Cardiac Fibroblast-Derived 3D Extracellular Matrix Seeded with Mesenchymal Stem Cells as a Novel Device to Transfer Cells to the Ischemic Myocardium


Demonstrate a novel manufacturing method to generate extracellular matrix scaffolds from cardiac fibroblasts (CF-ECM) as a therapeutic mesenchymal stem cell-transfer device. Rat CF were cultured at high-density (~1.6 × 105/cm2) for 10–14 days. Cell sheets were removed from the culture dish by incubation with EDTA and decellularized with water and peracetic acid. CF-ECM was characterized by mass spectrometry, immunofluorescence and scanning electron microscopy. CF-ECM seeded with human embryonic stem cell derived mesenchymal stromal cells (hEMSCs) were transferred into a mouse myocardial infarction model. 48 h later, mouse hearts were excised and examined for CF-ECM scaffold retention and cell transfer. CF-ECM scaffolds are composed of fibronectin (82%), collagens type I (13%), type III (3.4%), type V (0.2%), type II (0.1%) elastin (1.3%) and 18 non-structural bioactive molecules. Scaffolds remained intact on the mouse heart for 48 h without the use of sutures or glue. Identified hEMSCs were distributed from the epicardium to the endocardium. High density cardiac fibroblast culture can be used to generate CF-ECM scaffolds. CF-ECM scaffolds seeded with hEMSCs can be maintained on the heart without suture or glue. hEMSC are successfully delivered throughout the myocardium.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


  1. 1.

    Abdel-Latif, A., R. Bolli, I. M. Tleyjeh, V. M. Montori, E. C. Perin, C. A. Hornung, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch. Intern. Med. 167(10):989–997, 2007. doi:10.1001/archinte.167.10.989.

  2. 2.

    Bader, A., T. Schilling, O. E. Teebken, G. Brandes, T. Herden, G. Steinhoff, et al. Tissue engineering of heart valves—human endothelial cell seeding of detergent acellularized porcine valves. Eur. J. Cardiothorac. Surg. 14(3):279–284, 1998.

  3. 3.

    Badylak, S. F., D. O. Freytes, and T. W. Gilbert. Extracellular matrix as a biological scaffold material: Structure and function. Acta Biomater. 5(1):1–13, 2009.

  4. 4.

    Badylak, S. F., J. E. Valentin, A. K. Ravindra, G. P. McCabe, and A. M. Stewart-Akers. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng. Part A 14(11):1835–1842, 2008. doi:10.1089/ten.tea; (2007.0264).

  5. 5.

    Baharvand, H., M. Azarnia, K. Parivar, and S. K. Ashtiani. The effect of extracellular matrix on embryonic stem cell-derived cardiomyocytes. J. Mol. Cell. Cardiol. 38(3):495–503, 2005.

  6. 6.

    Berger, S., L. Dyugovskaya, A. Polyakov, and L. Lavie. Short-term fibronectin treatment induces endothelial-like and angiogenic properties in monocyte-derived immature dendritic cells: Involvement of intracellular VEGF and MAPK regulation. Eur. J. Cell Biol. 2012. doi:10.1016/j.ejcb.2012.02.003.

  7. 7.

    Bolli, R., A. R. Chugh, D. D’Amario, J. H. Loughran, M. F. Stoddard, S. Ikram, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378(9806):1847–1857, 2011. doi:10.1016/S0140-6736(11)61590-0.

  8. 8.

    Bonios, M., J. Terrovitis, C. Y. Chang, J. M. Engles, T. Higuchi, R. Lautamaki, et al. Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells. J. Nucl. Cardiol. 18(3):443–450, 2011. doi:10.1007/s12350-011-9369-9.

  9. 9.

    Booth, C., S. A. Korossis, H. E. Wilcox, K. G. Watterson, J. N. Kearney, J. Fisher, et al. Tissue engineering of cardiac valve prostheses I: development and histological characterization of an acellular porcine scaffold. J. Heart Valve Dis. 11(4):457–462, 2002.

  10. 10.

    Bornstein, P. Matricellular proteins: an overview. J. Cell Commun. Signal. 3(3–4):163–165, 2009. doi:10.1007/s12079-009-0069-z.

  11. 11.

    Borschel, G. H., R. G. Dennis, and W. M. Kuzon, Jr. Contractile skeletal muscle tissue-engineered on an acellular scaffold. Plast. Reconstr. Surg. 113(2):595–602, 2004; (discussion 3–4).

  12. 12.

    Brizzi, M. F., G. Tarone, and P. Defilippi. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 24(5):645–651, 2012. doi:10.1016/

  13. 13.

    Brown, B. N., R. Londono, S. Tottey, L. Zhang, K. A. Kukla, M. T. Wolf, et al. Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater. 8(3):978–987, 2012. doi:10.1016/j.actbio.2011.11.031.

  14. 14.

    Bujak, M., and N. G. Frangogiannis. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc. Res. 74(2):184–195, 2007. doi:10.1016/j.cardiores.2006.10.002.

  15. 15.

    Chachques, J. C., J. C. Trainini, N. Lago, O. H. Masoli, J. L. Barisani, M. Cortes-Morichetti, et al. Myocardial assistance by grafting a new bioartificial upgraded myocardium (MAGNUM clinical trial): one year follow-up. Cell Transplant. 16(9):927–934, 2007.

  16. 16.

    Chang, H. Y., J. T. Chi, S. Dudoit, C. Bondre, M. van de Rijn, D. Botstein, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. U.S.A. 99(20):12877–12882, 2002.

  17. 17.

    Chimenti, I., R. R. Smith, T. S. Li, G. Gerstenblith, E. Messina, A. Giacomello, et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ. Res. 106(5):971–980, 2010.

  18. 18.

    Choi, H., and A. I. Nesvizhskii. False discovery rates and related statistical concepts in mass spectrometry-based proteomics. J. Proteome Res. 7(1):47–50, 2008. doi:10.1021/pr700747q.

  19. 19.

    Cortes-Morichetti, M., G. Frati, O. Schussler, J. P. Duong Van Huyen, E. Lauret, J. A. Genovese, et al. Association between a cell-seeded collagen matrix and cellular cardiomyoplasty for myocardial support and regeneration. Tissue Eng. 13(11):2681–2687, 2007. doi:10.1089/ten; (2006.0447).

  20. 20.

    Dubey, R. K., D. G. Gillespie, Z. Mi, and E. K. Jackson. Exogenous and endogenous adenosine inhibits fetal calf serum-induced growth of rat cardiac fibroblasts: role of A2B receptors. Circulation 96(8):2656–2666, 1997.

  21. 21.

    Dvir, T., A. Kedem, E. Ruvinov, O. Levy, I. Freeman, N. Landa, et al. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc. Natl Acad. Sci. U.S.A. 106(35):14990–14995, 2009. doi:10.1073/pnas.0812242106.

  22. 22.

    Forest, V. F., A. M. Tirouvanziam, C. Perigaud, S. Fernandes, M. S. Fusellier, J. C. Desfontis, et al. Cell distribution after intracoronary bone marrow stem cell delivery in damaged and undamaged myocardium: implications for clinical trials. Stem Cell Res Ther. 1(1):4, 2010.

  23. 23.

    Freytes, D. O., L. Santambrogio, and G. Vunjak-Novakovic. Optimizing dynamic interactions between a cardiac patch and inflammatory host cells. Cells Tissues Organs 195(1–2):171–182, 2012. doi:10.1159/000331392.

  24. 24.

    Fries, K. M., T. Blieden, R. J. Looney, G. D. Sempowski, M. R. Silvera, R. A. Willis, et al. Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis. Clin. Immunol. Immunopathol. 72(3):283–292, 1994.

  25. 25.

    Gilbert, T. W., T. L. Sellaro, and S. F. Badylak. Decellularization of tissues and organs. Biomaterials 27(19):3675–3683, 2006.

  26. 26.

    Giraud, M. N., E. Ayuni, S. Cook, M. Siepe, T. P. Carrel, and H. T. Tevaearai. Hydrogel-based engineered skeletal muscle grafts normalize heart function early after myocardial infarction. Artif. Organs 32(9):692–700, 2008. doi:10.1111/j.1525-1594.2008.00595.x.

  27. 27.

    Giraud, M. N., R. Flueckiger, S. Cook, E. Ayuni, M. Siepe, T. Carrel, et al. Long-term evaluation of myoblast seeded patches implanted on infarcted rat hearts. Artif. Organs 34(6):E184–E192, 2010. doi:10.1111/j.1525-1594.2009.00979.x.

  28. 28.

    Godier-Furnemont, A. F., T. P. Martens, M. S. Koeckert, L. Wan, J. Parks, K. Arai, et al. Composite scaffold provides a cell delivery platform for cardiovascular repair. Proc. Natl Acad. Sci. U.S.A. 108(19):7974–7979, 2011. doi:10.1073/pnas.1104619108.

  29. 29.

    Hamdi, H., V. Planat-Benard, A. Bel, E. Puymirat, R. Geha, L. Pidial, et al. Epicardial adipose stem cell sheets results in greater post-infarction survival than intramyocardial injections. Cardiovasc. Res. 91(3):483–491, 2011.

  30. 30.

    Hare, J. M., J. E. Fishman, G. Gerstenblith, D. L. Difede Velazquez, J. P. Zambrano, V. Y. Suncion, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON Randomized Trial. JAMA 1–11, 2012. doi:10.1001/jama.2012.25321.

  31. 31.

    Hare, J. M., J. H. Traverse, T. D. Henry, N. Dib, R. K. Strumpf, S. P. Schulman, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J. Am. Coll. Cardiol. 54(24):2277–2286, 2009.

  32. 32.

    Hata, H., A. Bar, S. Dorfman, Z. Vukadinovic, Y. Sawa, A. Haverich, et al. Engineering a novel three-dimensional contractile myocardial patch with cell sheets and decellularised matrix. Eur. J. Cardiothorac. Surg. 38(4):450–455, 2010. doi:10.1016/j.ejcts.2010.02.009.

  33. 33.

    Hou, D., E. Youssef, T. Brinton, P. Zhang, P. Rogers, E. Price, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112(9 Suppl):I150–I156, 2005.

  34. 34.

    Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326(5957):1216–1219, 2009.

  35. 35.

    Janssens, S., C. Dubois, J. Bogaert, K. Theunissen, C. Deroose, W. Desmet, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367(9505):113–121, 2006.

  36. 36.

    Kalogeropoulos, A., V. Georgiopoulou, S. B. Kritchevsky, B. M. Psaty, N. L. Smith, A. B. Newman, et al. Epidemiology of incident heart failure in a contemporary elderly cohort: the health, aging, and body composition study. Arch. Intern. Med. 169(7):708–715, 2009. doi:10.1001/archinternmed.2009.40.

  37. 37.

    Kawamura, M., S. Miyagawa, K. Miki, A. Saito, S. Fukushima, T. Higuchi, et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation 126(11 Suppl 1):S29–S37, 2012. doi:10.1161/CIRCULATIONAHA.111.084343.

  38. 38.

    Kellar, R. S., B. R. Shepherd, D. F. Larson, G. K. Naughton, and S. K. Williams. Cardiac patch constructed from human fibroblasts attenuates reduction in cardiac function after acute infarct. Tissue Eng. 11(11–12):1678–1687, 2005.

  39. 39.

    Konstandin, M. H., H. Toko, G. M. Gastelum, P. J. Quijada, A. De La Torre, M. Quintana, et al. Fibronectin is essential for reparative cardiac progenitor cell response following myocardial infarction. Circ. Res. 2013. doi:10.1161/CIRCRESAHA.113.301152.

  40. 40.

    Korossis, S. A., C. Booth, H. E. Wilcox, K. G. Watterson, J. N. Kearney, J. Fisher, et al. Tissue engineering of cardiac valve prostheses II: biomechanical characterization of decellularized porcine aortic heart valves. J. Heart Valve Dis. 11(4):463–471, 2002.

  41. 41.

    Kouris, N. A., J. A. Schaefer, M. Hatta, B. T. Freeman, T. J. Kamp, Y. Kawaoka, et al. Directed fusion of mesenchymal stem cells with cardiomyocytes via VSV-G facilitates stem cell programming. Stem Cells Int. 2012:414038, 2012. doi:10.1155/2012/414038.

  42. 42.

    Kumar, D., T. A. Hacker, J. Buck, L. F. Whitesell, E. H. Kaji, P. S. Douglas, et al. Distinct mouse coronary anatomy and myocardial infarction consequent to ligation. Coron. Artery Dis. 16(1):41–44, 2005.

  43. 43.

    Kuwabara, I., and F. T. Liu. Galectin-3 promotes adhesion of human neutrophils to laminin. J. Immunol. 156(10):3939–3944, 1996.

  44. 44.

    Lekic, P. C., N. Pender, and C. A. McCulloch. Is fibroblast heterogeneity relevant to the health, diseases, and treatments of periodontal tissues? Crit. Rev. Oral Biol. Med. 8(3):253–268, 1997.

  45. 45.

    Makkar, R. R., R. R. Smith, K. Cheng, K. Malliaras, L. E. Thomson, D. Berman, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379(9819):895–904, 2012. doi:10.1016/S0140-6736(12)60195-0.

  46. 46.

    Masuda, S., T. Shimizu, M. Yamato, and T. Okano. Cell sheet engineering for heart tissue repair. Adv. Drug Deliv. Rev. 60(2):277–285, 2008.

  47. 47.

    Matsuura, K., Y. Haraguchi, T. Shimizu, and T. Okano. Cell sheet transplantation for heart tissue repair. J. Control. Rel. 169(3):336–340, 2013. doi:10.1016/j.jconrel.2013.03.003.

  48. 48.

    McCurdy, S. M., Q. Dai, J. Zhang, R. Zamilpa, T. A. Ramirez, T. Dayah, et al. SPARC mediates early extracellular matrix remodeling following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 301(2):H497–H505, 2011. doi:10.1152/ajpheart.0; (1070.2010).

  49. 49.

    Menasche, P., O. Alfieri, S. Janssens, W. McKenna, H. Reichenspurner, L. Trinquart, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117(9):1189–1200, 2008. doi:10.1161/CIRCULATIONAHA.107.734103.

  50. 50.

    Meyer, G. P., K. C. Wollert, J. Lotz, J. Pirr, U. Rager, P. Lippolt, et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur. Heart J. 30(24):2978–2984, 2009. doi:10.1093/eurheartj/ehp374.

  51. 51.

    Meyer, G. P., K. C. Wollert, J. Lotz, J. Steffens, P. Lippolt, S. Fichtner, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 113(10):1287–1294, 2006.

  52. 52.

    Mirotsou, M., Z. Zhang, A. Deb, L. Zhang, M. Gnecchi, N. Noiseux, et al. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc. Natl Acad. Sci. U.S.A. 104(5):1643–1648, 2007. doi:10.1073/pnas.0610024104.

  53. 53.

    Miyagawa, S., A. Saito, T. Sakaguchi, Y. Yoshikawa, T. Yamauchi, Y. Imanishi, et al. Impaired myocardium regeneration with skeletal cell sheets—a preclinical trial for tissue-engineered regeneration therapy. Transplantation 90(4):364–372, 2010. doi:10.1097/TP.0b013e3181e6f201.

  54. 54.

    Muller-Ehmsen, J., P. Whittaker, R. A. Kloner, J. S. Dow, T. Sakoda, T. I. Long, et al. Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. J. Mol. Cell. Cardiol. 34(2):107–116, 2002.

  55. 55.

    Murry, C. E., M. H. Soonpaa, H. Reinecke, H. Nakajima, H. O. Nakajima, M. Rubart, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428(6983):664–668, 2004.

  56. 56.

    Pankov, R., and K. M. Yamada. Fibronectin at a glance. J. Cell Sci. 115(Pt 20):3861–3863, 2002.

  57. 57.

    Pflieger, D., S. Chabane, O. Gaillard, B. A. Bernard, P. Ducoroy, J. Rossier, et al. Comparative proteomic analysis of extracellular matrix proteins secreted by two types of skin fibroblasts. Proteomics 6(21):5868–5879, 2006.

  58. 58.

    Plow, E. F., T. A. Haas, L. Zhang, J. Loftus, and J. W. Smith. Ligand binding to integrins. J. Biol. Chem. 275(29):21785–21788, 2000. doi:10.1074/jbc.R000003200.

  59. 59.

    Qian, H., Y. Yang, J. Huang, R. Gao, K. Dou, G. Yang, et al. Intracoronary delivery of autologous bone marrow mononuclear cells radiolabeled by 18F-fluoro-deoxy-glucose: tissue distribution and impact on post-infarct swine hearts. J. Cell. Biochem. 102(1):64–74, 2007.

  60. 60.

    Rabinovich, G. A., C. E. Sotomayor, C. M. Riera, I. Bianco, and S. G. Correa. Evidence of a role for galectin-1 in acute inflammation. Eur. J. Immunol. 30(5):1331–1339, 2000. doi:10.1002/(SICI)1521-4141(200005)30:5<1331::AID-IMMU1331>3.0.CO;2-H.

  61. 61.

    Rane, A. A., and K. L. Christman. Biomaterials for the treatment of myocardial infarction: a 5-year update. J. Am. Coll. Cardiol. 58(25):2615–2629, 2011. doi:10.1016/j.jacc.2011.11.001.

  62. 62.

    Ratner, B. D., and S. J. Bryant. Biomaterials: where we have been and where we are going. Annu. Rev. Biomed. Eng. 6:41–75, 2004.

  63. 63.

    Rifkin, D. B. Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J. Biol. Chem. 280(9):7409–7412, 2005. doi:10.1074/jbc.R400029200.

  64. 64.

    Roger, V. L., A. S. Go, D. M. Lloyd-Jones, E. J. Benjamin, J. D. Berry, W. B. Borden, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 125(1):e2–e220, 2012. doi:10.1161/CIR.0b013e31823ac046.

  65. 65.

    Ruoslahti, E. Fibronectin and its receptors. Annu. Rev. Biochem. 57:375–413, 1988. doi:10.1146/

  66. 66.

    Sano, H., D. K. Hsu, L. Yu, J. R. Apgar, I. Kuwabara, T. Yamanaka, et al. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J. Immunol. 165(4):2156–2164, 2000.

  67. 67.

    Schachinger, V., S. Erbs, A. Elsasser, W. Haberbosch, R. Hambrecht, H. Holschermann, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355(12):1210–1221, 2006.

  68. 68.

    Schaefer, A., C. Zwadlo, M. Fuchs, G. P. Meyer, P. Lippolt, K. C. Wollert, et al. Long-term effects of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: 5-year results from the randomized-controlled BOOST trial–an echocardiographic study. Eur. J. Echocardiogr. 11(2):165–171, 2010. doi:10.1093/ejechocard/jep191.

  69. 69.

    Silva, E. A., and D. J. Mooney. Synthetic extracellular matrices for tissue engineering and regeneration. Curr. Top. Dev. Biol. 64:181–205, 2004.

  70. 70.

    Singla, D. K., T. A. Hacker, L. Ma, P. S. Douglas, R. Sullivan, G. E. Lyons, et al. Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J. Mol. Cell. Cardiol. 40(1):195–200, 2006.

  71. 71.

    Tan, M. Y., W. Zhi, R. Q. Wei, Y. C. Huang, K. P. Zhou, B. Tan, et al. Repair of infarcted myocardium using mesenchymal stem cell seeded small intestinal submucosa in rabbits. Biomaterials 30(19):3234–3240, 2009. doi:10.1016/j.biomaterials.2009.02.013.

  72. 72.

    Terrovitis, J., R. Lautamaki, M. Bonios, J. Fox, J. M. Engles, J. Yu, et al. Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J. Am. Coll. Cardiol. 54(17):1619–1626, 2009. doi:10.1016/j.jacc.2009.04.097.

  73. 73.

    Terrovitis, J. V., R. R. Smith, and E. Marban. Assessment and optimization of cell engraftment after transplantation into the heart. Circ. Res. 106(3):479–494, 2010. doi:10.1161/CIRCRESAHA.109.208991.

  74. 74.

    Trivedi, P., and P. Hematti. Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells. Exp. Hematol. 36(3):350–359, 2008. doi:10.1016/j.exphem.2007.10.007.

  75. 75.

    Valentin, J. E., A. M. Stewart-Akers, T. W. Gilbert, and S. F. Badylak. Macrophage participation in the degradation and remodeling of extracellular matrix scaffolds. Tissue Eng. Part A 15(7):1687–1694, 2009. doi:10.1089/ten.tea; (2008.0419).

  76. 76.

    Vunjak-Novakovic, G., N. Tandon, A. Godier, R. Maidhof, A. Marsano, T. P. Martens, et al. Challenges in cardiac tissue engineering. Tissue Eng. B 16(2):169–187, 2010. doi:10.1089/ten.TEB; (2009.0352).

  77. 77.

    Wei, H. J., C. H. Chen, W. Y. Lee, I. Chiu, S. M. Hwang, W. W. Lin, et al. Bioengineered cardiac patch constructed from multilayered mesenchymal stem cells for myocardial repair. Biomaterials 29(26):3547–3556, 2008. doi:10.1016/j.biomaterials.2008.05.009.

  78. 78.

    Westermann, D., J. Mersmann, A. Melchior, T. Freudenberger, C. Petrik, L. Schaefer, et al. Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 117(10):1269–1276, 2008. doi:10.1161/CIRCULATIONAHA.107.714147.

  79. 79.

    Willems, I. E., J. W. Arends, and M. J. Daemen. Tenascin and fibronectin expression in healing human myocardial scars. J. Pathol. 179(3):321–325, 1996. doi:10.1002/(SICI)1096-9896(199607)179:3<321::AID-PATH555>3.0.CO;2-8.

  80. 80.

    Zimmermann, W. H., I. Melnychenko, G. Wasmeier, M. Didie, H. Naito, U. Nixdorff, et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12(4):452–458, 2006.

Download references


This study was supported by the National Heart, Lung, and Blood Institute grant number 1R21HL092477 and the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 07936 from the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center.

Conflict of interest

Author ES, Author JM, Author RE, Author NK, Author BO, Author AR, and Author KS declare that they have no conflict of interest.

Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the University of Wisconsin Madison animal care and use committee.

Author information

Correspondence to Eric G. Schmuck.

Additional information

K. W. Saupe died June 23, 2012.

Associate Editor Ajit P. Yoganathan oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (MPEG 11638 kb)

Supplementary material 1 (MPEG 11638 kb)

Supplementary material 2 (MPEG 1174 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schmuck, E.G., Mulligan, J.D., Ertel, R.L. et al. Cardiac Fibroblast-Derived 3D Extracellular Matrix Seeded with Mesenchymal Stem Cells as a Novel Device to Transfer Cells to the Ischemic Myocardium. Cardiovasc Eng Tech 5, 119–131 (2014) doi:10.1007/s13239-013-0167-1

Download citation


  • Cardiac fibroblast
  • Extracellular matrix
  • Stem cell
  • Cardiac
  • Regeneration
  • Heart failure
  • Myocardial infarction