Inherently Bio-Active Scaffolds: Intelligent Constructs to Model the Stem Cell Niche

  • Paolo Di NardoEmail author
  • Marilena Minieri
  • Annalisa Tirella
  • Giancarlo Forte
  • Arti Ahluwalia
Part of the Studies in Mechanobiology, Tissue Engineering and Biomaterials book series (SMTEB, volume 6)


The oft-abused phrase “genes load the gun, environment pulls the trigger” can be applied to stem cells and stem cell niches as well as to cell–material interfaces. Much is known about cell–material interaction in general, perhaps a little less about how these interactions condition cell phenotype. With the increasing interest in stem cells and, in particular, their applications in tissue regeneration, the regulation of the stem cell microenvironment through modulation of intuitive or smart materials and structures, or what we term IBAS (Inherently Bio-Active Scaffolds) is poised to become a major field of research. Here, we discuss how cardiac regeneration strategies have undergone a gradual shift from the emphasis on biochemical signals and basic biology to one in which the material or scaffold plays a major role in establishing an equilibrium state. From being a constant battle or tug-of-war between the cells and synthetic environments, we conceive IBAS as intuitively responding to the cell’s requirements to instate a sort of equilibrium in the system.


Stem Cell Progenitor Cell Hyaluronic Acid Stem Cell Niche Cardiac Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Adamo, L., Naveiras, O., Wenzel, P.L., et al.: Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009)CrossRefGoogle Scholar
  2. 2.
    Ahmed, T.A., Dare, E.V., Hincke, M.: Fibrin: a versatile scaffold for tissue engineering applications. Tissue Eng. Part B 14, 199–215 (2008)CrossRefGoogle Scholar
  3. 3.
    Andersen, D.C., Andersen, P., Schneider, M., et al.: Murine “cardiospheres” are not a source of stem cells with cardiomyogenic potential. Stem Cells 27, 1571–1581 (2009)CrossRefGoogle Scholar
  4. 4.
    Anversa, P., Kajstura, J., Leri, A., et al.: Life and death of cardiac stem cells: a paradigm shift in cardiac biology. Circulation 113, 1451–1463 (2006)CrossRefGoogle Scholar
  5. 5.
    Baharvand, H., Hashemi, S.M., Ashtiani, S.M., et al.: Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int. J. Dev. Biol. 50, 645–652 (2006)CrossRefGoogle Scholar
  6. 6.
    Beltrami, A.P., Cesselli, D., Bergamin, N., et al.: Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 110, 3438–3446 (2007)CrossRefGoogle Scholar
  7. 7.
    Bergmann, O., Bhardwaj, R.D., Bernard, S., et al.: Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009)CrossRefGoogle Scholar
  8. 8.
    Bhana, B., Iyer, R.K., Chen, W.L.K., et al.: Influence of substrate stiffness on the phenotype of heart cells. Biotechnol. Bioeng. 105(6), 1148–1160 (2010)Google Scholar
  9. 9.
    Boublik, J., Park, H., Radisic, M., et al.: Mechanical properties and remodelling of hybrid cardiac constructs made from heart cells, fibrin, and biodegradable, elastomeric knitted fabric. Tissue Eng. 11, 1122–1132 (2005)CrossRefGoogle Scholar
  10. 10.
    Brännvall, K., Bergman, K., Wallenquist, U., et al.: Enhanced neuronal differentiation in a three-dimensional collagen–hyaluronan matrix. J. Neurosci. Res. 85, 2138–2146 (2007)CrossRefGoogle Scholar
  11. 11.
    Burdick, J.A., Vunjak-Novakovic, G.: Engineered microenvironments for controlled stem cell differentiation. Tissue Eng. Part A 15, 205–219 (2009)CrossRefGoogle Scholar
  12. 12.
    Chen, S.L., Fang, W.W., Ye, F., et al.: Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am. J. Cardiol. 94, 92–95 (2004)CrossRefGoogle Scholar
  13. 13.
    Chiono, V., Pulieri, E., Vozzi, G., et al.: Genipin-crosslinked chitosan/gelatin blends for biomedical applications. J. Mater. Sci. Mater. Med. 19, 889–898 (2008)CrossRefGoogle Scholar
  14. 14.
    Claycomb, W.C., Di Nardo, P. (eds.): Cardiac Growth and Regeneration, vol. 752. New York Academy of Sciences, New York (1995)Google Scholar
  15. 15.
    Coupland, P.G., Briddon, S.J., Aylott, J.W.: Using fluorescent pH-sensitive nanosensors to report their intracellular location after Tat-mediated delivery. Integr. Biol. 1, 318–323 (2009)CrossRefGoogle Scholar
  16. 16.
    Cross, M.A., Enver, T.: The lineage commitment of haemopoietic progenitor cells. Curr. Opin. Genet. Dev. 7, 609–613 (1997)CrossRefGoogle Scholar
  17. 17.
    Dawn, B., Stein, A.B., Urbanek, K., et al.: Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc. Natl. Acad. Sci. USA 102, 3766–3771 (2005)CrossRefGoogle Scholar
  18. 18.
    Di Nardo, P., Forte, G., Ahluwalia, A., et al.: Cardiac progenitor cells: potency and control. J. Cell. Physiol. 224, 590–600 (2010)CrossRefGoogle Scholar
  19. 19.
    Drury, J.L., Dennis, R.G., Mooney, D.J.: The tensile properties of alginate hydrogels. Biomaterials 25, 3187–3199 (2004)CrossRefGoogle Scholar
  20. 20.
    Eghbali, M., Weber, K.T.: Collagen and the myocardium: fibrillar structure, biosynthesis and degradation in relation to hypertrophy and its regression. Mol. Cell Biochem. 96, 1–14 (1990)CrossRefGoogle Scholar
  21. 21.
    Engler, A.J., Carag-Krieger, C., Johnson, C.P., et al.: Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. J. Cell Sci. 121, 3794–3802 (2008)CrossRefGoogle Scholar
  22. 22.
    Engler, A.J., Sen, S., Sweeney, H.L., et al.: Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006)CrossRefGoogle Scholar
  23. 23.
    Fischer-Rasokat, U., Assmus, B., Seeger, F.H., et al.: A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ. Heart Fail. 2, 417–423 (2009)CrossRefGoogle Scholar
  24. 24.
    Forte, G., Carotenuto, F., Pagliari, F., et al.: Criticality of the biological and physical stimuli array inducing resident cardiac stem cell determination. Stem Cells 26, 2093–2103 (2008)CrossRefGoogle Scholar
  25. 25.
    Fuchs, E., Tumbar, T., Guasch, G.: Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)CrossRefGoogle Scholar
  26. 26.
    Gaetani, R., Ledda, M., Barile, L., et al.: Differentiation of human adult cardiac stem cells exposed to extremely low-frequencies electromagnetic fields. Cardiovasc. Res. 82, 411–420 (2009)Google Scholar
  27. 27.
    Gelain, F., Bottai, D., Vescovi, A., et al.: Designer self-assembling peptide nanofiber scaffolds for adult mouse neural stem cell 3-dimensional cultures. PLoS ONE 1, e119 (2006)CrossRefGoogle Scholar
  28. 28.
    Genove, E., Shen, C., Zhang, S., et al.: The effect of functionalised self-assembling peptide scaffolds on human aortic endothelial cell function. Biomaterials 26, 3341–3351 (2005)CrossRefGoogle Scholar
  29. 29.
    Hare, J.M., Traverse, J.H., Henry, T.D., 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, 2277–2286 (2009)CrossRefGoogle Scholar
  30. 30.
    Hwang, N.S., Varghese, S., Elisseeff, J.: Controlled differentiation of stem cells. Adv. Drug Deliv. Rev. 60, 199–214 (2008)CrossRefGoogle Scholar
  31. 31.
    Jacot, J.G., Kita-Matsuo, H., Wei, K.A., et al.: Cardiac myocyte force development during differentiation and maturation. Ann. NY Acad. Sci. 1188, 121–127 (2010)CrossRefGoogle Scholar
  32. 32.
    Jacot, J.G., McCulloch, A.D., Omens, J.H.: Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys. J. 95, 3479–3487 (2008)CrossRefGoogle Scholar
  33. 33.
    Karp, J.M., Yeh, J., Eng, G., et al.: Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. Lab Chip 7, 786–794 (2007)CrossRefGoogle Scholar
  34. 34.
    Keegan, B.R., Feldman, J.L., Begemann, G., et al.: Retinoic acid signalling restricts the cardiac progenitor pool. Science 307, 247–249 (2005)CrossRefGoogle Scholar
  35. 35.
    Khademhosseini, A., Eng, G., Yeh, J., et al.: Microfluidic patterning for fabrication of contractile cardiac organoids. Biomed. Microdevices 9, 149–157 (2007)CrossRefGoogle Scholar
  36. 36.
    Laugwitz, K.L., Moretti, A., Lam, J., et al.: Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005)CrossRefGoogle Scholar
  37. 37.
    Leslie-Barbick, J.E., Moon, J.J., West, J.L.: Covalently-immobilized vascular endothelial growth factor promotes endothelial cell tubulogenesis in poly(ethylene glycol) diacrylate hydrogels. J. Biomater. Sci. 20, 1763–1779 (2009)CrossRefGoogle Scholar
  38. 38.
    Levenberg, S., Huang, N.F., Lavik, E., et al.: Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl. Acad. Sci. 100, 12741–12746 (2003)CrossRefGoogle Scholar
  39. 39.
    Li, L., Xie, T.: Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005)MathSciNetCrossRefGoogle Scholar
  40. 40.
    Linask, K.K., Han, M., Cai, D.H., et al.: Cardiac morphogenesis: matrix metalloproteinase coordination of cellular mechanism underlying heart tube formation and directionality of looping. Dev. Dyn. 233, 739–753 (2005)CrossRefGoogle Scholar
  41. 41.
    Liu, H., Lin, J., Roy, K.H.: Effect of 3D scaffold and dynamic culture condition on the global gene expression profile of mouse embryonic stem cells. Biomaterials 27, 5978–5989 (2006)CrossRefGoogle Scholar
  42. 42.
    Liu, H., Roy, K.: Biomimetic three-dimensional cultures significantly increase hematopoietic differentiation efficacy of embryonic stem cells. Tissue Eng. 11, 319–330 (2005)CrossRefGoogle Scholar
  43. 43.
    Ma, W., Liu, Q.Y., Jung, D., et al.: Central neuronal synapse formation on micropatterned surfaces. Brain Res. Dev. Brain Res. 111, 231–243 (1998)CrossRefGoogle Scholar
  44. 44.
    Mann, B.K., Gobin, A.S., Tsai, A.T., et al.: Smooth muscle cell growth in photopolymerised hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. Biomaterials 22, 3045–3051 (2001)CrossRefGoogle Scholar
  45. 45.
    Martin, C.M., Meeson, A.P., Robertson, S.M., et al.: Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev. Biol. 265, 262–275 (2004)CrossRefGoogle Scholar
  46. 46.
    Masuda, S., Shimizu, T., Yamato, M., et al.: Cell sheet engineering for heart tissue repair. Adv. Drug Del. Rev. 60, 277–285 (2008)CrossRefGoogle Scholar
  47. 47.
    Mattioli-Belmonte, M., Vozzi, G., Seggiani, M., et al.: Tuning polycaprolactone-carbon nanotube composites for bone tissue engineering scaffolds. Mater. Sci. Eng. Biomimetic Mater. (2010, in press)Google Scholar
  48. 48.
    Matsuura, K., Nagai, T., Nishigaki, N, et al.: Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J. Biol. Chem. 279, 11384–11391 (2004)CrossRefGoogle Scholar
  49. 49.
    Menasché, P.: Cell therapy: results in cardiology. Bull. Acad. Natl. Med. 193, 559–568 (2009)Google Scholar
  50. 50.
    Messina, E., De Angelis, L., Frati, G., et al.: Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 95, 911–921 (2004)CrossRefGoogle Scholar
  51. 51.
    Metallo, C.M., Vodyanik, M.A., de Pablo, J.J., et al.: The response of human embryonic stem cell-derived endothelial cells to shear stress. Biotechnol. Bioeng. 100, 830–837 (2008)CrossRefGoogle Scholar
  52. 52.
    Mironov, V., Boland, T., Trusk, T., et al.: Organ printing: computer-aided jet-based 3D tissue engineering. TRENDS Biotechnol. 21, 157–161 (2003)CrossRefGoogle Scholar
  53. 53.
    Murry, C.E., Soonpaa, M.H., Reinecke, H., et al.: Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428, 664–668 (2004)CrossRefGoogle Scholar
  54. 54.
    Napolitano, A.P., Chai, P., Dean, D.M., et al.: Dynamics of the self-assembly of complex cellular aggregates on micromolded nonadhesive hydrogels. Tissue Eng. 13, 2087–2094 (2007)CrossRefGoogle Scholar
  55. 55.
    Nemir, S., West, J.L.: Synthetic materials in the study of cell response to substrate rigidity. Ann. Biomed. Eng. 38, 2–20 (2010)CrossRefGoogle Scholar
  56. 56.
    Oh, H., Bradfute, S.B., Gallardo, T.D., et al.: Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl. Acad. Sci. USA 100, 12313–12318 (2003)CrossRefGoogle Scholar
  57. 57.
    Pagliari, S., Vilela-Silva, A.C., Forte, G.C., Pagliari, F., Mandoli, C., Vozzi, G., Pietronave, S., Prat, M., Licoccia, S., Ahluwalia, A., Traversa, E., Minieri, M., Di Nardo, P., Cooperation of biological and mechanical signals in cardiac progenitor cell differentiation. Adv. Mater. (2010) 12 Nov 2010. doi: 10.1002/adma.201003479.
  58. 58.
    Paguirigan, A.L., Beebe, D.J.: Protocol for the fabrication of enzymatically crosslinked gelatin microchannels for microfluidic cell culture. Nat Protocols 2, 1782–1788 (2007)CrossRefGoogle Scholar
  59. 59.
    Palmer, L.C., Stupp, S.I.: Molecular self-assembly into one-dimensional nanostructures. Acc. Chem. Res. 41, 1674–1684 (2008)CrossRefGoogle Scholar
  60. 60.
    Pego, A.P., Siebum, B., Van Luyn, M.J., et al.: Preparation of degradable porous structures based on 1, 3-trimethylene carbonate and d,l-lactide (co)polymers for heart tissue engineering. Tissue Eng. 9, 981–994 (2003)CrossRefGoogle Scholar
  61. 61.
    Reilly, G.C., Engler, A.J.: Intrinsic extracellular matrix properties regulate stem cell differentiation. J. Biomech. 43, 55–62 (2010)CrossRefGoogle Scholar
  62. 62.
    Rosenblatt-Velin, N., Lepore, M.G., et al.: FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. J. Clin. Invest. 115, 1724–1733 (2005)CrossRefGoogle Scholar
  63. 63.
    Saha, K., Pollock, J.F., Schaffer, D.V., et al.: Designing synthetic materials to control stem cell phenotype. Curr. Opin. Chem. Biol. 11, 381–387 (2007)CrossRefGoogle Scholar
  64. 64.
    Scadden, D.T.: The stem-cell niche as an entity of action. Nature 441, 1075–1079 (2006)CrossRefGoogle Scholar
  65. 65.
    Schneider, H.J., Strongin, R.M.: Supramolecular interactions in chemomechanical polymers. Acc. Chem. Res. 42, 1489–1500 (2010)CrossRefGoogle Scholar
  66. 66.
    Seliktar, D., Zisch, A.H., Lutolf, M.P., et al.: MMP-2 sensitive, VEGF-bearing bioactive hydrogels for promotion of vascular healing. J. Biomed. Mater. Res. A 68, 704–716 (2004)CrossRefGoogle Scholar
  67. 67.
    Serban, M.A., Prestwich, G.D.: Modular extracellular matrices: solutions for the puzzle. Methods 45, 93–98 (2008)CrossRefGoogle Scholar
  68. 68.
    Smith, R.R., Barile, L., Cho, H.C., et al.: Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896–908 (2007)CrossRefGoogle Scholar
  69. 69.
    Stankus, J.J., Guan, J., Fujimoto, K., et al.: Microintegrating smooth muscle cells into a biodegradable, elastomeric fiber matrix. Biomaterials 27, 735–744 (2006)CrossRefGoogle Scholar
  70. 70.
    Tenney, R.M., Discher, D.E.: Stem cells, microenvironment mechanics, and growth factor activation. Curr. Opin. Cell Biol. 21, 630–635 (2009)CrossRefGoogle Scholar
  71. 71.
    Vozzi, G., Previti, A., De Rossi, D., et al.: Microsyringe-based deposition of two-dimensional and three-dimensional polymer scaffolds with a well-defined geometry for application to tissue engineering. Tissue Eng. 8, 1089–1098 (2002)CrossRefGoogle Scholar
  72. 72.
    Wang, H., Riha, G.M., Yan, S., et al.: Shear stress induces endothelial differentiation from a murine embryonic mesenchymal progenitor cell line. Arterioscler. Thromb. Vasc. Biol. 25, 1817–1823 (2005)CrossRefGoogle Scholar
  73. 73.
    Wang, Q., Mynar, J.L., Yoshida, M., et al.: High-water-content mouldable hydrogels by mixing clay and a dendritic molecular binder. Nature 463, 339–343 (2010)CrossRefGoogle Scholar
  74. 74.
    White, S.M., Claycomb, W.C.: Embryonic stem cells form an organised, functional cardiac conduction system in vitro. Am. J. Physiol. Heart Circ. Physiol. 288, H670–H679 (2005)CrossRefGoogle Scholar
  75. 75.
    Whulanza, Y., Uccifferri, N., Vozzi, G., Domenici, C.: Sensing scaffolds to monitor cellular activities using impedance measurements. Biosensors Bioelectronics (in press)Google Scholar
  76. 76.
    Williams, C.G., Malik, A.N., Kim, T.K., et al.: Variable cytocompatibility of six cell lines with photoinitiators used for polymerising hydrogels and cells encapsulation. Biomaterials 26, 1211–1218 (2005)CrossRefGoogle Scholar
  77. 77.
    Wollert, K.C., Meyer, G.P., Lotz, J., et al.: Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364, 141–148 (2004)CrossRefGoogle Scholar
  78. 78.
    Wu, C.C., Chao, Y.C., Chen, C.N., et al.: Synergism of biochemical and mechanical stimuli in the differentiation of human placenta-derived multipotent cells into endothelial cells. J. Biomech. 41, 813–821 (2008)CrossRefGoogle Scholar
  79. 79.
    Yao, H., Dao, M., Imholt, T., et al.: Protection mechanisms of the iron-plated armor of a deep-sea hydrothermal vent gastropod. Proc. Natl. Acad. Sci. USA 107, 987–992 (2010)CrossRefGoogle Scholar
  80. 80.
    Zampetaki, A., Kirton, J.P., Xu, Q.: Vascular repair by endothelial progenitor cells. Cardiovasc. Res. 78, 413–421 (2008)CrossRefGoogle Scholar
  81. 81.
    Zhang, G., Palmer, G.M., Dewhirst, M.W., et al.: A dual-emissive-materials design concept enables tumour hypoxia imaging. Nat. Mater. 8, 747–751 (2009)CrossRefGoogle Scholar
  82. 82.
    Zipori, D.: The stem state: plasticity is essential, whereas self-renewal and hierarchy are optional. Stem Cells 23, 719–726 (2005)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Paolo Di Nardo
    • 1
    • 2
    • 3
    Email author
  • Marilena Minieri
    • 1
    • 2
    • 3
  • Annalisa Tirella
    • 1
    • 4
  • Giancarlo Forte
    • 1
    • 2
    • 3
  • Arti Ahluwalia
    • 4
  1. 1.Laboratorio di Cardiologia Molecolare e Cellulare, Dipartimento di Medicina InternaUniversità di Roma Tor VergataRomeItaly
  2. 2.Istituto Nazionale per le Ricerche Cardiovascolari (INRC)BolognaItaly
  3. 3.Japanese-Italian Tissue Engineering Laboratory (JITEL)Tokyo Women’s Medical University-Waseda University Joint Institution for Advanced Biomedical Sciences (TWIns)TokyoJapan
  4. 4.Centro Interdipartimentale di Ricerca “E. Piaggio”Università di PisaPisaItaly

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