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Microengineering Approach for Directing Embryonic Stem Cell Differentiation

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Biomaterials as Stem Cell Niche

Abstract

The microenvironment plays an integral role in directing the differentiation of stem cells. The ability to control and manipulate systems on the microscale can be used to control the cellular microenvironment to direct stem cell behavior. For stem cells, this control greatly improves our ability to study cell–microenvironment interactions in a rapid and precise manner to regulate stem cell behaviors such as differentiation and proliferation. Combining microscale technologies with high throughput techniques could also greatly increase the possibility for probing the multivariable complexity of biological systems. In this chapter, microengineering approaches to control the cellular microenvironment and to influence embryonic stem cell (ESC) self-renewal and differentiation are introduced and specific examples of the use of microfabrication technologies for directing ESC fate decisions are discussed.

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References

  1. Martin, G.R.: Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78(12), 7634–7638 (1981)

    Article  Google Scholar 

  2. Thomson, J.A. et al.: Embryonic stem cell lines derived from human blastocysts. Science 282(5391), 1145–1147 (1998)

    Article  Google Scholar 

  3. Rolletschek, A., Wobus, A.M.: Induced human pluripotent stem cells: promises and open questions. Biol. Chem. 390(9), 845–849 (2009)

    Article  Google Scholar 

  4. Takahashi, K., Yamanaka, S.: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663–676 (2006)

    Article  Google Scholar 

  5. Amabile, G., Meissner, A.: Induced pluripotent stem cells: current progress and potential for regenerative medicine. Trends Mol. Med. 15(2), 59–68 (2009)

    Article  Google Scholar 

  6. Hochedlinger, K., Plath, K.: Epigenetic reprogramming and induced pluripotency. Development 136(4), 509–523 (2009)

    Article  Google Scholar 

  7. Ebert, A.D., et al.: Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457(7227), 277–280 (2009)

    Article  Google Scholar 

  8. Tateishi, K., et al.: Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J. Biol. Chem. 283(46), 31601–31607 (2008)

    Article  Google Scholar 

  9. Park, I.H., et al.: Disease-specific induced pluripotent stem cells. Cell 134(5), 877–886 (2008)

    Article  Google Scholar 

  10. Wobus, A.M., Boheler, K.R.: Embryonic stem cells: prospects for developmental biology and cell therapy. Physiol. Rev. 85(2), 635–678 (2005)

    Article  Google Scholar 

  11. Burdick, J.A., Vunjak-Novakovic, G.: Engineered microenvironments for controlled stem cell differentiation. Tissue Eng. Part A 15(2), 205–219 (2009)

    Article  Google Scholar 

  12. Khademhosseini, A., et al.: Microscale technologies for tissue engineering and biology. Proc. Natl. Acad. Sci. USA 103(8), 2480–2487 (2006)

    Article  Google Scholar 

  13. Bonassar, L.J., Vacanti, C.A.: Tissue engineering: The first decade and beyond. J. Cell. Biochem. 297 (1998)

    Google Scholar 

  14. Atala, A.: Tissue engineering of artificial organs. J. Endourol. 14(1), 49–57 (2000)

    Article  Google Scholar 

  15. Ren, D.F., et al.: Evaluation of RGD modification on collagen matrix. Artif. Cells Blood Subst. Biotechnol. 34(3), 293–303 (2006)

    Article  Google Scholar 

  16. Shin, H.: Fabrication methods of an engineered microenvironment for analysis of cell-biomaterial interactions. Biomaterials 28(2), 126–133 (2007)

    Article  Google Scholar 

  17. Langer, R., Vacanti, J.P.: Tissue engineering. Science 260(5110), 920–926 (1993)

    Article  Google Scholar 

  18. Murtuza, B., Nichol, J.W., Khademhosseini, A.: Micro- and nanoscale control of the cardiac stem cell niche for tissue fabrication. Tissue Eng. Part B Rev. 15(4), 443–454 (2009)

    Article  Google Scholar 

  19. Alsberg, E., von Recum, H.A., Mahoney, M.J.: Environmental cues to guide stem cell fate decision for tissue engineering applications. Exp. Opin. Biol. Ther. 6(9), 847–866 (2006)

    Article  Google Scholar 

  20. Lensch, M.W., Daheron, L., Schlaeger, T.M.: Pluripotent stem cells and their niches. Stem Cell Rev. 2(3), 185–201 (2006)

    Article  Google Scholar 

  21. Metallo, et al. C.M.: Engineering the stem cell microenvironment. Biotechnol. Prog. 23(1), 18–23 (2007)

    Article  Google Scholar 

  22. Tsai, R.Y., McKay, R.D.: Cell contact regulates fate choice by cortical stem cells. J. Neurosci. 20(10), 3725–3735 (2000)

    Google Scholar 

  23. Gavard, J., et al.: N-cadherin activation substitutes for the cell contact control in cell cycle arrest and myogenic differentiation: involvement of p120 and beta-catenin. J. Biol. Chem. 279(35), 36795–36802 (2004)

    Article  Google Scholar 

  24. Nose, A., Tsuji, K., Takeichi, M.: Localization of specificity determining sites in cadherin cell adhesion molecules. Cell 61(1), 147–155 (1990)

    Article  Google Scholar 

  25. Niessen, C.M., Gumbiner, B.M.: Cadherin-mediated cell sorting not determined by binding or adhesion specificity. J. Cell Biol. 156(2), 389–399 (2002)

    Article  Google Scholar 

  26. Volk, T., et al.: Formation of heterotypic adherens-type junctions between L-cam-containing liver-cells and A-cam-containing lens cells. Cell 50(6), 987–994 (1987)

    Article  Google Scholar 

  27. Halbleib, J.M., Nelson, W.J.: Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20(23), 3199–3214 (2006)

    Article  Google Scholar 

  28. Takeichi, M.: The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development 102, 639–655 (1988)

    Google Scholar 

  29. Aberle, H., et al.: Cadherin-catenin complex: protein interactions and their implications for cadherin function. J. Cell Biochem. 61(4), 514–523 (1996)

    Article  Google Scholar 

  30. Qureshi, H.S., et al.: E-cadherin status in breast cancer correlates with histologic type but does not correlate with established prognostic parameters. Am. J. Clin. Pathol. 125(3), 377–385 (2006)

    Article  Google Scholar 

  31. Tlsty, T.D.: Cell-adhesion-dependent influences on genomic instability and carcinogenesis. Curr. Opin. Cell Biol. 10(5), 647–653 (1998)

    Article  Google Scholar 

  32. Cowin, P., et al.: Cadherins and catenins in breast cancer. Curr. Opin. Cell Biol. 17(5), 499–508 (2005)

    Article  MathSciNet  Google Scholar 

  33. Chen, W.C., Obrink, B.: Cell-cell contacts mediated by E-cadherin (uvomorulin) restrict invasive behavior of L-cells. J. Cell Biol. 114(2), 319–327 (1991)

    Article  Google Scholar 

  34. Frixen, U.H., et al.: E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol. 113(1), 173–185 (1991)

    Article  Google Scholar 

  35. Silvestre, J., et al.: Cadherin and integrin regulation of epithelial cell migration. Langmuir 25(17), 10092–10099 (2009)

    Article  Google Scholar 

  36. Potthoff, S., et al.: N-cadherin engagement provides a dominant stop signal for the migration of MDA-MB-468 breast carcinoma cells. Breast Cancer Res. Treat. 105(3), 287–295 (2007)

    Article  Google Scholar 

  37. Bloor, D.J., et al.: Expression of cell adhesion molecules during human preimplantation embryo development. Mol. Hum. Reprod. 8, 237–245 (2002)

    Article  Google Scholar 

  38. Dang, S.M., et al.: Controlled, scalable embryonic stem cell differentiation culture. Stem Cells 22, 275–282 (2004)

    Article  Google Scholar 

  39. Huber, B.T.L., et al.: Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm. Blood 92(11), 4128–4137 (1998)

    Google Scholar 

  40. Johansson, B.M., Wiles, M.V.: Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development. Mol. Cell Biol. 15(1), 141–151 (1995)

    Google Scholar 

  41. Valdimarsdotter, G., Mummery, C.: Functions of the TGF-b superfamily in human embryonic stem cells. APMIS 113, 773–789 (2005)

    Article  Google Scholar 

  42. Morali, O.G. et al.: IGF-II promotes mesoderm formation. Dev. Biol. 227, 133–145 (2000)

    Article  Google Scholar 

  43. M. Schuldiner, et al., Effect of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. 97(21), 11307–11312 (2000)

    Article  Google Scholar 

  44. Dutta, R.C., Dutta, A.K.: Cell-interactive 3D-scaffold; advances and applications. Biotechnol. Adv. 27(4), 334–339 (2009)

    Article  Google Scholar 

  45. Weisenberg, E.: Pocket companion to robbins pathologic basis of disease. Arch. Pathol. Lab. Med. 124(10), 1566 (2000)

    Google Scholar 

  46. Engler, A.J., et al.: Matrix elasticity directs stem cell lineage specification. Cell 126(4), 677–689 (2006)

    Article  Google Scholar 

  47. Handschel, J., et al.: Compatibility of embryonic stem cells with biomaterials. J. Biomater. Appl. 0885328208094305 (2008)

    Google Scholar 

  48. Levenberg, S., et al.: Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl. Acad. Sci. USA 100(22), 12741–12746 (2003)

    Article  Google Scholar 

  49. Battista, S., et al.: The effect of matrix composition of 3D constructs on embryonic stem cell differentiation. Biomaterials 26(31), 6194–6207 (2005)

    Article  Google Scholar 

  50. Fukuda, J., et al.: Micromolding of photocrosslinkable chitosan hydrogel for spheroid microarray and co-cultures. Biomaterials (2006)

    Google Scholar 

  51. Tien, J., Chen, C.S.: Patterning the cellular microenvironment. IEEE Eng. Med. Biol. Mag. 21(1), 95–98 (2002)

    Article  Google Scholar 

  52. Tien, J., et al.: Fabrication of aligned microstructures with a single elastomeric stamp. Proc. Natl. Acad. Sci. USA 99(4), 1758–1762 (2002)

    Article  Google Scholar 

  53. Nelson, C.M., Chen, C.S.: VE-cadherin simultaneously stimulates and inhibits cell proliferation by altering cytoskeletal structure and tension. J. Cell Sci. Sep 1(116), 3571–3581 (2003)

    Google Scholar 

  54. Khademhosseini, A., et al.: Molded polyethylene glycol microstructures for capturing cells within microfluidic channels. Lab Chip 4(5), 425–430 (2004)

    Article  Google Scholar 

  55. Karp, J.M., et al.: Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. Lab Chip 7, 786–794 (2007)

    Article  Google Scholar 

  56. Khademhosseini, A., et al.: Micromolding of photocrosslinkable hyaluronic acid for cell encapsulation and entrapment. J. Biomed. Mater. Res. A 79(3), 522–532 (2006)

    Article  Google Scholar 

  57. Napolitano, A.P., et al.: Dynamics of the self-assembly of complex cellular aggregates on micromolded nonadhesive hydrogels. Tissue Eng. Part A 13(8), 2087–2094 (2007)

    Article  Google Scholar 

  58. Nichol, J.W., Khademhosseini, A.: Modular tissue engineering: engineering biological tissues from the bottom up. Soft Matter 5, 1312–1319 (2009)

    Article  Google Scholar 

  59. Peppas, N.A., et al.: Hydrogels in biology and medicine: from molecular principles to bionanotechnology. Adv. Mater. 18(11), 1345–1360 (2006)

    Article  Google Scholar 

  60. Whitesides, G.M.: The origins and the future of microfluidics. Nature 442(7101), 368–373 (2006)

    Article  Google Scholar 

  61. Purcell, E.M.: Life at low reynolds-number. Am. J. Phys. 45(1), 3–11 (1977)

    Article  MathSciNet  Google Scholar 

  62. McDonald, J.C., et al.: Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis 21(1), 27–40 (2000)

    Article  Google Scholar 

  63. Park, T.H., Shuler, M.L.: Integration of cell culture and microfabrication technology. Biotechnol. Prog. 19(2), 243–253 (2003)

    Article  Google Scholar 

  64. Rhee, S.W., et al.: Patterned cell culture inside microfluidic devices. Lab Chip 5(1), 102–107 (2005)

    Article  Google Scholar 

  65. Tan, W., Desai, T.A.: Microfluidic patterning of cells in extracellular matrix biopolymers: effects of channel size, cell type, and matrix composition on pattern integrity. Tissue Eng. 9(2), 255–267 (2003)

    Article  Google Scholar 

  66. Chiu, D.T., et al.: Patterned deposition of cells and proteins onto surfaces by using three-dimensional microfluidic systems. Proc. Natl. Acad. Sci. USA 97(6), 2408–2413 (2000)

    Article  Google Scholar 

  67. Takayama, S., et al.: Subcellular positioning of small molecules. Nature 411(6841), 1016 (2001)

    Article  Google Scholar 

  68. Kim, L., et al.: Microfluidic arrays for logarithmically perfused embryonic stem cell culture. Lab Chip 6(3), 394–406 (2006)

    Article  Google Scholar 

  69. Meinel, L., et al.: Bone tissue engineering using human mesenchymal stem cells: effects of scaffold material and medium flow. Ann. Biomed. Eng. 32(1), 112–122 (2004)

    Article  Google Scholar 

  70. Vollmer, A.P., et al.: Development of an integrated microfluidic platform for dynamic oxygen sensing and delivery in a flowing medium. Lab Chip 5(10), 1059–1066 (2005)

    Article  Google Scholar 

  71. Park, S.H., et al.: An electromagnetic compressive force by cell exciter stimulates chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Tissue Eng. 12(11), 3107–3117 (2006)

    Article  Google Scholar 

  72. Metallo, C.M., et al.: The response of human embryonic stem cell-derived endothelial cells to shear stress. Biotechnol. Bioeng. 100(4), 830–837 (2008)

    Article  Google Scholar 

  73. Tourovskaia, A., et al.: Differentiation-on-a-chip: a microfluidic platform for long-term cell culture studies. Lab Chip 5(1), 14–19 (2005)

    Article  Google Scholar 

  74. Zhong, J.F., et al.: A microfluidic processor for gene expression profiling of single human embryonic stem cells. Lab Chip 8(1), 68–74 (2008)

    Article  Google Scholar 

  75. Davey, R.E., Zandstra, P.W.: Spatial organization of embryonic stem cell responsiveness to autocrine Gp130 ligands reveals an autoregulatory stem cell niche. Stem Cells 24(11), 2538–2548 (2006)

    Article  Google Scholar 

  76. Kirmizidis, G., Birch, M.A.: Microfabricated grooved substrates influence cell-cell communication and osteoblast differentiation in vitro. Tissue Eng. Part A. 15(6), 1427–1436 (2009)

    Article  Google Scholar 

  77. Abbott, A.: Cell culture: biology’s new dimension. Nature 424(6951), 870–872 (2003)

    Article  Google Scholar 

  78. Zhang, S.: Beyond the petri dish. Nat. Biotech. 22(2), 151–152 (2004)

    Article  Google Scholar 

  79. Freed, L.E., et al.: Tissue engineering of cartilage in space. Proc. Natl. Acad. Sci. USA 94(25), 13885–13890 (1997)

    Article  Google Scholar 

  80. Radisic, M., et al.: Medium perfusion enables engineering of compact and contractile cardiac tissue. Am. J. Physiol. Heart Circ. Physiol. 286(2), H507–516 (2004)

    Article  Google Scholar 

  81. Radisic, M., et al.: Oxygen gradients correlate with cell density and cell viability in engineered cardiac tissue. Biotechnol. Bioeng. 93(2), 332–343 (2006)

    Article  Google Scholar 

  82. Chung, B.G., et al.: Micro- and nanoscale approaches for tissue engineering and drug discovery. Exp. Opin. Drug Dis. 2(12), 1653–1668 (2007)

    Article  Google Scholar 

  83. Moeller, H.-C., et al.: A microwell array system for stem cell culture. Biomaterials 29(6), 752–763 (2008)

    Article  Google Scholar 

  84. Bauwens, C.L., et al.: Control of human embryonic stem cell colony and aggregate size heterogeneity influences differentiation trajectories. Stem Cells 26(9), 2300–2310 (2008)

    Article  Google Scholar 

  85. Khademhosseini, A., et al.: Layer-by-layer deposition of hyaluronic acid and poly-L-lysine for patterned cell co-cultures. Biomaterials 25(17), 3583–3592 (2004)

    Article  Google Scholar 

  86. Mohr, J.C., et al.: 3-D microwell culture of human embryonic stem cells. Biomaterials 27(36), 6032–6042 (2006)

    Article  Google Scholar 

  87. Kang, L., et al.: Cell confinement in patterned nanoliter droplets in a microwell array by wiping. J. Biomed. Mater. Res. A (2009)

    Google Scholar 

  88. Ungrin, M.D., et al.: Reproducible, ultra high-throughput formation of multicellular organization from single cell suspension-derived human embryonic stem cell aggregates. PLoS ONE 3(2), e1565 (2008)

    Article  Google Scholar 

  89. Rosenthal, A., Macdonald, A., Voldman, J.: Cell patterning chip for controlling the stem cell microenvironment. Biomaterials 28(21), 3208–3216 (2007)

    Article  Google Scholar 

  90. Wright, D., et al.: Generation of static and dynamic patterned co-cultures using microfabricated parylene-C stencils. Lab Chip 7(10), 1272–1279 (2007)

    Article  Google Scholar 

  91. Wu, X., et al.: Small molecules that induce cardiomyogenesis in embryonic stem cells. J. Am. Chem. Soc. 126(6), 1590–1591 (2004)

    Article  Google Scholar 

  92. Xu, Y., Shi, Y., Ding, S.: A chemical approach to stem-cell biology and regenerative medicine. Nature 453(7193), 338–344 (2008)

    Article  Google Scholar 

  93. Ding, S., Schultz, P.G.: A role for chemistry in stem cell biology. Nat. Biotechnol. 22(7), 833–840 (2004)

    Article  Google Scholar 

  94. Urquhart, A.J., et al.: TOF-SIMS analysis of a 576 micropatterned copolymer array to reveal surface moieties that control wettability. Anal. Chem. 80(1), 135–142 (2008)

    Article  MathSciNet  Google Scholar 

  95. Levenberg, S., et al.: Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds. Proc. Natl. Acad. Sci. U.S.A 100(22), 12741–12746 (2003)

    Article  Google Scholar 

  96. Chaudhry, G.R., et al.: Osteogenic cells derived from embryonic stem cells produced bone nodules in three-dimensional scaffolds. J. Biomed. Biotechnol. 4, 203–210 (2004)

    Google Scholar 

  97. Levenberg, S., et al.: Neurotrophin-induced differentiation of human embryonic stem cells on three-dimensional polymeric scaffolds. Tissue Eng. 11(3–4), 506–512 (2005)

    Article  Google Scholar 

  98. Tsang, V.L., Bhatia, S.N.: Fabrication of three-dimensional tissues. Adv. Biochem. Eng. Biotechnol. 103, 189–205 (2007)

    Google Scholar 

  99. Tsang, V.L., Bhatia, S.N.: Three-dimensional tissue fabrication. Adv. Drug. Deliv. Rev. 56(11), 1635–1647 (2004)

    Article  Google Scholar 

  100. Tsang, V.L., et al.: Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J. 21(3), 790–801 (2007)

    Article  Google Scholar 

  101. McGuigan, A.P., Sefton, M.V.: Vascularized organoid engineered by modular assembly enables blood perfusion. Proc. Natl. Acad. Sci. USA 103(31), 11461–11466 (2006)

    Article  Google Scholar 

  102. Du, Y., et al.: Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs. Proc. Natl. Acad. Sci. USA 105(28), 9522–9527 (2008)

    Article  Google Scholar 

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Bae, H., Nichol, J.W., Foudeh, A., Zamanian, B., Kwon, C.H., Khademhosseini, A. (2010). Microengineering Approach for Directing Embryonic Stem Cell Differentiation. In: Roy, K. (eds) Biomaterials as Stem Cell Niche. Studies in Mechanobiology, Tissue Engineering and Biomaterials, vol 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8415_2010_7

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