Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids
Summary: In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220305605 |
| _version_ | 1818340718671822848 |
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| author | Woojung Shin Alexander Wu Soyoun Min Yong Cheol Shin R. Y. Declan Fleming S. Gail Eckhardt Hyun Jung Kim |
| author_facet | Woojung Shin Alexander Wu Soyoun Min Yong Cheol Shin R. Y. Declan Fleming S. Gail Eckhardt Hyun Jung Kim |
| author_sort | Woojung Shin |
| collection | DOAJ |
| description | Summary: In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-shaped hydrogel show significant size heterogeneity in different locations inside the hydrogel. Computational simulations revealed that the instability and diffusion limitation of Wnt3a constitutively generate a concentration gradient inside the hydrogel. The location-dependent heterogeneity of organoids in a hydrogel dome substantially perturbed the transcriptome profile associated with epithelial functions, cytodifferentiation including mucin 2 expression, and morphological characteristics. This heterogeneous phenotype was significantly mitigated when the Wnt3a was frequently replenished in the culture medium. Our finding suggests that the morphological, transcriptional, translational, and functional heterogeneity in conventional organoid cultures may lead to a false interpretation of the experimental results in organoid-based studies. |
| first_indexed | 2024-12-13T15:47:21Z |
| format | Article |
| id | doaj.art-d796b1ac37cb424ab58e2473ad1322ef |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-13T15:47:21Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-d796b1ac37cb424ab58e2473ad1322ef2022-12-21T23:39:40ZengElsevieriScience2589-00422020-08-01238101372Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal OrganoidsWoojung Shin0Alexander Wu1Soyoun Min2Yong Cheol Shin3R. Y. Declan Fleming4S. Gail Eckhardt5Hyun Jung Kim6Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USADepartment of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USADepartment of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USADepartment of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USADepartment of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USADepartment of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USADepartment of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton St., Austin, TX 78712, USA; Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Corresponding authorSummary: In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-shaped hydrogel show significant size heterogeneity in different locations inside the hydrogel. Computational simulations revealed that the instability and diffusion limitation of Wnt3a constitutively generate a concentration gradient inside the hydrogel. The location-dependent heterogeneity of organoids in a hydrogel dome substantially perturbed the transcriptome profile associated with epithelial functions, cytodifferentiation including mucin 2 expression, and morphological characteristics. This heterogeneous phenotype was significantly mitigated when the Wnt3a was frequently replenished in the culture medium. Our finding suggests that the morphological, transcriptional, translational, and functional heterogeneity in conventional organoid cultures may lead to a false interpretation of the experimental results in organoid-based studies.http://www.sciencedirect.com/science/article/pii/S2589004220305605CancerComputer ModelingTissue Engineering |
| spellingShingle | Woojung Shin Alexander Wu Soyoun Min Yong Cheol Shin R. Y. Declan Fleming S. Gail Eckhardt Hyun Jung Kim Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids iScience Cancer Computer Modeling Tissue Engineering |
| title | Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids |
| title_full | Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids |
| title_fullStr | Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids |
| title_full_unstemmed | Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids |
| title_short | Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids |
| title_sort | spatiotemporal gradient and instability of wnt induce heterogeneous growth and differentiation of human intestinal organoids |
| topic | Cancer Computer Modeling Tissue Engineering |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220305605 |
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