Abstract
Highly organized structures are a defining feature of biological tissues, from vascular and neural networks to hexagonal liver lobules and striated muscle fibers. This spatial organization of cells and their surrounding extracellular matrix (ECM) is an essential aspect to the development, maintenance, and function of tissues and organs. We discuss available strategies that have been developed for spatially arranging cells within ECM environments—by patterning cell–ECM and cell–cell adhesion, soluble cues, and substrate mechanical properties—and how such strategies can subsequently affect cell and tissue function. These approaches to recreate organized structures in vitro ultimately will play a key role in engineering the recapitulation of tissue function and thereby further efforts in regenerative medicine.
Similar content being viewed by others
References
Aguilar R. C.,and B. Wendland. Endocytosis of membrane receptors: two pathways are better than one. Proc. Natl. Acad. Sci. U. S. A. 102:2679–2680, 2005
Albrecht D. R., G. H. Underhill, T. B. Wassermann, R. L. Sah and S. N. Bhatia. Probing the role of multicellular organization in three-dimensional microenvironments. Nat. Methods 3:369–375, 2006
Bernstein S. A. and G. E. Morley. Gap junctions and propagation of the cardiac action potential. Adv. Cardiol. 42:71–85, 2006
Bhatia S. N., U. J. Balis, M. L. Yarmush and M. Toner. Probing heterotypic cell interactions: hepatocyte function in microfabricated co-cultures. J. Biomater. Sci. Polym. Ed. 9:1137–1160, 1998
Bhatia S. N., M. L. Yarmush and M. Toner. Controlling cell interactions by micropatterning in co-cultures: hepatocytes and 3T3 fibroblasts. J. Biomed. Mater. Res. 34:189–199, 1997
Burdick J. A., A. Khademhosseini and R. Langer. Fabrication of gradient hydrogels using a microfluidics/photopolymerization process. Langmuir 20:5153–5156, 2004
Carmeliet P. and M. Tessier-Lavigne. Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200, 2005
Carter S. B. Principles of cell motility: the direction of cell movement and cancer invasion. Nature 208:1183–1187, 1965
Chen C. S., M. Mrksich, S. Huang, G. M. Whitesides and D. E. Ingber. Geometric control of cell life and death. Science 276:1425–1428, 1997
Chen C. S., M. Mrksich, S. Huang, G. M. Whitesides and D. E. Ingber. Micropatterned surfaces for control of cell shape, position, and function. Biotechnol. Prog. 14:356–363, 1998
Chung B. G., L. A. Flanagan, S. W. Rhee, P. H. Schwartz, A. P. Lee, E. S. Monuki and N. L. Jeon. Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab. Chip 5:401–406, 2005
Dike L. E., C. S. Chen, M. Mrksich, J. Tien, G. M. Whitesides and D. E. Ingber. Geometric control of switching between growth, apoptosis, and differentiation during angiogenesis using micropatterned substrates. In Vitro Cell. Dev. Biol. Anim. 35:441–448, 1999
Discher D. E., P. Janmey and Y. L. Wang. Tissue cells feel and respond to the stiffness of their substrate. Science 310:1139–1143, 2005
Driever W. and C. Nusslein-Volhard. The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner. Cell 54:95–104, 1988
Elbjeirami W. M. and J. L. West. Angiogenesis-like activity of endothelial cells co-cultured with VEGF-producing smooth muscle cells. Tissue Eng. 12:381–390, 2006
Engler A. J., S. Sen, H. L. Sweeney and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006
Farge E. Mechanical induction of Twist in the Drosophila foregut/stomodeal primordium. Curr. Biol. 13:1365–1377, 2003
Gospodarowicz D., G. Greenburg and C. R. Birdwell. Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res. 38:4155–4171, 1978
Gray D. S., J. Tien and C. S. Chen. Repositioning of cells by mechanotaxis on surfaces with micropatterned Young’s modulus. Journal of Biomedical Materials Research Part A 66A:605–614, 2003
Hahn M. S., M. K. McHale, E. Wang, R. H. Schmedlen and J. L. West. Physiologic pulsatile flow bioreactor conditioning of poly(ethylene glycol)-based tissue engineered vascular grafts. Ann. Biomed. Eng 35:190–200, 2007
Hahn, M. S., J. S. Miller and J. L. West. Three-dimensional biochemical and biomechanical patterning of hydrogels for guiding cell behavior. Adv Mater 18:2679, 2006
Harbers G. M. and K. E. Healy. The effect of ligand type and density on osteoblast adhesion, proliferation, and matrix mineralization. J. Biomed. Mater. Res. A. 75:855–869, 2005
Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell 80:213–223, 1995
Hsu S., R. Thakar, D. Liepmann and S. Li. Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces. Biochem. Biophys. Res. Commun. 337:401–409, 2005
Huang S., C. P. Brangwynne, K. K. Parker and D. E. Ingber. Symmetry-breaking in mammalian cell cohort migration during tissue pattern formation: role of random-walk persistence. Cell Motil. Cytoskeleton 61:201–213, 2005
Ingber D. E. Fibronectin controls capillary endothelial cell growth by modulating cell shape. Proc. Natl. Acad. Sci. U. S. A. 87:3579–3583, 1990
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
Jiang X., R. Ferrigno, M. Mrksich and G. M. Whitesides. Electrochemical desorption of self-assembled monolayers noninvasively releases patterned cells from geometrical confinements. J. Am. Chem. Soc. 125:2366–2367, 2003
Karp J. M., J. Yeh, G. Eng, J. Fukuda, J. Blumling, K. Y. Suh, J. Cheng, A. Mahdavi, J. Borenstein, R. Langer and A. Khademhosseini. Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. Lab. Chip 7:786–794, 2007
Kim B. S., J. Nikolovski, J. Bonadio and D. J. Mooney. Cyclic mechanical strain regulates the development of engineered smooth muscle tissue. Nat. Biotechnol. 17:979–983, 1999
LaMack J. A. and M. H. Friedman. Individual and combined effects of shear stress magnitude and spatial gradient on endothelial cell gene expression. Am. J. Physiol. Heart Circ. Physiol. 293:H2853–9, 2007
Levenberg S., J. Rouwkema, M. Macdonald, E. S. Garfein, D. S. Kohane, D. C. Darland, R. Marini, C. A. van Blitterswijk, R. C. Mulligan, P. A. D’Amore and R. Langer. Engineering vascularized skeletal muscle tissue. Nat. Biotechnol. 23:879–884, 2005
Li Jeon N., H. Baskaran, S. K. Dertinger, G. M. Whitesides, L. Van de Water and M. Toner. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat. Biotechnol. 20:826–830, 2002
Liu Tsang V., A. A. Chen, L. M. Cho, K. D. Jadin, R. L. Sah, S. DeLong, J. L. West and S. N. Bhatia. Fabrication of 3D hepatic tissues by additive photopatterning of cellular hydrogels. FASEB J. 21:790–801, 2007
Liu L., B. D. Ratner, E. H. Sage and S. Jiang. Endothelial cell migration on surface-density gradients of fibronectin, VEGF, or both proteins. Langmuir 23:11168–11173, 2007
Lo C., H. Wang, M. Dembo and Y. Wang. Cell Movement Is Guided by the Rigidity of the Substrate. Biophys. J. 79:144–152, 2000
Matsuda T., Y. Saito and K. Shoda. Cell sorting technique based on thermoresponsive differential cell adhesiveness. Biomacromolecules 8:2345–2349, 2007
Matsumoto T., J. Sasaki, E. Alsberg, H. Egusa, H. Yatani and T. Sohmura. Three-dimensional cell and tissue patterning in a strained fibrin gel system. PLoS ONE 2:e1211, 2007
Matsumoto T., Y. C. Yung, C. Fischbach, H. J. Kong, R. Nakaoka and D. J. Mooney. Mechanical strain regulates endothelial cell patterning in vitro. Tissue Eng. 13:207–217, 2007
McBeath R., D. M. Pirone, C. M. Nelson, K. Bhadriraju and C. S. Chen. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell. 6:483–495, 2004
McNeill H. Sticking together and sorting things out: adhesion as a force in development. Nat. Rev. Genet. 1:100–108, 2000
Nakatsu M. N., R. C. Sainson, J. N. Aoto, K. L. Taylor, M. Aitkenhead, S. Perez-del-Pulgar, P. M. Carpenter and C. C. Hughes. Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: the role of fibroblasts and Angiopoietin-1. Microvasc. Res. 66:102–112, 2003
Nelson C. M., R. P. Jean, J. L. Tan, W. F. Liu, N. J. Sniadecki, A. A. Spector and C. S. Chen. Emergent patterns of growth controlled by multicellular form and mechanics. Proc. Natl. Acad. Sci. U. S. A. 102:11594–11599, 2005
Pallante B. A., I. Duignan, D. Okin, A. Chin, M. C. Bressan, T. Mikawa and J. M. Edelberg. Bone marrow Oct3/4 + cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms. Circ. Res. 100:e1–11, 2007
Park J., F. Berthiaume, M. Toner, M. L. Yarmush and A. W. Tilles. Microfabricated grooved substrates as platforms for bioartificial liver reactors. Biotechnol. Bioeng. 90:632–644, 2005
Park J. W., B. Vahidi, A. M. Taylor, S. W. Rhee and N. L. Jeon. Microfluidic culture platform for neuroscience research. Nat. Protoc. 1:2128–2136, 2006
Park S., P. M. Wolanin, E. A. Yuzbashyan, P. Silberzan, J. B. Stock and R. H. Austin. Motion to Form a Quorum. Science 301:188, 2003
Paszek M. J., N. Zahir, K. R. Johnson, J. N. Lakins, G. I. Rozenberg, A. Gefen, C. A. Reinhart-King, S. S. Margulies, M. Dembo and D. Boettiger. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254, 2005
Plummer S. T., Q. Wang, P. W. Bohn, R. Stockton and M. A. Schwartz. Electrochemically derived gradients of the extracellular matrix protein fibronectin on gold. Langmuir 19:7528–7536, 2003
Ray R. P., K. Arora, C. Nusslein-Volhard and W. M. Gelbart. The control of cell fate along the dorsal-ventral axis of the Drosophila embryo. Development 113:35–54, 1991
Re F., A. Zanetti, M. Sironi, N. Polentarutti, L. Lanfrancone, E. Dejana and F. Colotta. Inhibition of anchorage-dependent cell spreading triggers apoptosis in cultured human endothelial cells. J. Cell Biol. 127:537–546, 1994
Ridley A. J., M. A. Schwartz, K. Burridge, R. A. Firtel, M. H. Ginsberg, G. Borisy, J. T. Parsons and A. R. Horwitz. Cell Migration: Integrating Signals from Front to Back. Science 302:1704–1709, 2003
Sakiyama-Elbert S. E., A. Panitch and J. A. Hubbell. Development of growth factor fusion proteins for cell-triggered drug delivery. FASEB J 15:1300–2, 2001
Singh A. B., K. Sugimoto and R. C. Harris. Juxtacrine activation of epidermal growth factor (EGF) receptor by membrane-anchored heparin-binding EGF-like growth factor protects epithelial cells from anoikis while maintaining an epithelial phenotype. J. Biol. Chem. 282:32890–32901, 2007
Singhvi R., A. Kumar, G. P. Lopez, G. N. Stephanopoulos, D. I. Wang, G. M. Whitesides and D. E. Ingber. Engineering cell shape and function. Science 264:696–698, 1994
Smith J. T., J. K. Tomfohr, M. C. Wells, T. P. Beebe Jr, T. B. Kepler and W. M. Reichert. Measurement of cell migration on surface-bound fibronectin gradients. Langmuir 20:8279–8286, 2004
Steinberg M. S. On the mechanism of tissue reconstruction by dissociated cells. I. Population kinetics, differential adhesiveness. and the absence of directed migration. Proc. Natl. Acad. Sci. U. S. A. 48:1577–1582, 1962
Takayama S., J. C. McDonald, E. Ostuni, M. N. Liang, P. J. Kenis, R. F. Ismagilov and G. M. Whitesides. Patterning cells and their environments using multiple laminar fluid flows in capillary networks. Proc. Natl. Acad. Sci. U. S. A. 96:5545–5548, 1999
Takayama S., E. Ostuni, P. LeDuc, K. Naruse, D. E. Ingber and G. M. Whitesides. Subcellular positioning of small molecules. Nature 411:1016, 2001
Taylor A. M., M. Blurton-Jones, S. W. Rhee, D. H. Cribbs, C. W. Cotman and N. L. Jeon. A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nat. Methods 2:599–605, 2005
Tepass U., D. Godt and R. Winklbauer. Cell sorting in animal development: signalling and adhesive mechanisms in the formation of tissue boundaries. Curr. Opin. Genet. Dev. 12:572–582, 2002
Van Haastert P. J. M. and P. N. Devreotes. Chemotaxis: signalling the way forward. Nat Rev Mol Cell Biol 5:626–634, 2004
von Degenfeld G., A. Banfi, M. L. Springer, R. A. Wagner, J. Jacobi, C. R. Ozawa, M. J. Merchant, J. P. Cooke and H. M. Blau. Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia. FASEB J. 20:2657–2659, 2006
Wang S. J., W. Saadi, F. Lin, C. Minh-Canh Nguyen and N. Li Jeon. Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. Exp. Cell Res. 300:180–189, 2004
Wong J. Y., A. Velasco, P. Rajagopalan and Q. Pham. Directed Movement of Vascular Smooth Muscle Cells on Gradient-Compliant Hydrogels. Langmuir 19:1908–1913, 2003
Yeo W. S. and M. Mrksich. Electroactive self-assembled monolayers that permit orthogonal control over the adhesion of cells to patterned substrates. Langmuir 22:10816–10820, 2006
Yousaf M. N., B. T. Houseman and M. Mrksich. Using electroactive substrates to pattern the attachment of two different cell populations. Proc. Natl. Acad. Sci. U. S. A. 98:5992–5996, 2001
Zaari, N., P. Rajagopalan, S. K. Kim, A. J. Engler, and J. Y. Wong. Photopolymerization in microfluidic gradient generators: microscale control of substrate compliance to manipulate cell response. Adv. Mater. 16:2133–2137, 2004
Zisch A. H., M. P. Lutolf, M. Ehrbar, G. P. Raeber, S. C. Rizzi, N. Davies, H. Schmokel, D. Bezuidenhout, V. Djonov, P. Zilla and J. A. Hubbell. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth. FASEB J. 17:2260–2262, 2003
Acknowledgments
This work was supported in part by the NIH (EB00262, HL73305, GM74048). Shen acknowledges support from the Paul and Daisy Soros Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shen, C.J., Fu, J. & Chen, C.S. Patterning Cell and Tissue Function. Cel. Mol. Bioeng. 1, 15–23 (2008). https://doi.org/10.1007/s12195-008-0005-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12195-008-0005-y