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Engineering Complex Kidney Structures for Disease Modelling, Drug Testing, and Studying Kidney Development

Brizi, Valerio (2018). Engineering Complex Kidney Structures for Disease Modelling, Drug Testing, and Studying Kidney Development. PhD thesis The Open University.

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Abstract

Although existing kidney tissue engineering systems and cell-based strategies favoured significant advances in the field, they cannot reproduce the organ’s complex architecture. This prevented the use of these tissues in studying kidney development realistically, modelling diseases, and establishing therapeutic approaches.

To fill these gaps, we devised a 3D engineering system for rapid generation of custom-made geometrically predefined kidney units that more faithfully resemble their counterparts in vivo.

Combining 3D printing and PDMS prototyping, we fabricated differently sized and shaped scaffolds into which MDCK cells were seeded and cultured under tubulogenic conditions. Cells grew and self-assembled into branched tubules with single lumen delimited by a polarised monolayered epithelium, exhibiting kidney-specific functions.

To model polycystic kidney disease (PKD), we pharmacologically induced cyst formation within engineered tubules. Next, we tested and quantified different compounds’ effect on cyst regression, identifying new potential pharmacological treatment; we showed that 2-deoxy-D-glucose is more effective than other compounds and discovered that berberine possesses high therapeutic potential for PKD treatment.

Optimising the protocol and using different human iPSC lines, we successfully engineered functional human ureteric bud (UB)-like tubules capable of recapitulating early steps of UB morphogenesis. Exploiting these developmental capacities, we used tubules to identify a novel growth factor combination that induces budding events in a way comparable to mouse embryonic kidneys and that may therefore be involved in human UB development. Observing a marked reduction of ramified buds in tubules derived from a patient with heterozygous PAX2 mutation affected by focal segmental glomerulosclerosis, we speculated that such developmental disorder might have contributed to the patient’s condition.

Overall, these findings document that our innovative and robust technology for controlled tubule engineering provides a valuable and reliable platform for kidney disease modelling, drug discovery and developmental studies, and may lay the groundwork for creating anatomically correct kidney tissue in vitro.

Item Type: Thesis (PhD)
Copyright Holders: 2017 The Author
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM)
Associated Research Centre: IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Item ID: 53445
Depositing User: Valerio Brizi
Date Deposited: 22 May 2018 12:15
Last Modified: 10 Nov 2018 06:24
URI: http://oro.open.ac.uk/id/eprint/53445
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