Human neural tube morphogenesis in vitro by geometric constraints
Open accessPublished version of a preprint
Abstract
Understanding human organ formation is a scientific challenge with far-reaching medical implications 1,2. Three-dimensional stem-cell cultures have provided insights into human cell differentiation 3,4. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction 5,6, neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients 7. Our approach provides a new route to the study of human organ morphogenesis in health and disease.
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Topographical cues such as curvature and the shape of neighboring cells can influence stem cell decisions.
“Topographical cues, such as curvature and shape of neighboring cells, can affect stem cell decisions25.”
From Organoids (2022) · cites this paper as [25]
The ‘Reproducible morphogenesis with stem cells’ section describes a geometrically controlled configuration as a starting point for cell-fate patterning. But the paper does not show that curvature or the shape of neighboring cells affects stem-cell fate decisions; ‘Neural plate size sets neural tube shape’ reports no change in cell fate with tissue size, despite changes in fold shape. The copy provides no page numbers for these passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe topography of the substrate modulates cell area, shape, and cell-cell interactions, producing biochemical signals that can affect stem cell fate.
“the topography of the substrate is known to modulate cell area, shape, and cell-cell interactions, resulting in biochemical signals that can affect stem cell fate25.”
From Organoids (2022) · cites this paper as [25]
In “Reproducible morphogenesis with stem cells” (page not provided), the paper says surface micropatterning controls the size, density, and shape of stem-cell cultures and provides a physical and biochemical starting point for cell-fate patterning. It does not establish the claimed chain in which substrate topography changes individual cell area, shape, and cell–cell interactions, thereby producing biochemical signals that affect fate. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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- Authors
- Karzbrun, E., Khankhel, A. H., Megale, H. C., Glasauer, S. M. K., Wyle, Y., Britton, G., Warmflash, A., Kosik, K. S., Siggia, E. D., Shraiman, B. I., & Streichan, S. J.
- Affiliations
- University of California, Santa Barbara (US)
- Rice University (US)
- Rockefeller University (US)
- Corresponding author
- Karzbrun, Eyal
- Streichan, Sebastian J.
- ORCID
- Venue
- Nature
- Published
- 2021-10-27
- Volume
- 599
- Issue
- 7884
- Pages
- 268-272
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8828633
- OpenAlex
- W3210728577
- Cited by
- 246
- References
- 43
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 44 · 2023: 58 · 2022: 40 · 2021: 4
- FWCI
- 11.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186800, 174753)
- National Institute of General Medical Sciences (R01GM126122)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD099598)
- Topics
- 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
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- neural tube morphogenesis, human stem cells, organoid culture, neural induction, neuroectoderm, extracellular matrix synthesis, cell adhesion, neural tube defects, anterior-posterior axis, organ shape, organ formation
- MeSH terms
- Ectoderm, Humans, Models, Biological, Morphogenesis, Neural Tube Defects, Organ Culture Techniques, Regeneration, Stem Cells, Neural Plate, Neural Tube
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