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Adv Mater. 2018 Oct;30(43):e1801621. doi: 10.1002/adma.201801621. Epub 2018 Sep 10.

Growth of Epithelial Organoids in a Defined Hydrogel.

Author information

1
Department of Health Sciences and Technology, ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland.
2
Institute of Molecular Health Sciences, ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland.
3
Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Zurich, 8091, Switzerland.
4
Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland.
5
Department of Biomedicine, University Hospital Basel, University of Basel, Basel, CH-4031, Switzerland.
6
Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, CH-4031, Switzerland.
7
Charles River Research Services Germany GmbH, Am Flughafen 12, 79108, Freiburg im Breisgau, Germany.

Abstract

Epithelial organoids are simplified models of organs grown in vitro from embryonic and adult stem cells. They are widely used to study organ development and disease, and enable drug screening in patient-derived primary tissues. Current protocols, however, rely on animal- and tumor-derived basement membrane extract (BME) as a 3D scaffold, which limits possible applications in regenerative medicine. This prompted us to study how organoids interact with their matrix, and to develop a well-defined hydrogel that supports organoid generation and growth. It is found that soft fibrin matrices provide suitable physical support, and that naturally occurring Arg-Gly-Asp (RGD) adhesion domains on the scaffold, as well as supplementation with laminin-111, are key parameters required for robust organoid formation and expansion. The possibility to functionalize fibrin via factor XIII-mediated anchoring also allows to covalently link fluorescent nanoparticles to the matrix for 3D traction force microscopy. These measurements suggest that the morphogenesis of budding intestinal organoids results from internal pressure combined with higher cell contractility in the regions containing differentiated cells compared to the regions containing stem cells. Since the fibrin/laminin matrix supports long-term expansion of all tested murine and human epithelial organoids, this hydrogel can be widely used as a defined equivalent to BME.

KEYWORDS:

fibrin; hydrogels; organoids

PMID:
30203567
DOI:
10.1002/adma.201801621
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