Kong, Qingyang;
(2020)
The human kidney extracellular matrix: composition and function.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The extracellular matrix (ECM) provides structural support for cells, regulates cell function and accumulates in renal ageing and in diseases characterised by fibrosis including chronic kidney disease (CKD) and understanding the normal ECM is key to understanding pathological changes. In the kidney, information on the ECM largely derives from candidate-based studies although recently, proteomic analysis has revealed the complex composition of the human glomerular (G) ECM. Despite the accumulation of tubulointerstitial (TI) ECM provides the best prognostic indicator of progression to end-stage renal disease in CKD, information on the TI ECM is lacking. The aim of this thesis was to characterise the human TI ECM and examine how this ECM regulates cell function. Proteomic analysis of the TI ECM from 6 human kidneys, identified 140 proteins of which 75 were newly identified in the TI matrix, 4 were newly detected in the human kidney and 2 detected in the kidney of any species for the first time. Comparison with the G matrix showed both common (126 proteins) and unique proteins (14 proteins only in TI, 38 only in G). Age-related analysis revealed 8 TI ECM proteins that increased with age, while 17 G ECM proteins increased and 3 decreased, with age. A decellularisation protocol was developed to generate human kidney cortex ECM scaffolds. These scaffolds retained a complex composition (478 proteins) and ultrastructure. Repopulation with human proximal tubular epithelia, interstitial fibroblasts and podocytes, showed that ECM scaffolds promote differentiation of all three cell types. This study provides the first detailed characterisation of the human kidney TI ECM, describes a novel protocol for decellularisation of cortical tissue cubes and shows these scaffolds promote differentiation of human kidney cells. These data enhance our understanding of the human kidney ECM and form the basis for a better understanding of renal fibrosis. These scaffolds also provide the potential to develop more complex multicellular tissue mimetics to investigate ECM regulation of human kidney cell function and for use as a platform for drug screening.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The human kidney extracellular matrix: composition and function |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Kidney, ECM, Extracellular matrix, Decellularisation, Proteomics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10099120 |
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