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Supervisors names
Professor David Long / Dr Karen Price
Professor Paolo de Coppi
Background
Around 1,000 people in the UK are living with childhood kidney failure. These children’s kidneys fail in infancy, meaning they begin dialysis early, often receiving their first of several kidney transplants before their tenth birthday. These two life-saving yet debilitating interventions are the only options available for these children. The field of regenerative medicine may provide a new therapeutic avenue, with research over the last decade leading to the production of kidney-like organoids; synthetic mini-organs resembling primitive kidneys. Organoids have gained attention as diagnostic tools to replace animal testing and drug development, but they may also have therapeutic potential by supplementing renal function to slow or prevent kidney failure.
However, to-date, researchers have been unable to implant these organoids successfully, because of the ‘transfer challenge’. The ‘transfer challenge’ means finding a way to move an organoid from a dish into a human or first, an animal recipient body and provide nutrients, normally delivered by the blood, to keep it alive. This project aims to solve this challenge in an innovative and multi-disciplinary way. Our solution centres around two technologies: building a ‘delivery scaffold’ that mimics the environment within the kidney by combining polymer and decellularised kidney material with modern fabrication techniques. Secondly, we will use a second organoid of blood vessel origin to surround and integrate with the kidney organoid to develop into a combined ‘renovascular’
organoid. We predict that this combination of delivery scaffold containing a rich and dense blood vessel network will enhance the survival of implanted organoids and replicate the majority of the blood-filtration features of a real kidney to enable function. We will take the above technologies through a pathway of individual refinements and additions to individually optimise each. This will allow us to achieve the following objectives.
Aims/Methods and Timeline
1) Optimise a hybrid delivery scaffold using a combination of decellularised matrix and biomaterials (0-15 months).
We will generate a hybrid scaffold using a combination of electrospun poly-lactide glycolic acid (PLGA) with decellularised matrix obtained from either piglet or human fetal kidneys. We will evaluate how different proportions of matrix to PLGA influence blood vessel growth.
2) Co-embed kidney and vascular organoids together into hybrid scaffolds which will then be placed on the chick chorioallantoic membrane to promote vessel growth (13-24 months).
Success will be judged by the size and number of surviving organoids and their internal architecture as well as the closeness of their final transcriptome profile to real human kidney datasets.
3) Evaluate renovascular organoids within delivery scaffolds in-vivo (25 - 36 months)
We will transfer the optimised renovascular organoid-in-delivery scaffold unit into immune compromised mice recipients. Using fluorescent-labelled markers, we will assess urine production, indicative of a functional kidney organoid.
By the end of this studentship, we hope to build a ‘renovascular organoid’ combining elements of both a kidneys filtering capacity and full infrastructure of blood vessels on a scaffold that a surgeon can handle. Taken together we hope this will be a proof-in-concept of an organoid-based medical device that can treat the life-limiting early kidney failure in children.
References
1. Takasato M, et al Nature. 2015 526: 564-568.
2. Wimmer RA, et al Nature. 2019 565: 505- 510.
3. Randles MJ, et al J Am Soc Nephrol 2015 26: 3021-3034.
4. Urbani L, et al Nat Commun. 2018 9: 4286.
5. Price KL, Cell Death Discov 2018 4: 13.
Contact
Professor David Long, d.long@ucl.ac.uk