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Human kidney extracellular matrix hydrogels as a natural 3D platform for bioengineered models of kidney fibrosis
Chronic kidney disease (CKD), which is characterised by progressive fibrosis and decline in renal function over time, leads to thousands of premature deaths each year, diminishes quality of life and represents a significant financial burden on the NHS. Each month, approximately 600 more people in the UK will reach end-stage renal disease (ESRD), the most advanced form of CKD, and will require life-saving therapy in the form of dialysis and/or transplantation. Tubulointerstitial fibrosis is the final common pathway of most progressive renal diseases and effective anti-fibrotic drugs that ameliorate CKD are lacking. Transplantation is the ultimate treatment but the number of patients on the waiting-list far exceeds availability of donors, and despite advances, long-term survival of transplants has remained largely unchanged for the last two decades. In addition, recipients must remain on immunosuppression that increases the risks of long-term morbidity. The aim of the work is to develop, characterize, and validate a novel in vitro 3D human kidney organoid culture system ultimately aimed at screening for compounds capable of modulating the tubulointerstitial microenvironment crosstalk that perpetuates development of fibrosis in CKD. Kidney organoids will be developed using adult human renal cells combined with hydrogels derived from decellularized adult human kidney extracellular matrix (ECM). Although current synthetic and xenogenic ECM (eg. Matrigel) hydrogels offer robust mechanical support for in vitro cell culture, they lack the necessary organ-specific biochemical and mechanical cues to promote endogenous cell function. Our hypothesis is that scaffolds composed of native kidney ECM will support more optimal organoid development by providing an organ-specific 3D human renal microenvironment.
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