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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Main Authors:	Woojung Shin, Alexander Wu, Soyoun Min, Yong Cheol Shin, R. Y. Declan Fleming, S. Gail Eckhardt, Hyun Jung Kim
Format:	Article
Language:	English
Published:	Elsevier 2020-08-01
Series:	iScience
Subjects:	Cancer Computer Modeling Tissue Engineering
Online Access:	http://www.sciencedirect.com/science/article/pii/S2589004220305605

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spelling	doaj-d796b1ac37cb424ab58e2473ad1322ef2020-11-25T03:56:23ZengElsevieriScience2589-00422020-08-01238101372Spatiotemporal 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
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Woojung Shin Alexander Wu Soyoun Min Yong Cheol Shin R. Y. Declan Fleming S. Gail Eckhardt Hyun Jung Kim
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
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
title	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_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_sort	spatiotemporal gradient and instability of wnt induce heterogeneous growth and differentiation of human intestinal organoids
publisher	Elsevier
series	iScience
issn	2589-0042
publishDate	2020-08-01
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.
topic	Cancer Computer Modeling Tissue Engineering
url	http://www.sciencedirect.com/science/article/pii/S2589004220305605
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Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids

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