A method to recapitulate early embryonic spatial patterning in human embryonic stem cells
Open accessAbstract
Embryos allocate cells to the three germ layers in a spatially ordered sequence. Human embryonic stem cells (hESCs) can generate the three germ layers in culture; however, differentiation is typically heterogeneous and spatially disordered. We show that geometric confinement is sufficient to trigger self-organized patterning in hESCs. In response to BMP4, colonies reproducibly differentiated to an outer trophectoderm-like ring, an inner ectodermal circle and a ring of mesendoderm expressing primitive-streak markers in between. Fates were defined relative to the boundary with a fixed length scale: small colonies corresponded to the outer layers of larger ones. Inhibitory signals limited the range of BMP4 signaling to the colony edge and induced a gradient of Activin-Nodal signaling that patterned mesendodermal fates. These results demonstrate that the intrinsic tendency of stem cells to make patterns can be harnessed by controlling colony geometries and provide a quantitative assay for studying paracrine signaling in early development.
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Technical challenges to rapid and high-throughput screening of 3D organoids have been addressed and surpassed by different means, including alternative plate design or seeding geometries.
“Technical challenges to rapid and high-throughput screening of 3D organoids have been addressed in recent years and surpassed by different means, including alternative plate design or seeding geometries16,151,152.”
From Organoids (2022) · cites this paper as [16]
The Online Methods (PDMS microwells; Cell culture) describe controlled well dimensions and seeding cells onto micropatterned surfaces. The Discussion describes this geometric confinement as a platform for studying early hESC differentiation, but discusses its use to make organoids more reproducible only as a future possibility. The paper does not show that these methods overcame challenges in rapid, high-throughput screening of 3D organoids. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTumor tissue from biopsies or surgical resections is typically processed similarly to normal tissue to isolate tumor cells for organoid growth.
“Tumor tissue, derived from either biopsies or surgical resections, is also typically processed akin to normal tissue to isolate tumour cells to grow as organoids16,49–51.”
From Organoids (2022) · cites this paper as [16]
The Discussion (page unavailable) mentions organoids generated from embryonic stem cells, and Online Methods > Cell culture (page unavailable) describes culturing human embryonic stem cells. Neither addresses processing tumour tissue from biopsies or resections to isolate cells for organoid growth; searches for those terms found no relevant passage. (LLM, conf=0.78)
Experimental — accuracy not yet measuredTumor organoids can be compared with their cancer of origin in cellular organization, tissue structure, and protein expression patterns.
“Cellular organization, tissue structure and protein expression patterns of tumor organoids can be easily compared to the cancer of origin16.”
From Organoids (2022) · cites this paper as [16]
The Discussion discusses organoids derived from embryonic stem cells, while the Results examine spatial patterning in human embryonic stem-cell colonies; page numbers are not provided in our copy. Searches for tumor organoids and comparison with a cancer of origin found no passage addressing the claimed comparison of cellular organization, tissue structure, or protein expression. (LLM, conf=0.78)
Experimental — accuracy not yet measuredOrganoids have been deployed to identify therapeutic leads in a number of tumors, including rare cancers that are understudied and poorly characterized at the molecular level.
“Organoids are ideally suited for FPM due to their ease of establishment, similarity with the tissue of origin and tractability158,167 and have been deployed to identify therapeutic leads in a number of tumors168, including rare cancers that tend to be understudied and poorly characterized at the molecular level16,151,169,170.”
From Organoids (2022) · cites this paper as [16]
The Discussion (page unavailable) mentions brain-like organoids and possible ways to make organoids more reproducible, but does not discuss tumor organoids or therapeutic leads. Searches for rare cancers, tumors, and drug screening found no passage addressing the attributed claim. (LLM, conf=0.76)
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References 40 · Cited by 885
Research works printed but not linked: 1
- [33]Tam PPL Gad JM Stern CD Gastrulation: From Cells to Embryo CSHL Press 2004
- Authors
- Warmflash, A., Sorre, B., Etoc, F., Siggia, E. D., & Brivanlou, A. H.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Siggia, Eric D
- Brivanlou, Ali H
- Venue
- Nature Methods
- Published
- 2014-06-29
- Volume
- 11
- Issue
- 8
- Pages
- 847-854
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC4341966
- OpenAlex
- W1998317358
- Cited by
- 885
- References
- 40
- Citations by year
- 2026: 66 · 2025: 90 · 2024: 94 · 2023: 78 · 2022: 88 · 2021: 114 · 2020: 84 · 2019: 75 · 2018: 69 · 2017: 49 · 2016: 38 · 2015: 33 · 2014: 7
- FWCI
- 17.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM101653)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD032105, R01 HD32105)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- human embryonic stem cells, spatial patterning, micropatterning, confined geometries, BMP4 signaling, Activin/Nodal signaling, three germ layers, mesendoderm, trophectoderm, primitive streak, paracrine signaling, self-organization, early embryonic development
- MeSH terms
- Cell Differentiation, Embryo, Mammalian, Humans, Transforming Growth Factor beta, Bone Morphogenetic Proteins, Body Patterning, Embryonic Stem Cells, Gastrulation
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