Bioengineering the Human Intestinal Mucosa and the Importance of Stromal Support for Pharmacological Evaluation In Vitro

Freer, Matthew; Cooper, Jim; Goncalves, Kirsty; Przyborski, Stefan

Abstract

Drug discovery is associated with high levels of compound elimination in all stages of develop-ment. 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 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.

Citation

Freer, M., Cooper, J., Goncalves, K., & Przyborski, S. (2024). Bioengineering the Human Intestinal Mucosa and the Importance of Stromal Support for Pharmacological Evaluation In Vitro. Cells, 13(22), Article 1859. https://doi.org/10.3390/cells13221859

• Journal Article Type: Article
• Acceptance Date: Nov 5, 2024
• Online Publication Date: Nov 8, 2024
• Publication Date: 2024-11
• Deposit Date: Nov 7, 2024
• Publicly Available Date: Nov 20, 2024
• Journal: Cells
• Electronic ISSN: 2073-4409
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 22
• Article Number: 1859
• DOI: https://doi.org/10.3390/cells13221859
• Public URL: https://durham-repository.worktribe.com/output/3084984