku CH, Johnson PH, Batten P, Sarathchandra P, Chambers RC, Taylor PM, Yacoub MH, Chester AH (2006) Collagen synthesis by mesenchymal stem cells and aortic valve interstitial cells in response to mechanical stretch. Cardiovasc Res 71:548–556

    Article  PubMed  CAS  Google Scholar 

  • Kuo CK, Tuan RS (2008) Mechanoactive tenogenic differentiation of human mesenchymal stem cells. Tissue Eng Part A 14:1615–1627

    Article  PubMed  CAS  Google Scholar 

  • Lawrence DA (1996) Transforming growth factor-beta: a general review. Eur Cytokine Netw 7:363–374

    PubMed  CAS  Google Scholar 

  • Lee RT, Yamamoto C, Feng Y, Potter-Perigo S, Briggs WH, Landschulz KT, Turi TG, Thompson JF, Libby P, Wight TN (2001) Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells. J Biol Chem 276:13847–13851

    PubMed  CAS  Google Scholar 

  • Lehmann S, Walther T, Kempfert J, Rastan A, Garbade J, Dhein S, Mohr FW (2009) Mechanical strain and the aortic valve: influence on fibroblasts, extracellular matrix, and potential stenosis. Ann Thorac Surg 88:1476–1483

    Article  PubMed  Google Scholar 

  • Mol A, Bouten CV, Zund G, Günter CI, Visjager JF, Turina MI, Baaijens FP, Hoerstrup SP (2003) The relevance of large strains in functional tissue engineering of heart valves. Thorac Cardiovasc Surg 51:78–83

    Article  PubMed  CAS  Google Scholar 

  • Mol A, van Lieshout MI, Dam-de Veen CG, Neuenschwander S, Hoerstrup SP, Baaijens FP, Bouten CV (2005) Fibrin as a cell carrier in cardiovascular tissue engineering applications. Biomaterials 26:3113–3121

    Article  PubMed  CAS  Google Scholar 

  • Mol A, Rutten MC, Driessen NJ, Bouten CV, Zünd G, Baaijens FP, Hoerstrup SP (2006) Autologous human tissue-engineered heart valves: prospects for systemic application. Circulation 114:I152–I158

    Article  PubMed  Google Scholar 

  • Norris RA, Potts JD, Yost MJ, Junor L, Brooks T, Tan H, Hoffman S, Hart MM, Kern MJ, Damon B, Markwald RR, Goodwin RL (2009) Periostin promotes a fibroblastic lineage pathway in atrioventricular valve progenitor cells. Dev Dyn 238:1052–1063

    Article  PubMed  CAS  Google Scholar 

  • O’Callaghan CJ, Williams B (2000) Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-beta(1). Hypertension 36:319–324

    Article  PubMed  Google Scholar 

  • Papakrivopoulou J, Lindahl GE, Bishop JE, Laurent GJ (2004) Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen alpha1(I) gene expression in cardiac fibroblasts. Cardiovasc Res 61:736–744

    Article  PubMed  CAS  Google Scholar 

  • Peacock JD, Lu Y, Koch M, Kadler KE, Lincoln J (2008) Temporal and spatial expression of collagens during murine atrioventricular heart valve development and maintenance. Dev Dyn 237:3051–3058

    Article  PubMed  Google Scholar 

  • Powell HM, McFarland KL, Butler DL, Supp DM, Boyce ST (2010) Uniaxial strain regulates morphogenesis, gene expression, and tissue strength in engineered skin. Tissue Eng Part A 16:1083–1092

    Article  PubMed  CAS  Google Scholar 

  • Rabkin-Aikawa E, Farber M, Aikawa M, Schoen FJ (2004) Dynamic and reversible changes of interstitial cell phenotype during remodeling of cardiac valves. J Heart Valve Dis 13:841–847

    PubMed  Google Scholar 

  • Reed CC, Iozzo RV (2002) The role of decorin in collagen fibrillogenesis and skin homeostasis. Glycoconj J 19:249–255

    Article  PubMed  CAS  Google Scholar 

  • Rios HF, Ma D, Xie Y, Giannobile WV, Bonewald LF, Conway SJ, Feng JQ (2008) Periostin is essential for the integrity and function of the periodontal ligament during occlusal loading in mice. J Periodontol 79:1480–1490

    Article  PubMed  CAS  Google Scholar 

  • Ronnov-Jessen L, Petersen OW (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblasts generation in breast neoplasia. Lab Invest 68:696–707

    PubMed  CAS  Google Scholar 

  • Rubbens MP, Mol A, Boerboom RA, Bank RA, Baaijens FP, Bouten CV (2009a) Intermittent straining accelerates the development of tissue properties in engineered heart valve tissue. Tissue Eng Part A 15:999–1008

    Article  PubMed  CAS  Google Scholar 

  • Rubbens MP, Mol A, van Marion MH, Hanemaaijer R, Bank RA, Baaijens FP, Bouten CV (2009b) Straining mode-dependent collagen remodeling in engineered cardiovascular tissue. Tissue Eng Part A 15:841–849

    Article  PubMed  CAS  Google Scholar 

  • Rubbens MP, Driessen-Mol A, Boerboom RA, Koppert MM, van Assen HC TerHaar Romeny BM, Baaijens FP, Bouten CV (2009c) Quantification of the temporal evolution of collagen orientation in mechanically conditioned engineered cardiovascular tissues. Ann Biomed Eng 37:1263–1272

    Article  PubMed  Google Scholar 

  • Schnell AM, Hoerstrup SP, Zund G, Kolb S, Sodian R, Visjager JF, Grunenfelder J, Suter A, Turina M (2001) Optimal cell source for cardiovascular tissue engineering: venous vs. aortic human myofibroblasts. Thorac Cardiovasc Surg 49:221–225

    Article  PubMed  CAS  Google Scholar 

  • Seliktar D, Nerem RM, Galis ZS (2003) Mechanical strain-stimulated remodeling of tissue-engineered blood vessel constructs. Tissue Eng 9:657–666

    Article  PubMed  CAS  Google Scholar 

  • Skutek M, van Griensven M, Zeichen J, Brauer N, Bosch U (2001) Cyclic mechanical stretching modulates secretion pattern of growth factors in human tendon fibroblasts. Eur J Appl Physiol 86:48–52

    Article  PubMed  CAS  Google Scholar 

  • van der Slot AJ Zuurmond AM, Bardoel AF, Wijmenga C, Pruijs HE, Sillence DO, Brinckmann J, Abraham DJ, Black CM, Verzijl N, DeGroot J, Hanemaaijer R, TeKoppele JM, Huizinga TW, Bank RA (2003) Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem 278:40967–40972

    Article  PubMed  Google Scholar 

  • Snider P, Hinton RB, Moreno-Rodriguez RA, Wang J, Rogers R, Lindsley A, Li F, Ingram DA, Menick D, Field L, Firulli AB, Molkentin JD, Markwald R, Conway SJ (2008) Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res 102:752–760

    Article  PubMed  CAS  Google Scholar 

  • Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200:448–464

    Article  PubMed  CAS  Google Scholar 

  • Stekelenburg M, Rutten MCM, Snoeckx LHEH, Baaijens FPT (2009) Dynamic straining combined with fibrin gel cell seeding improves strength of tissue-engineered small-diameter vascular grafts. Tissue Eng Part A 15:1081–1089

    Article  PubMed  CAS  Google Scholar 

  • Syedain ZH, Tranquillo RT (2011) TGF-beta1 diminishes collagen production during long-term cyclic stretching of engineered connective tissue: implication of decreased ERK signaling. J Biomech 44:848–855

    Article  PubMed  Google Scholar 

  • Syedain ZH, Weinberg JS, Tranquillo RT (2008) Cyclic distension of fibrin-based tissue constructs: evidence of adaptation during growth of engineered connective tissue. Proc Natl Acad Sci USA 105:6537–6542

    Article  PubMed  CAS  Google Scholar 

  • Thubrikar M, Piepgrass WC, Bosher LP, Nolan SP (1980) The elastic modulus of canine aortic valve leaflets in vivo and in vitro. Circ Res 47:792–800

    Article  PubMed  CAS  Google Scholar 

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034

    Article  PubMed  Google Scholar 

  • Votteler M, Kluger PJ, Walles H, Schenke-Layland K (2010) Stem cell microenvironments—unveiling the secret of how stem cell fate is defined. Macromol Biosci 10:1302–1315

    Article  PubMed  CAS  Google Scholar 

  • Wang JH, Thampatty BP (2006) An introductory review of cell mechanobiology. Biomech Model Mechanobiol 5:1–16

    Article  PubMed  CAS  Google Scholar 

  • Webb K, Hitchcock RW, Smeal RM, Li W, Gray SD, Tresco PA (2006) Cyclic strain increases fibroblast proliferation, matrix accumulation, and elastic modulus of fibroblast-seeded polyurethane constructs. J Biomech 39:1136–1144

    Article  PubMed  Google Scholar 

  • Wen W, Chau E, Jackson-Boeters L, Elliott C, Daley TD, Hamilton DW (2010) TGF-β1 and FAK regulate periostin expression in PDL fibroblasts. J Dent Res 89:1439–1443

    Article  PubMed  CAS  Google Scholar 

  • Xing Y, Warnock JN, He Z, Hilbert SL, Yoganathan AP (2004a) Cyclic pressure affects the biological properties of porcine aortic valve leaflets in a magnitude and frequency dependent manner. Ann Biomed Eng 32:1461–1470

    Article  PubMed  Google Scholar 

  • Xing Y, He Z, Warnock JN, Hilbert SL, Yoganathan AP (2004b) Effects of constant static pressure on the biological properties of porcine aortic valve leaflets. Ann Biomed Eng 32:555–562

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Soft Tissue Biomechanics & Engineering, Department of Biomedical Engineering, Eindhoven University of Technology, GEM-Z 4.110, PO Box 513, 5600 MB, Eindhoven, The Netherlands

    Daphne van Geemen, Anita Driessen-Mol, Frank P. T. Baaijens & Carlijn V. C. Bouten

Authors
  1. Daphne van Geemen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anita Driessen-Mol
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank P. T. Baaijens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlijn V. C. Bouten
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anita Driessen-Mol.

Additional information

The authors thank the Dutch Technology Foundation (STW), Applied Science Division of NWO and the Technology Program of the Dutch Ministry of Economic Affairs for supporting this research.

The authors confirm no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Geemen, D., Driessen-Mol, A., Baaijens, F.P.T. et al. Understanding strain-induced collagen matrix development in engineered cardiovascular tissues from gene expression profiles. Cell Tissue Res 352, 727–737 (2013). https://doi.org/10.1007/s00441-013-1573-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-013-1573-2

Keywords

Search

Navigation