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Bioengineering the human intestinal mucosa and the importance of stromal support for pharmacological evaluation in vitro [dataset] Open Access

Drug discovery is associated with high levels of compound elimination in all stages of development. The current practices for pharmacokinetic testing of intestinal absorption combines Transwell® inserts with the Caco-2 cell line and is associated with a wide range of limitations. The improvement of pharmacokinetic research relies on the development of more advanced in vitro intestinal constructs that better represent human native tissue and its response to drugs, providing greater predictive accuracy. Here, we present a humanised bioengineered intestinal construct, that recapitulates aspects of intestinal microanatomy. We present improved histotypic characteristics reminiscent of human intestine, such as a reduction in transepithelial electrical resistance (TEER) and the formation of a robust basement membrane, which are contributed to in-part by a strong stromal foundation. We explore the link between stromal-epithelial crosstalk, paracrine communication and the role of keratinocyte growth factor (KGF) as a soluble mediator, underpinning the the tissue-specific role of fibroblast subpopulations. Permeability studies adapted to a 96-well format, allow for high throughput screening and demonstrate the role of the stromal compartment and tissue architecture on permeability and functionality, which, is thought to be one of many factors responsible for unexpected drug outcomes using current approaches for pharmacokinetic testing.

Descriptions

Resource type

Dataset

Contributors

Data collector: Freer, Matthew ¹
Data curator: Freer, Matthew ¹
Contact person: Cooper, Jim ²
Creator: Goncalves, Kirsty ¹
Contact person: Goncalves, Kirsty ¹
Data curator: Goncalves, Kirsty ¹
Editor: Goncalves, Kirsty ¹
Contact person: Przyborski, Stefan ¹
Editor: Przyborski, Stefan ¹

¹ Durham University, UK
² ECACC, UK

Funder

Biotechnology and Biological Sciences Research Council

Research methods

Other description

Keyword

Intestines
Tissue engineering
Drug discovery
Fibroblast
Keratinocyte growth factor
Caco-2
Pharmacology
3D cell culture
Scaffold

Subject

Tissue engineering

Location

Language

Cited in

Identifier

ark:/32150/r26w924b89c
doi:10.15128/r26w924b89c

Rights

Creative Commons Attribution 4.0 International (CC BY)

Publisher

Durham University

Date Created

File Details

Depositor

K.E. Goncalves

Date Uploaded

14 October 2024, 09:10:03

Date Modified

14 October 2024, 14:10:20

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Characterization

File format: zip (ZIP Format)

Mime type: application/zip

File size: 52813135

Last modified: 2024:10:14 14:11:04+01:00

Filename: Intestinal_Construct_Permeability-r26w924b89c-version1.zip

Original checksum: f2f7aa63b446a430e383d54d6d21a1b7