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Title: The human kidney extracellular matrix : composition and function
Author: Kong, Qingyang
ISNI:       0000 0004 9359 1961
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available