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From Molecular Cell Engineering to Biologically Inspired Engineering

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Abstract

The field of Molecular Cell Engineering melds techniques from molecular cell biology, engineering and the physical sciences to quantitatively define mechanisms that govern the shape and function of living cells. This discipline offers a new and powerful approach to confront fundamental questions in the life sciences, such as how cells self organize through collective interactions among thousands of individual molecular components, and function physically as part of larger tissues and organs in our bodies. This approach has led to deeper understanding of the fundamental design principles that govern the mechanical behavior of living cells, and greater insight into mechanotransduction—how cells sense physical forces and convert them into changes in biochemistry. This article briefly describes the history and current status of this field in context of the larger discipline of Cellular and Molecular Bioengineering, and discusses how new advances in this area can be leveraged to develop new ‘biologically inspired’ engineering approaches for cell and developmental control, as well as non-medical applications, in the future.

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References

  1. Alenghat, F., and D. E. Ingber. Mechanotransduction: all signals point to cytoskeleton, matrix, and integrins. Science’s STKE 119:PE6, 2002

    Google Scholar 

  2. Alenghat F.J., S.M. Nauli, R. Kolb, J. Zhou, and D.E. Ingber. Global cytoskeletal control of mechanotransduction in kidney epithelial cells. Exp. Cell Res. 301: 23–20 2004

    Article  Google Scholar 

  3. Bereiter-Hahn J., M. Luck, T. Miebach, H.K. Stelzer, and M. Voth. Spreading of trypsinized cells: cytoskeletal dynamics and energy requirements. J. Cell Sci. 96: 171–188 1990

    Google Scholar 

  4. Brangwynne C.P., F.C. Macintosh, S. Kumar, N.A. Geisse, L. Mahadevan, K.K. Parker, D.E. Ingber, and D. Weitz. Microtubules can bear enhanced compressive loads in living cells due to lateral reinforcement. J. Cell Biol. 173: 1175–1183 2006

    Article  Google Scholar 

  5. Cai S., L. Pestic-Dragovich, M.E. O’Donnell, N. Wang, D.E. Ingber, E. Elson, and and P. de Lanerolle. Regulation of cytoskeletal mechanics and cell growth by myosin light chain phosphorylation. Am. J. Physiol. 275: C1349–C1356 1998

    Google Scholar 

  6. Cañadas P., V.M. Laurent, P. Chabrand, D. Isabey S. Wendling-Mansuy. Mechanisms governing the visco-elastic responses of living cells assessed by foam and tensegrity models. Med Biol Eng Comput. 41: 733–739 2003

    Article  Google Scholar 

  7. Cañadas P, Wendling-Mansuy S, Isabey D. Frequency response of a viscoelastic tensegrity model: Structural rearrangement contribution to cell dynamics. J Biomech Eng. 128: 487–495 2006

    Article  Google Scholar 

  8. Chang H., P. Oh, D.E. Ingber, and S. Huang. Multi-stable and multi-step dynamics in mammalian cell differentiation. B.M.C. Cell Biol. 7: 11 2006

    Article  Google Scholar 

  9. Chen C.S., M. Mrksich, S. Huang, G. Whitesides, and D.E. Ingber. Geometric control of cell life and death. Science 276: 1425–1428 1997

    Article  Google Scholar 

  10. Chen R.R., E.A. Silva, W.W. Yuen, and D.J. Mooney.. Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation. Pharm Res. 24: 258–264 2007

    Article  Google Scholar 

  11. Chicurel M.E., R.H. Singer, C. Meyer, and D.E. Ingber. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 392: 730–733 1998

    Article  Google Scholar 

  12. Choquet D., D.P. Felsenfeld, M.P. Sheetz. Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88: 39–48 1997

    Article  Google Scholar 

  13. Coughlin M.F., and D. Stamenovic. A tensegrity model of the cytoskeleton in spread and round cells. ASME J Biomech Eng. 120: 770–7 1998

    Article  Google Scholar 

  14. Davies P.F., A. Robotewskyj, M.L. Griem. Quantitative studies of endothelial cell adhesion. Directional remodeling of focal adhesion sites in response to flow forces. J. Clin. Invest. 93: 2031–2038 1994

    Article  Google Scholar 

  15. Dike L., C.S. Chen, M. Mrkisch, J. Tien, G.M. Whitesides, D.E. Ingber. Geometric control of switching between growth, apoptosis, and differentiation during angiogenesis using micro-patterned substrates. In Vitro Cell Dev. Biol. 35: 441–448 1999

    Article  Google Scholar 

  16. Dong C., R. Skalak, and K.L. Sung. Cytoplasmic rheology of passive neutrophils. Biorheology 28: 557–567 1991).

    Google Scholar 

  17. Evans E. and A. Yeung. Apparent viscosity and cortical tension of blood granulocytes determined by micropipet aspiration. Biophys. J. 56: 151–160 1989

    Google Scholar 

  18. Fabry B., G.N. Maksym, J.P. Butler, M. Glogauer, D. Navajas, and J.J. Fredberg. Scaling the microrheology of living cells. Phys. Rev. Let. 87: 148102–4 2001

    Article  Google Scholar 

  19. Folkman J and A. Moscona. Role of cell shape in growth control. Nature 273: 345–349 1978

    Article  Google Scholar 

  20. Forgacs G.. On the possible role of cytoskeletal filamentous networks in intracellular signaling: an approach based on percolation. J. Cell Sci. 108: 2131–2143 1995

    Google Scholar 

  21. Forster A.C., and G.M. Church. Synthetic biology projects in vitro. Genome Res. 17: 1–6 2007

    Article  Google Scholar 

  22. Gardel M.L., F. Nakamura, J.H. Hartwig, J.C. Crocker , T.P. Stossel, D.A. Weitz. Prestressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc. Natl. Acad. Sci. U.S. A. 103: 1762–176 2006

    Article  Google Scholar 

  23. Geiger B., A. Bershadsky, R. Pankov, K.M. Yamada. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nat. Rev. Mol. Cell. Biol. 2: 793–805 2001

    Article  Google Scholar 

  24. Hasty J., D. McMillen, J.J. Collins. Engineered gene circuits. Nature. 420: 224–230 2002

    Article  Google Scholar 

  25. Hu S., J. Chen, B. Fabry, Y. Numaguchi, A. Gouldstone, D.E. Ingber, J.J. Fredberg, J.P. Butler, N. Wang. Intracellular stress tomography reveals stress focusing and structural anisotropy in cytoskeleton of living cells. Am. J. Physiol.: Cell Physiol. 285: C1082–1090 2003

    Google Scholar 

  26. Hu S, J. Chen, N. Wang. Cell spreading controls balance of pre-stress by microtubules and extracellular matrix. Front Biosci. 9: 2177–2182 2004

    Article  Google Scholar 

  27. Huang S., G. Eichler, Y. Bar-Yam, and D.E. Ingber. Cell fates as attractors in gene expression state space. Phys. Rev. Lett. 94: 128701–12802 2005

    Article  Google Scholar 

  28. Huang S., and D.E. Ingber. The structural and mechanical complexity of cell growth control. Nature Cell Biol. 1: E131–E138 1999

    Article  Google Scholar 

  29. Huang S and Ingber DE.. Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. Exp. Cell Res. 261: 91–103 2000

    Article  Google Scholar 

  30. Ingber D.E.. Integrins as mechanochemical transducers. Curr. Opin. Cell Biol. 3: 841–848 1991

    Article  Google Scholar 

  31. Ingber D.E. Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J. Cell Sci. 104: 613–627 1993

    Google Scholar 

  32. Ingber D.E. The riddle of morphogenesis: a question of solution chemistry or molecular cell engineering? Cell 75: 1249–1252 1993

    Article  Google Scholar 

  33. Ingber D.E. Cellular tensegrity revisited I. Cell structure and hierarchical systems biology. J. Cell Sci. 116: 1157–1173 2003

    Article  Google Scholar 

  34. Ingber D.E. Tensegrity II. How structural networks influence cellular information processing networks. J. Cell Sci. 116: 1397–1408 2003

    Article  Google Scholar 

  35. Ingber D.E. Mechanobiology and diseases of mechanotransduction. Ann. Med.; 35: 564–77 2003

    Article  Google Scholar 

  36. Ingber D.E. Mechanical control of tissue morphogenesis during embryological development. Intl. J. Dev. Biol. 50: 255–66 2006

    Article  Google Scholar 

  37. Ingber D.E. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 20: 811–827 2006

    Article  Google Scholar 

  38. Ingber D.E., and J. Folkman. Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. J. Cell Biol. 109: 317–330 1989

    Article  Google Scholar 

  39. Ingber, D.E., J.D. Jamieson. Cells as tensegrity structures: architectural regulation of histodifferentiation by physical forces tranduced over basement membrane. In: Gene Expression During Normal and Malignant Differentiation, edited by L.C. Andersson, C.G. Gahmberg, and P. Ekblom. Orlando: Academic Press; 1985; 13–32

    Google Scholar 

  40. Ingber D.E., J.A. Madri, J.D. Jamieson. Role of basal lamina in the neoplastic disorganization of tissue architecture. Proc. Natl. Acad. Sci. U.S.A. 78: 3901–3905 1981

    Article  Google Scholar 

  41. Janmey P.A. The cytoskeleton and cell signaling: component localization and mechanical coupling. Physiol. Rev. 78: 763–781 1998

    Google Scholar 

  42. Kumar S., I.Z. Maxwell, A. Heisterkamp, T.R. Polte, T.P. Lele, M. Salanga, E. Mazur, and D.E. Ingber. Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization and extracellular matrix mechanics. Biophys. J. 90: 1–12 2006

    Article  Google Scholar 

  43. Lin D.C., B. Yurke, and N.A. Langrana. Mechanical properties of a reversible, DNA-crosslinked polyacrylamide hydrogel. J. Biomech. Eng. 126: 104–110 2004

    Article  Google Scholar 

  44. Liu D., M. Wang, Z. Deng, R. Walulu, and C. Mao. Tensegrity: construction of rigid DNA triangles with flexible four-arm DNA junctions. J. Am. Chem. Soc. 126: 2324–2325 2004

    Article  Google Scholar 

  45. Mammoto T., S.M. Parikh, A. Mammoto, D. Gallagher, B. Chan, G. Mostoslavsky, D.E. Ingber, and V.P. Sukhatme Angiopoietin–1 requires P190RhoGap to protect against vascular leakage in vivo. J. Biol. Chem. 282: 23910–23918 2007

    Article  Google Scholar 

  46. Maniotis A., C.S. Chen, and D.E. Ingber. Demonstration of mechanical connections between integrins, cytoskeletal filaments and nucleoplasm that stabilize nuclear structure. Proc. Natl. Acad. Sci. U.S.A. 94: 849–854 1997

    Article  Google Scholar 

  47. Mannix R.J., S. Kumar, F. Cassiola, M. Montoya-Zavala, D.E. Ingber. Magnetic actuation of receptor-mediated signal transduction. Nat. Nanotech. 3: 36–40 2008

    Article  Google Scholar 

  48. Matthews B.D., D.R. Overby, R. Mannix, D.E. Ingber. Cellular adaptation to mechanical stress: role of integrins, Rho, cytoskeletal tension and mechanosensitive ion channels. J. Cell Sci. 119: 508–18 2006

    Article  Google Scholar 

  49. Meyer C.J., F.J. Alenghat, P. Rim, JH-J. Fong, B. Fabry, and D.E. Ingber. Mechanical control of cyclic AMP signalling and gene transcription through integrins. Nature Cell Biol. 2: 666–668 2000

    Article  Google Scholar 

  50. Miyamoto S., M. Teramoto, O.A. Coso, J.S. Gutkind, P.D. Burbelo, S.K. Akiyama, and K.M. Yamada. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J. Cell Biol. 131: 791–805 1995

    Article  Google Scholar 

  51. Mooney D., R. Langer and D.E. Ingber. Cytoskeletal filament assembly and the control of cell shape and function by extracellular matrix. J. Cell Sci. 108: 2311–2320 1995

    Google Scholar 

  52. Nauli S.M., F.J. Alenghat, Y. Luo, E. Williams, P. Vassilev, X. Li, A.E. Elia, W. Lu, E.M. Brown, S.J. Quinn, D.E. Ingber, J. Zhou. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33: 129–37 2003

    Article  Google Scholar 

  53. Parker K.K., A.L. Brock, C. Brangwynne, R.J. Mannix, N. Wang, E. Ostuni, N. Geisse, J.C. Adams, G.M. Whitesides, and D.E. Ingber. Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces. FASEB J. 16: 1195–1204 2002

    Article  Google Scholar 

  54. Pienta K.J., D.S. Coffey. Cellular harmonic information transfer through a tissue tensegrity-matrix system. Med. Hypotheses. 34: 88–95 1991

    Article  Google Scholar 

  55. Pienta K.J., R.H. Getzenberg, D.S. Coffey. Cell Structure and DNA Organization. Crit. Rev. Eukary. Gene Express. 1: 355–385 1991

    Google Scholar 

  56. Plopper G., H. McNamee, L. Dike, K. Bojanowski, D.E. Ingber. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol. Biol.Cell 6: 1349–1365 1995

    Google Scholar 

  57. Satcher, R.L., Jr., C.F. Dewey. Jr. Theoretical estimates of mechanical properties of the endothelial cell cytoskeleton. Biophys J. 71, 109–18 1996

    Google Scholar 

  58. Shih W.M., J.D. Quispe, G.F. Joyce. A 1.7–kilobase single-stranded DNA that folds into a nanoscale octahedron. Nature 427: 618–621 2004

    Article  Google Scholar 

  59. Singhvi R., A. Kumar, G. Lopez, G.N. Stephanopoulos, D.I.C. Wang, G.M. Whitesides, D.E. Ingber. Engineering cell shape and function. Science 264: 696–698 1994

    Article  Google Scholar 

  60. Stamenovic D., M.F. Coughlin. The role of prestress and architecture of the cytoskeleton and deformability of cytoskeletal filaments in mechanics of adherent cells: a quantitative analysis. J. Theor. Biol. 201: 63–74 1999

    Article  Google Scholar 

  61. Stamenovic D., M.F. Coughlin. A quantitative model of cellular elasticity based on tensegrity. A.S.M.E. J. Biomech. Eng. 122: 39–43 2000

    Article  Google Scholar 

  62. Stamenovic D., J.J. Fredberg, N. Wang, J. Butler and D.E. Ingber. A microstructural approach to cytoskeletal mechanics based on tensegrity. J. Theor. Biol. 181: 125–136 1996

    Article  Google Scholar 

  63. Stamenović D., S.M. Mijailovich, I.M. Tolić-Nørrelykke, J. Chen, and N. Wang. Cell prestress. II. Contribution of microtubules. Am J Physiol Cell Physiol. 282: C617–624 2002

    Google Scholar 

  64. Stamenovic D., S.M. Mijailovich, I.M. Tolic-Norrelykke, and N. Wang. Experimental tests of the cellular tensegrity hypothesis. Biorheol. 40: 221–225 2003

    Google Scholar 

  65. Stamenović D., B. Suki, B. Fabry, N. Wang and J.J. Fredberg. Rheology of airway smooth muscle cells is associated with cytoskeletal contractile stress. J. Appl. Physiol. 96: 1600–1605 2004

    Article  Google Scholar 

  66. Sultan C., D. Stamenovic and D.E. Ingber. A computational tensegrity model predicts dynamic rheological behaviors in living cells. Ann. Biomed Engin. 32: 520–530 2004

    Article  Google Scholar 

  67. Thompson D.W. On Growth and Form. Cambridge: Cambridge University Press 1952

    Google Scholar 

  68. Volokh K.Y., O. Vilnay, and M. Belsky. Tensegrity architecture explains linear stiffening and predicts softening of living cells. J. Biomech. 33: 1543–1549 2000

    Article  Google Scholar 

  69. Volokh K.Y., O. Vilnay, and M. Belsky. Cell cytoskeleton and tensegrity. Biorheol. 39: 63–67 2002

    Google Scholar 

  70. Wang Y., E.L. Botvinick., Y. Zhao., M.W. Berns, S. Usami, R.Y. Tsien, and S. Chien. Visualizing the mechanical activation of Src. Nature 434: 1040–1045 2005

    Article  Google Scholar 

  71. Wang N., J.P. Butler, and D.E. Ingber. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260: 1124–1127 1993

    Article  Google Scholar 

  72. Wang N., K. Naruse, D. Stamenovic, J.J. Fredberg, S.M. Mijailovic, G. Maksym, T. Polte, and D.E. Ingber. Mechanical behavior in living cells consistent with the tensegrity model. Proc. Natl. Acad. Sci. U.S.A. 98: 7765–7770 2001

    Article  Google Scholar 

  73. Waterman-Storer C.M. and E.D. Salmon. Acto-myosin based retrograde flow of microtubules in the lamella of migrating epithelial cells influences microtubule dynamic instability and turnover and is associated with microtubule breakage and treadmilling. J. Cell Biol. 139: 417–434 1997

    Article  Google Scholar 

  74. Wendling S., C. Oddou, and D. Isabey. Stiffening response of a cellular tensegrity model. J. Theor. Biol. 196: 309–325 1999

    Article  Google Scholar 

  75. Werfel, J., D. E. Ingber, and R. Nagpal. Collective construction of environmentally-adaptive structures. IEEE Intl. Conf. on Intelligent Robots and Systems (IROS), San Diego, CA, October 2007.

  76. Wilson N.R., M.T. Ty, D.E. Ingber, G.M. Whitesides, M. Sur, and G. Liu. Synaptic reorganization in scaled networks of controlled size. J. Neurosci. 27: 13581–9 2007

    Article  Google Scholar 

  77. Xia, N., C. K. Thodeti, T. P. Hunt, Q. Xu, M. Ho, G. M. Whitesides, R. Westervelt, and D. E. Ingber. Directional control of cell motility through focal adhesion positioning and special Rac activation. FASEB J. January 7, 2008 [Epub ahead of print].

  78. Yu, C., F. Willems, D. E. Ingber, and R. Nagpal. Self-organization of environmentally-adaptive shapes on a modular robot. IEEE Intl. Conf. on Intelligent Robots and Systems (IROS), San Diego, CA, October 2007.

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Acknowledgments

This work was supported by grants from NIH, NASA, NSF, DARPA, DoD, and ARO. None of this work could have been accomplished without the mentorship of Judah Folkman, who unfortunately passed away only a few days ago.

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  1. Departments of Pathology and Surgery, Vascular Biology Program, Children’s Hospital and Harvard Medical School, KFRL 11.127, 300 Longwood Ave., Boston, MA, 02115-5737, USA

    Donald E. Ingber

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Ingber, D.E. From Molecular Cell Engineering to Biologically Inspired Engineering. Cel. Mol. Bioeng. 1, 51–57 (2008). https://doi.org/10.1007/s12195-008-0006-x

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