3D niche microarrays for systems-level analyses of cell fate
Open accessAbstract
The behaviour of mammalian cells in a tissue is governed by the three-dimensional (3D) microenvironment and involves a dynamic interplay between biochemical and mechanical signals provided by the extracellular matrix (ECM), cell–cell interactions and soluble factors. The complexity of the microenvironment and the context-dependent cell responses that arise from these interactions have posed a major challenge to understanding the underlying regulatory mechanisms. Here we develop an experimental paradigm to dissect the role of various interacting factors by simultaneously synthesizing more than 1,000 unique microenvironments with robotic nanolitre liquid-dispensing technology and by probing their effects on cell fate. Using this novel 3D microarray platform, we assess the combined effects of matrix elasticity, proteolytic degradability and three distinct classes of signalling proteins on mouse embryonic stem cells, unveiling a comprehensive map of interactions involved in regulating self-renewal. This approach is broadly applicable to gain a systems-level understanding of multifactorial 3D cell–matrix interactions. 3D cell culture matrices more closely resemble the natural microenvironments of stem cells than 2D systems. Here, the authors present a 3D cell culture approach to screen for the influence of environmental parameters on self-renewal and differentiation of single mouse embryonic stem cells.
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Optimal conditions (elastic moduli ranged from 2-4 kPa and scaffolds with MMP insensitivity) produce murine neural tube organoids that are more homogenous in colony size and morphology, as well as more polarized, than those grown in Matrigel.
“The optimal conditions (elastic moduli ranged from 2–4 kPa and scaffolds with MMP insensitivity) produce murine neural tube organoids that are more homogenous in colony size and morphology, as well as more polarized, than those grown in Matrigel.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [156]
Ranga and colleagues prepared PEG-based gels in 1536-well plates and studied murine ESCs expressing an Oct4-GFP reporter.
“A striking demonstration of the utility of high-throughput approaches was provided by Ranga and colleagues, who prepared PEG-based gels in 1536-well plates and studied murine ESCs (mESCs) expressing an Oct4-GFP reporter.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [156]
The authors analyzed 1000 variations of matrix elastic modulus, cell-binding peptides, and matrix susceptibility to MMP degradation and their effects on murine ESC fate.
“The authors analyzed 1000 variations of matrix elastic modulus, cell-binding peptides, and matrix susceptibility to MMP degradation and their effects on murine ESC fate156.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [156]
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Cites
Matrix elasticity directs stem cell lineage specification
Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006) · Cell · doi:10.1016/j.cell.2006.06.044 · Cited by 13,915 · see citing works
Lutolf, M. P., & Hubbell, J. A. (2005) · Nature Biotechnology · doi:10.1038/nbt1055 · Cited by 4,551 · see citing works
Niwa, H., Miyazaki, J., & Smith, A. G. (2000) · Nature Genetics · doi:10.1038/74199 · Cited by 3,606 · see citing works
The ground state of embryonic stem cell self-renewal
Ying, Q.-L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., & Smith, A. (2008) · Nature · doi:10.1038/nature06968 · Cited by 3,442 · see citing works
Modeling Tissue Morphogenesis and Cancer in 3D
Yamada, K. M., & Cukierman, E. (2007) · Cell · doi:10.1016/j.cell.2007.08.006 · Cited by 1,751 · see citing works
Matrigel: Basement membrane matrix with biological activity
Kleinman, H. K., & Martin, G. R. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.05.004 · Cited by 1,673 · see citing works
Substrate Elasticity Regulates Skeletal Muscle Stem Cell Self-Renewal in Culture
Gilbert, P. M., Havenstrite, K. L., Magnusson, K. E. G., Sacco, A., Leonardi, N. A., Kraft, P., Nguyen, N. K., Thrun, S., Lutolf, M. P., & Blau, H. M. (2010) · Science · doi:10.1126/science.1191035 · Cited by 1,587 · see citing works
Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate
Huebsch, N., Arany, P. R., Mao, A. S., Shvartsman, D. E., Ali, O. A., Bencherif, S. A., Rivera‐Feliciano, J., & Mooney, D. J. (2010) · Nature Materials · doi:10.1038/nmat2732 · Cited by 1,572 · see citing works
Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro
Barker, N., Huch, M., Kujala, P., van de Wetering, M., Snippert, H. J., van Es, J. H., Sato, T., Stange, D. E., Begthel, H., van den Born, M., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2009.11.013 · Cited by 1,547 · see citing works
Lutolf, M. P., Lauer-Fields, J. L., Schmoekel, H. G., Metters, A. T., Weber, F. E., Fields, G. B., & Hubbell, J. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737381100 · Cited by 1,508 · see citing works
Self-citationSolid stress inhibits the growth of multicellular tumor spheroids
Helmlinger, G., Netti, P. A., Lichtenbeld, H. C., Melder, R. J., & Jain, R. K. (1997) · Nature Biotechnology · doi:10.1038/nbt0897-778 · Cited by 859 · see citing works
Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells
Mei, Y., Saha, K., Bogatyrev, S. R., Yang, J., Hook, A. L., Kalcioglu, Z. I., Cho, S., Mitalipova, M. M., Pyzocha, N., Rojas, F., et al. (2010) · Nature Materials · doi:10.1038/nmat2812 · Cited by 543 · see citing works
Patterson, J., & Hubbell, J. A. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.06.061 · Cited by 536 · see citing works
Qi, X., Li, T.-G., Hao, J., Hu, J., Wang, J., Simmons, H., Miura, S., Mishina, Y. M., & Zhao, G.-Q. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401367101 · Cited by 440 · see citing works
Artificial niche microarrays for probing single stem cell fate in high throughput
Gobaa, S., Hoehnel, S., Roccio, M., Negro, A., Kobel, S., & Lutolf, M. P. (2011) · Nature Methods · doi:10.1038/nmeth.1732 · Cited by 390 · see citing works
Self-citationElucidating the Role of Matrix Stiffness in 3D Cell Migration and Remodeling
Ehrbar, M., Sala, A., Lienemann, P. S., Ranga, A., Mosiewicz, K. A., Bittermann, A. G., Rizzi, S. C., Weber, F. E., & Lütolf, M. P. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2010.11.082 · Cited by 361 · see citing works
Self-citationCancer cell angiogenic capability is regulated by 3D culture and integrin engagement
Fischbach, C., Kong, H. J., Hsiong, S. X., Evangelista, M. B., Yuen, W. W., & Mooney, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808932106 · Cited by 312 · see citing works
Biomolecular Hydrogels Formed and Degraded via Site-Specific Enzymatic Reactions
Ehrbar, M., Rizzi, S. C., Schoenmakers, R. G., Miguel, B. S., Hubbell, J. A., Weber, F. E., & Lütolf, M. P. (2007) · Biomacromolecules · doi:10.1021/bm070228f · Cited by 299 · see citing works
Soen, Y., Mori, A., Palmer, T. D., & Brown, P. O. (2006) · Molecular Systems Biology · doi:10.1038/msb4100076 · Cited by 223 · see citing works
Combinatorial Signaling Microenvironments for Studying Stem Cell Fate
Flaim, C. J., Teng, D., Chien, S., & Bhatia, S. N. (2008) · Stem Cells and Development · doi:10.1089/scd.2007.0085 · Cited by 195 · see citing works
Musah, S., Morin, S. A., Wrighton, P. J., Zwick, D. B., Jin, S., & Kiessling, L. L. (2012) · ACS Nano · doi:10.1021/nn3039148 · Cited by 163 · see citing works
Uemura, M., Refaat, M. M., Shinoyama, M., Hayashi, H., Hashimoto, N., & Takahashi, J. B. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22223 · Cited by 150 · see citing works
Lee, S. T., Yun, J. I., Jo, Y. S., Mochizuki, M., van der Vlies, A. J., Kontos, S., Ihm, J. E., Lim, J. M., & Hubbell, J. A. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.10.054 · Cited by 134 · see citing works
Jung, J. P., Moyano, J. V., & Collier, J. H. (2011) · Integrative Biology · doi:10.1039/c0ib00112k · Cited by 116 · see citing works
Soncin, F., Mohamet, L., Eckardt, D., Ritson, S., Eastham, A. M., Bobola, N., Russell, A. J., Davies, S., Kemler, R., Merry, C. L. R., et al. (2009) · Stem Cells · doi:10.1002/stem.134 · Cited by 113 · see citing works
EpCAM Is Involved in Maintenance of the Murine Embryonic Stem Cell Phenotype
González, B., Denzel, S., Mack, B., Conrad, M., & Gires, O. (2009) · Stem Cells · doi:10.1002/stem.97 · Cited by 113 · see citing works
Prudhomme, W., Daley, G. Q., Zandstra, P. W., & Lauffenburger, D. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308768101 · Cited by 109 · see citing works
Khalilian, M., Navidbakhsh, M., Valojerdi, M. R., Chizari, M., & Eftekhari‐Yazdi, P. (2009) · Journal of The Royal Society Interface · doi:10.1098/rsif.2009.0380 · Cited by 102 · see citing works
Murayama, Y., Mizuno, J., Kamakura, H., et al. (2006) · Human Cell · doi:10.1111/j.1749-0774.2006.00019.x · Cited by 94 · see citing works
Cell-Cell Signaling Through NOTCH Regulates Human Embryonic Stem Cell Proliferation
Fox, V., Gokhale, P. J., Walsh, J. R., et al. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0368 · Cited by 79 · see citing works
Combinatorial Extracellular Matrices for Human Embryonic Stem Cell Differentiation in 3D
Yang, F., Cho, S., Son, S. M., Hudson, S. P., Bogatyrev, S. R., Keung, L., Kohane, D. S., Langer, R., & Anderson, D. G. (2010) · Biomacromolecules · doi:10.1021/bm100357t · Cited by 68 · see citing works
Salgado, C. L., Oliveira, M. B., & Mano, J. F. (2012) · Integrative Biology · doi:10.1039/c2ib00170e · Cited by 55 · see citing works
Immobilization of growth factors on solid supports for the modulation of stem cell fate
Pompe, W., Salchert, K., Alberti, K., et al. (2010) · Nature Protocols · doi:10.1038/nprot.2010.70 · Cited by 52 · see citing works
Roeder, I., Loeffler, M., & Glauche, I. (2011) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2011.03.001 · Cited by 38 · see citing works
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Gjorevski, N., Sachs, N., Manfrin, A., Giger, S., Bragina, M. E., Ordóñez-Morán, P., Clevers, H., & Lutolf, M. P. (2016) · Nature · doi:10.1038/nature20168 · Cited by 1,426 · see citing works
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184 · see citing works
Developmental cognitive neuroscience using latent change score models: A tutorial and applications
Kievit, R. A., Brandmaier, A. M., Ziegler, G., van Harmelen, A.-L., de Mooij, S. M. M., Moutoussis, M., Goodyer, I. M., Bullmore, E., Jones, P. B., Fonagy, P., et al. (2018) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2017.11.007 · Cited by 516 · see citing works
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Self-citationDefined three-dimensional microenvironments boost induction of pluripotency
Caiazzo, M., Okawa, Y., Ranga, A., Piersigilli, A., Tabata, Y., & Lutolf, M. P. (2016) · Nature Materials · doi:10.1038/nmat4536 · Cited by 271 · see citing works
Self-citationNeural tube morphogenesis in synthetic 3D microenvironments
Ranga, A., Girgin, M., Meinhardt, A., Eberle, D., Caiazzo, M., Tanaka, E. M., & Lutolf, M. P. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603529113 · Cited by 221 · see citing works
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Nguyen, E. H., Daly, W. T., Le, N. N. T., Farnoodian, M., Belair, D. G., Schwartz, M. P., Lebakken, C. S., Ananiev, G. E., Saghiri, M. A., Knudsen, T. B., et al. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-017-0096 · Cited by 136 · see citing works
Ovadia, E. M., Colby, D. W., & Kloxin, A. M. (2018) · Biomaterials Science · doi:10.1039/c8bm00099a · Cited by 40 · see citing works
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- Authors
- Ranga, A., Gobaa, S., Okawa, Y., Mosiewicz, K., Negro, A., & Lutolf, M. P.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Venue
- Nature Communications
- Published
- 2014-07-14
- Volume
- 5
- Issue
- 1
- Pages
- 4324-4324
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4104440
- OpenAlex
- W1966101847
- Cited by
- 238
- References
- 34
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 13 · 2021: 22 · 2020: 23 · 2019: 21 · 2018: 33 · 2017: 40 · 2016: 38 · 2015: 13 · 2014: 3
- FWCI
- 15.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Lirias (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125290, 125426)
- Fonds Québécois de la Recherche sur la Nature et les Technologies
- Natural Sciences and Engineering Research Council of Canada
- FP7 Ideas: European Research Council (311422)
- FP7 Nanosciences, Nanotechnologies, Materials and new Production Technologies
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- cell fate, extracellular matrix microenvironment, matrix elasticity, cell-matrix interactions, mouse embryonic stem cells, self-renewal, stem cell differentiation, mechanical signalling
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Cell Survival, Extracellular Matrix, Hydrogel, Polyethylene Glycol Dimethacrylate, Tissue Array Analysis, Mice, Embryonic Stem Cells
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