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PNAS 102 (33): 11594-11599

Copyright © 2005 by the National Academy of Sciences.

From the Cover


Emergent patterns of growth controlled by multicellular form and mechanics

Celeste M. Nelson *, {dagger}, Ronald P. Jean *, John L. Tan *, Wendy F. Liu *, Nathan J. Sniadecki *, Alexander A. Spector *, and Christopher S. Chen *, {dagger}, {ddagger}

*Departments of Biomedical Engineering and Oncology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205; and {ddagger}Department of Bioengineering, University of Pennsylvania, Translational Research Labs Suite 1400, 125 South 31st Street, Philadelphia, PA 19104

Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved June 17, 2005

Received for publication March 29, 2005.

Abstract: Spatial patterns of cellular growth generate mechanical stresses that help to push, fold, expand, and deform tissues into their specific forms. Genetic factors are thought to specify patterns of growth and other behaviors to drive morphogenesis. Here, we show that tissue form itself can feed back to regulate patterns of proliferation. Using microfabrication to control the organization of sheets of cells, we demonstrated the emergence of stable patterns of proliferative foci. Regions of concentrated growth corresponded to regions of high tractional stress generated within the sheet, as predicted by a finite-element model of multicellular mechanics and measured directly by using a micromechanical force sensor array. Inhibiting actomyosin-based tension or cadherin-mediated connections between cells disrupted the spatial pattern of proliferation. These findings demonstrate the existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth. Thus, tissue form is not only a consequence but also an active regulator of tissue growth.

Key Words: morphogenesis • pattern formation • micropatterning • cytoskeleton • mechanotransduction

Author contributions: C.M.N. and C.S.C. designed research; C.M.N., R.P.J., J.L.T., W.F.L., N.J.S., and A.A.S. performed research; C.M.N. and C.S.C. analyzed data; and C.M.N. and C.S.C. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: VE, vascular endothelial; FEM, finite-element method.

See Commentary on page 11571.

{dagger} To whom correspondence may be addressed. E-mail: cmnelson{at} or chrischen{at}

© 2005 by The National Academy of Sciences of the USA

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D. D. Klumpers, A. S. Mao, T. H. Smit, and D. J. Mooney (2014)
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   Abstract »    Full Text »    PDF »
Spatial constraints control cell proliferation in tissues.
S. J. Streichan, C. R. Hoerner, T. Schneidt, D. Holzer, and L. Hufnagel (2014)
PNAS 111, 5586-5591
   Abstract »    Full Text »    PDF »
A constitutive model for cytoskeletal contractility of smooth muscle cells.
T. Liu (2014)
Proc R Soc A 470, 20130771
   Abstract »    Full Text »    PDF »
Collective cell traction force analysis on aligned smooth muscle cell sheet between three-dimensional microwalls.
Y. Zhang, S. S. Ng, Y. Wang, H. Feng, W. N. Chen, M. B. Chan-Park, C. Li, and V. Chan (2014)
Interface Focus 4, 20130056
   Abstract »    Full Text »    PDF »
Growth, homeostatic regulation and stem cell dynamics in tissues.
E. Hannezo, J. Prost, and J.- F. Joanny (2014)
J R Soc Interface 11, 20130895
   Abstract »    Full Text »    PDF »
Rapid disorganization of mechanically interacting systems of mammary acini.
Q. Shi, R. P. Ghosh, H. Engelke, C. H. Rycroft, L. Cassereau, J. A. Sethian, V. M. Weaver, and J. T. Liphardt (2014)
PNAS 111, 658-663
   Abstract »    Full Text »    PDF »
In Drosophila, RhoGEF2 cooperates with activated Ras in tumorigenesis through a pathway involving Rho1-Rok-Myosin-II and JNK signalling.
P. Khoo, K. Allan, L. Willoughby, A. M. Brumby, and H. E. Richardson (2013)
Dis. Model. Mech. 6, 661-678
   Abstract »    Full Text »    PDF »
How the tooth got its stripes: patterning via strain-cued motility.
B. N. Cox (2013)
J R Soc Interface 10, 20130266
   Abstract »    Full Text »    PDF »
Assembly of complex cell microenvironments using geometrically docked hydrogel shapes.
G. Eng, B. W. Lee, H. Parsa, C. D. Chin, J. Schneider, G. Linkov, S. K. Sia, and G. Vunjak-Novakovic (2013)
PNAS 110, 4551-4556
   Abstract »    Full Text »    PDF »
Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions.
W. R. Legant, C. K. Choi, J. S. Miller, L. Shao, L. Gao, E. Betzig, and C. S. Chen (2013)
PNAS 110, 881-886
   Abstract »    Full Text »    PDF »
Host epithelial geometry regulates breast cancer cell invasiveness.
E. Boghaert, J. P. Gleghorn, K. Lee, N. Gjorevski, D. C. Radisky, and C. M. Nelson (2012)
PNAS 109, 19632-19637
   Abstract »    Full Text »    PDF »
Nanopatterning reveals an ECM area threshold for focal adhesion assembly and force transmission that is regulated by integrin activation and cytoskeleton tension.
S. R. Coyer, A. Singh, D. W. Dumbauld, D. A. Calderwood, S. W. Craig, E. Delamarche, and A. J. Garcia (2012)
J. Cell Sci. 125, 5110-5123
   Abstract »    Full Text »    PDF »
Finding the weakest link - exploring integrin-mediated mechanical molecular pathways.
P. Roca-Cusachs, T. Iskratsch, and M. P. Sheetz (2012)
J. Cell Sci. 125, 3025-3038
   Abstract »    Full Text »    PDF »
Mechanosensitive mechanisms in transcriptional regulation.
A. Mammoto, T. Mammoto, and D. E. Ingber (2012)
J. Cell Sci. 125, 3061-3073
   Abstract »    Full Text »    PDF »
Flow mechanotransduction regulates traction forces, intercellular forces, and adherens junctions.
L. H. Ting, J. R. Jahn, J. I. Jung, B. R. Shuman, S. Feghhi, S. J. Han, M. L. Rodriguez, and N. J. Sniadecki (2012)
Am J Physiol Heart Circ Physiol 302, H2220-H2229
   Abstract »    Full Text »    PDF »
Src, p130Cas, and Mechanotransduction in Cancer Cells.
H. Matsui, I. Harada, and Y. Sawada (2012)
Genes & Cancer 3, 394-401
   Abstract »    Full Text »    PDF »
Tissue deformation spatially modulates VEGF signaling and angiogenesis.
N. C. Rivron, E. J. Vrij, J. Rouwkema, S. Le Gac, A. van den Berg, R. K. Truckenmuller, and C. A. van Blitterswijk (2012)
PNAS 109, 6886-6891
   Abstract »    Full Text »    PDF »
Left-Right Symmetry Breaking in Tissue Morphogenesis via Cytoskeletal Mechanics.
T.-H. Chen, J. J. Hsu, X. Zhao, C. Guo, M. N. Wong, Y. Huang, Z. Li, A. Garfinkel, C.-M. Ho, Y. Tintut, et al. (2012)
Circ. Res. 110, 551-559
   Abstract »    Full Text »    PDF »
Mechanical compression drives cancer cells toward invasive phenotype.
J. M. Tse, G. Cheng, J. A. Tyrrell, S. A. Wilcox-Adelman, Y. Boucher, R. K. Jain, and L. L. Munn (2012)
PNAS 109, 911-916
   Abstract »    Full Text »    PDF »
Lateral spacing of adhesion peptides influences human mesenchymal stem cell behaviour.
J. E. Frith, R. J. Mills, and J. J. Cooper-White (2012)
J. Cell Sci. 125, 317-327
   Abstract »    Full Text »    PDF »
Early integrin binding to Arg-Gly-Asp peptide activates actin polymerization and contractile movement that stimulates outward translocation.
C.-h. Yu, J. B. K. Law, M. Suryana, H. Y. Low, and M. P. Sheetz (2011)
PNAS 108, 20585-20590
   Abstract »    Full Text »    PDF »
Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche.
K. B. Blagoev (2011)
PNAS 108, 19216-19221
   Abstract »    Full Text »    PDF »
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation.
J.-H. Kim and A. R. Asthagiri (2011)
J. Cell Sci. 124, 1280-1287
   Abstract »    Full Text »    PDF »
A strain-cue hypothesis for biological network formation.
B. N. Cox (2011)
J R Soc Interface 8, 377-394
   Abstract »    Full Text »    PDF »
Micropatterning as a tool to decipher cell morphogenesis and functions.
M. Thery (2010)
J. Cell Sci. 123, 4201-4213
   Abstract »    Full Text »    PDF »
Mechanical tugging force regulates the size of cell-cell junctions.
Z. Liu, J. L. Tan, D. M. Cohen, M. T. Yang, N. J. Sniadecki, S. A. Ruiz, C. M. Nelson, and C. S. Chen (2010)
PNAS 107, 9944-9949
   Abstract »    Full Text »    PDF »
Mechanical control of tissue and organ development.
T. Mammoto and D. E. Ingber (2010)
Development 137, 1407-1420
   Abstract »    Full Text »    PDF »
Coordination of plant cell division and expansion in a simple morphogenetic system.
L. Dupuy, J. Mackenzie, and J. Haseloff (2010)
PNAS 107, 2711-2716
   Abstract »    Full Text »    PDF »
Matrix elasticity, cytoskeletal forces and physics of the nucleus: how deeply do cells 'feel' outside and in?.
A. Buxboim, I. L. Ivanovska, and D. E. Discher (2010)
J. Cell Sci. 123, 297-308
   Abstract »    Full Text »    PDF »
Electrical dimensions in cell science.
C. D. McCaig, B. Song, and A. M. Rajnicek (2009)
J. Cell Sci. 122, 4267-4276
   Abstract »    Full Text »    PDF »
Self-organization of engineered epithelial tubules by differential cellular motility.
H. Mori, N. Gjorevski, J. L. Inman, M. J. Bissell, and C. M. Nelson (2009)
PNAS 106, 14890-14895
   Abstract »    Full Text »    PDF »
Tunable interplay between epidermal growth factor and cell-cell contact governs the spatial dynamics of epithelial growth.
J.-H. Kim, K. Kushiro, N. A. Graham, and A. R. Asthagiri (2009)
PNAS 106, 11149-11153
   Abstract »    Full Text »    PDF »
Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues.
W. R. Legant, A. Pathak, M. T. Yang, V. S. Deshpande, R. M. McMeeking, and C. S. Chen (2009)
PNAS 106, 10097-10102
   Abstract »    Full Text »    PDF »
The rate of cell growth is governed by cell cycle stage.
A. I. Goranov, M. Cook, M. Ricicova, G. Ben-Ari, C. Gonzalez, C. Hansen, M. Tyers, and A. Amon (2009)
Genes & Dev. 23, 1408-1422
   Abstract »    Full Text »    PDF »
In silico biology of bone modelling and remodelling: regeneration.
L. Geris, J. Vander Sloten, and H. Van Oosterwyck (2009)
Phil Trans R Soc A 367, 2031-2053
   Abstract »    Full Text »    PDF »
Multiscale Modeling of Form and Function.
A. J. Engler, P. O. Humbert, B. Wehrle-Haller, and V. M. Weaver (2009)
Science 324, 208-212
   Abstract »    Full Text »    PDF »
Cell polarity triggered by cell-cell adhesion via E-cadherin.
R. A. Desai, L. Gao, S. Raghavan, W. F. Liu, and C. S. Chen (2009)
J. Cell Sci. 122, 905-911
   Abstract »    Full Text »    PDF »
Mechanotransduction - a field pulling together?.
C. S. Chen (2008)
J. Cell Sci. 121, 3285-3292
   Abstract »    Full Text »    PDF »
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M. L. Snead (2008)
J Dent Educ. 72, 903-911
   Abstract »    Full Text »    PDF »
Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay.
D. M. Pedrotty, R. Y. Klinger, N. Badie, S. Hinds, A. Kardashian, and N. Bursac (2008)
Am J Physiol Heart Circ Physiol 295, H390-H400
   Abstract »    Full Text »    PDF »
Niche-mediated control of human embryonic stem cell self-renewal and differentiation.
R. Peerani, B. M. Rao, C. Bauwens, T. Yin, G. A. Wood, A. Nagy, E. Kumacheva, and P. W. Zandstra (2007)
EMBO J. 26, 4744-4755
   Abstract »    Full Text »    PDF »
Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals.
W.-h. Guo and Y.-l. Wang (2007)
Mol. Biol. Cell 18, 4519-4527
   Abstract »    Full Text »    PDF »
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D. E. Ingber and M. Levin (2007)
Development 134, 2541-2547
   Abstract »    Full Text »    PDF »
Micromechanical control of cell-cell interactions.
E. E. Hui and S. N. Bhatia (2007)
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   Abstract »    Full Text »    PDF »
A model for the contractility of the cytoskeleton including the effects of stress-fibre formation and dissociation.
V. S Deshpande, R. M McMeeking, and A. G Evans (2007)
Proc R Soc A 463, 787-815
   Abstract »    Full Text »    PDF »
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L. Hufnagel, A. A. Teleman, H. Rouault, S. M. Cohen, and B. I. Shraiman (2007)
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   Abstract »    Full Text »    PDF »
Tissue Geometry Determines Sites of Mammary Branching Morphogenesis in Organotypic Cultures.
C. M. Nelson, M. M. VanDuijn, J. L. Inman, D. A. Fletcher, and M. J. Bissell (2006)
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   Abstract »    Full Text »    PDF »
Peristalsis of airway smooth muscle is developmentally regulated and uncoupled from hypoplastic lung growth.
E. C. Jesudason, N. P. Smith, M. G. Connell, D. G. Spiller, M. R. H. White, D. G. Fernig, and P. D. Losty (2006)
Am J Physiol Lung Cell Mol Physiol 291, L559-L565
   Abstract »    Full Text »    PDF »
A bio-chemo-mechanical model for cell contractility.
V. S. Deshpande, R. M. McMeeking, and A. G. Evans (2006)
PNAS 103, 14015-14020
   Abstract »    Full Text »    PDF »
The Multiple Languages of Endothelial Cell-to-Cell Communication.
S. Liebner, U. Cavallaro, and E. Dejana (2006)
Arterioscler Thromb Vasc Biol 26, 1431-1438
   Abstract »    Full Text »    PDF »
Cellular mechanotransduction: putting all the pieces together again.
D. E. Ingber (2006)
FASEB J 20, 811-827
   Abstract »    Full Text »    PDF »
Mechanical control of tissue growth: Function follows form.
D. E. Ingber (2005)
PNAS 102, 11571-11572
   Full Text »    PDF »

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