Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions
Open accessAbstract
Human enteroids-epithelial spheroids derived from primary gastrointestinal tissue-are a promising model to study pathogen-epithelial interactions. However, accessing the apical enteroid surface is challenging because it is enclosed within the spheroid. We developed a technique to reverse enteroid polarity such that the apical surface everts to face the media. Apical-out enteroids maintain proper polarity and barrier function, differentiate into the major intestinal epithelial cell (IEC) types, and exhibit polarized absorption of nutrients. We used this model to study host-pathogen interactions and identified distinct polarity-specific patterns of infection by invasive enteropathogens. Salmonella enterica serovar Typhimurium targets IEC apical surfaces for invasion via cytoskeletal rearrangements, and Listeria monocytogenes, which binds to basolateral receptors, invade apical surfaces at sites of cell extrusion. Despite different modes of entry, both pathogens exit the epithelium within apically extruding enteroid cells. This model will enable further examination of IECs in health and disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
β4 integrin expressed by intestinal organoids is distributed only at the basal surface, while β1 integrin is required for proper apical-basal polarization.
“β4 integrin expressed by intestinal organoids is distributed only at the basal surface94, while β1 integrin is required for proper apical-basal polarization95–97.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [97]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · see citing works
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,517 · see citing works
Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro
Spence, J. R., Mayhew, C. N., Rankin, S. A., Kuhar, M. F., Vallance, J. E., Tolle, K. A., Hoskins, E. E., Kalinichenko, V. V., Wells, S. I., Zorn, A. M., et al. (2010) · Nature · doi:10.1038/nature09691 · Cited by 1,911 · see citing works
Replication of human noroviruses in stem cell–derived human enteroids
Ettayebi, K., Crawford, S. E., Murakami, K., Broughman, J. R., Karandikar, U., Tenge, V. R., Neill, F. H., Blutt, S. E., Zeng, X.-L., Qu, L., et al. (2016) · Science · doi:10.1126/science.aaf5211 · Cited by 1,305 · see citing works
In Vitro Expansion of Human Gastric Epithelial Stem Cells and Their Responses to Bacterial Infection
Bartfeld, S., Bayram, T., van de Wetering, M., Huch, M., Begthel, H., Kujala, P., Vries, R., Peters, P. J., & Clevers, H. (2015) · Gastroenterology · doi:10.1053/j.gastro.2014.09.042 · Cited by 820 · see citing works
SalmonellaInteractions with Host Cells: Type III Secretion at Work
Galán, J. E. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.53 · Cited by 730 · see citing works
In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture
Miyoshi, H., & Stappenbeck, T. S. (2013) · Nature Protocols · doi:10.1038/nprot.2013.153 · Cited by 724 · see citing works
<i>Salmonella</i>, the host and disease: a brief review
Coburn, B., Grassl, G. A., & Finlay, B. B. (2007) · Immunology & Cell Biology · doi:10.1038/sj.icb.7100007 · Cited by 690 · see citing works
Listeria monocytogenes: a multifaceted model
Hamon, M. A., Bierne, H., & Cossart, P. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1413 · Cited by 613 · see citing works
VanDussen, K. L., Marinshaw, J. M., Shaikh, N., Miyoshi, H., Moon, C., Tarr, P. I., Ciorba, M. A., & Stappenbeck, T. S. (2015) · Gut · doi:10.1136/gutjnl-2013-306651 · Cited by 525 · see citing works
Sellin, M. E., Müller‐Hauser, A. A., Felmy, B., Dolowschiak, T., Diard, M., Tardivel, A., Maslowski, K. M., & Hardt, W. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.07.001 · Cited by 404 · see citing works
Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia
Knodler, L. A., Vallance, B. A., Celli, J., Winfree, S., Hansen, B. T., Montero, M., & Steele‐Mortimer, O. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006098107 · Cited by 395 · see citing works
Saxena, K., Blutt, S. E., Ettayebi, K., Zeng, X.-L., Broughman, J. R., Crawford, S. E., Karandikar, U. C., Sastri, N. P., Conner, M. E., Opekun, A. R., et al. (2016) · Journal of Virology · doi:10.1128/jvi.01930-15 · Cited by 375 · see citing works
β1-Integrin Orients Epithelial Polarity via Rac1 and Laminin
Yu, W., Datta, A., Leroy, P., O’Brien, L. E., Mak, G. Z., Jou, T., Matlin, K. S., Mostov, K. E., & Zegers, M. M. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-05-0435 · Cited by 361 · see citing works
Başak, O., Beumer, J., Wiebrands, K., Seno, H., van Oudenaarden, A., & Clevers, H. C. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.11.001 · Cited by 350 · see citing works
Salmonella Interactions with Polarized Human Intestinal Caco-2 Epithelial Cells
Finlay, B. B., & Falkow, S. (1990) · The Journal of Infectious Diseases · doi:10.1093/infdis/162.5.1096 · Cited by 320 · see citing works
Defining Lipid Transport Pathways in Animal Cells
Pagano, R. E., & Sleight, R. G. (1985) · Science · doi:10.1126/science.4035344 · Cited by 293 · see citing works
New insights into the molecular mechanism of intestinal fatty acid absorption
Wang, T. Y., Liu, M., Portincasa, P., & Wang, D. Q. ‐. (2013) · European Journal of Clinical Investigation · doi:10.1111/eci.12161 · Cited by 266 · see citing works
Laminin polymerization in vitro. Evidence for a two-step assembly with domain specificity.
Yurchenco, P. D., Tsilibary, E. C., CHARONIS, A. S., & Furthmayr, H. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)39656-4 · Cited by 265 · see citing works
Jensen, V. B., Harty, J. T., & Jones, B. D. (1998) · Infection and Immunity · doi:10.1128/iai.66.8.3758-3766.1998 · Cited by 217 · see citing works
Listeria monocytogenes Invades the Epithelial Junctions at Sites of Cell Extrusion
Pentecost, M., Otto, G. M., Theriot, J. A., & Amieva, M. R. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020003 · Cited by 215 · see citing works
Self-citationZhang, Y., Wu, S., Xia, Y., & Sun, J. (2014) · Physiological Reports · doi:10.14814/phy2.12147 · Cited by 203 · see citing works
Invasion of HeLa Cells by Salmonella typhimurium: A Model for Study of Invasiveness of Salmonella
Giannella, R. A., Washington, O., Gemski, P., et al. (1973) · The Journal of Infectious Diseases · doi:10.1093/infdis/128.1.69 · Cited by 185 · see citing works
Wang, A. Z., Ojakian, G. K., & Nelson, W. J. (1990) · Journal of Cell Science · doi:10.1242/jcs.95.1.153 · Cited by 181 · see citing works
Bartfeld, S., & Clevers, H. C. (2015) · Journal of Visualized Experiments · doi:10.3791/53359 · Cited by 160 · see citing works
Morphologic and Molecular Characterization of Salmonella typhimurium Infection in Neonatal Calves
Santos, R. L., Zhang, S., Tsolis, R. M., Bäumler, A. J., & Adams, L. G. (2002) · Veterinary Pathology · doi:10.1354/vp.39-2-200 · Cited by 148 · see citing works
Dynamic Behavior of Salmonella‐Induced Membrane Tubules in Epithelial Cells
Drecktrah, D., Levine‐Wilkinson, S., Dam, T., Winfree, S., Knodler, L. A., Schroer, T. A., & Steele‐Mortimer, O. (2008) · Traffic · doi:10.1111/j.1600-0854.2008.00830.x · Cited by 139 · see citing works
Trotter, P., & Storch, J. (1991) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42090-5 · Cited by 121 · see citing works
Regulation of epithelial cell surface polarity reversal by β1 integrins
Ojakian, G. K., & Schwimmer, R. (1994) · Journal of Cell Science · doi:10.1242/jcs.107.3.561 · Cited by 119 · see citing works
Pentecost, M., Kumaran, J., Ghosh, P., & Amieva, M. R. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000900 · Cited by 118 · see citing works
Self-citationHolly, M. K., & Smith, J. G. (2018) · Journal of Virology · doi:10.1128/jvi.00250-18 · Cited by 93 · see citing works
Rajan, A., Vela, L., Zeng, X., Yu, X., Shroyer, N. F., Blutt, S. E., Poole, N. M., Carlin, L. G., Nataro, J. P., Estes, M. K., et al. (2018) · mBio · doi:10.1128/mbio.02419-17 · Cited by 81 · see citing works
Lhocine, N., Arena, E. T., Bomme, P., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2014.12.003 · Cited by 74 · see citing works
Bartfeld, S., & Clevers, H. C. (2015) · Journal of Visualized Experiments · doi:10.3791/53359-v · Cited by 72 · see citing works
Criss, A. K., & Casanova, J. E. (2003) · Infection and Immunity · doi:10.1128/iai.71.5.2885-2891.2003 · Cited by 63 · see citing works
Bishop, A. L., House, D., Perkins, T. T., Baker, S. G., Kingsley, R. A., & Gordon Dougan, B. (2008) · Microbiology · doi:10.1099/mic.0.2008/016998-0 · Cited by 56 · see citing works
Proteomic Profiling of Enteroid Cultures Skewed toward Development of Specific Epithelial Lineages
Luu, L., Matthews, Z. J., Armstrong, S. D., Powell, P. P., Wileman, T., Wastling, J. M., & Coombes, J. L. (2018) · PROTEOMICS · doi:10.1002/pmic.201800132 · Cited by 14 · see citing works
Bugs and Barriers: Enteric Pathogens Exploit Yet Another Epithelial Function
Hecht, G. A. (1995) · Physiology · doi:10.1152/physiologyonline.1995.10.4.160 · Cited by 12 · see citing works
Graebert, K. S., Bauch, H.-J., Neumüller, W., et al. (1997) · Experimental Cell Research · doi:10.1006/excr.1996.3456 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hofer, M., & Lutolf, M. P. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00279-y · Cited by 1,184 · see citing works
Zhao, Z., Chen, X., Dowbaj, A. M., Sljukic, A., Bratlie, K., Lin, L., Fong, E. L. S., Balachander, G. M., Chen, Z., Soragni, A., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00174-y · Cited by 1,001 · see citing works
TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes
Zang, R., Castro, M. F. G., McCune, B. T., Zeng, Q., Rothlauf, P. W., Sonnek, N. M., Liu, Z., Brulois, K. F., Wang, X., Greenberg, H. B., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abc3582 · Cited by 982 · see citing works
Host–microbiota maladaptation in colorectal cancer
Janney, A., Powrie, F., & Mann, E. H. (2020) · Nature · doi:10.1038/s41586-020-2729-3 · Cited by 445 · see citing works
Progenitor identification and SARS-CoV-2 infection in human distal lung organoids
Salahudeen, A. A., Choi, S. S., Rustagi, A., Zhu, J., van Unen, V., de la O, S. M., Flynn, R. A., Margalef-Català, M., Santos, A. J. M., Ju, J., et al. (2020) · Nature · doi:10.1038/s41586-020-3014-1 · Cited by 416 · see citing works
Self-citationTowards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409 · see citing works
Organoids in immunological research
Bar-Ephraim, Y. E., Kretzschmar, K., & Clevers, H. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0248-y · Cited by 361 · see citing works
Applications of organoids for cancer biology and precision medicine
Lo, Y.-H., Karlsson, K., & Kuo, C. J. (2020) · Nature Cancer · doi:10.1038/s43018-020-0102-y · Cited by 182 · see citing works
Self-citationHydrogel-in-hydrogel live bioprinting for guidance and control of organoids and organotypic cultures
Urciuolo, A., Giobbe, G. G., Dong, Y., Michielin, F., Brandolino, L., Magnussen, M., Gagliano, O., Selmin, G., Scattolini, V., Raffa, P., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37953-4 · Cited by 121 · see citing works
Okkelman, I. A., Zhou, H., Borisov, S. M., Debruyne, A. C., Lefebvre, A. E. Y. T., Leomil Zoccoler, M., Chen, L., Devriendt, B., & Dmitriev, R. I. (2025) · Light: Science & Applications · doi:10.1038/s41377-025-01949-0 · Cited by 28 · see citing works
- Authors
- Co, J. Y., Margalef-Català, M., Li, X., Mah, A. T., Kuo, C. J., Monack, D. M., & Amieva, M. R.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Corresponding author
- Amieva, Manuel R.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 26
- Issue
- 9
- Pages
- 2509-2520.e4
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6391775
- OpenAlex
- W2917423992
- Cited by
- 488
- References
- 40
- Citations by year
- 2026: 58 · 2025: 76 · 2024: 64 · 2023: 81 · 2022: 80 · 2021: 72 · 2020: 46 · 2019: 9
- FWCI
- 39.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Stanford Child Health Research Institute Postdoctoral Award
- NIH (T32AI007328-29, U19AI116484-01)
- Bill and Melinda Gates Foundation (OPP1113682)
- Stanford CHSI Pilot
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- epithelial polarity, host-pathogen interaction, intestinal epithelial cells, Salmonella typhimurium, Listeria monocytogenes, cell extrusion, cytoskeletal rearrangement, intestinal barrier function, nutrient absorption, intestinal epithelial differentiation
- MeSH terms
- Cell Differentiation, Epithelial Cells, Fatty Acids, Humans, Intestinal Mucosa, Listeria monocytogenes, Models, Biological, Salmonella typhimurium, Cell Polarity, Spheroids, Cellular, Cell Culture Techniques, Host-Pathogen Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
