Kidney Regeneration
Our vision is to develop new treatments for inherited and chronic kidney disease. Using human stem cells to recreate kidney tissue, we hope to model kidney disease, find new therapies, and eventually develop replacement organs.
The kidney is a complex and essential organ required for maintaining fluid balance, blood volume, and electrolyte stability in the body.
The kidneys are essential organs that maintain fluid balance, blood volume, and electrolyte balance. In humans, all these functions are achieved by the approximately 1,000,000 individual nephrons present in each adult kidney. Remarkably, all of these nephrons are formed before birth, hence any disease no new nephrons can form.
In our research group, we have used our understanding of how the nephrons form during normal kidney development to recreate a model of the human kidney using pluripotent stem cells. These stem cell-derived mini-kidneys can be made using cells from patients with kidney disease.
They can also be generated using gene-edited stem cells engineered to recreate a disease state or a readout of function. Using stem cell-derived models of inherited kidney disease, we aim to screen for novel treatments. We also aim to engineer human kidney tissue to provide a source of renal replacement other than dialysis and organ transplantation.
Understanding, improving, and applying human pluripotent stem cell-derived kidney tissues
MCRI researcher, Professor Melissa Little spoke with Joel Topf, MD at American Society of Nephrology (ASN) Kidney Week 2024 about her research.
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Our projects
Rebuilding the kidney using human pluripotent stem cells
The prevalence of chronic kidney disease is continuing to rise worldwide, and with limited treatment options available and a shortage of suitable donor organs, there is a genuine need for new treatment options.
Our laboratory has pioneered methods of using stem cells to grow mini kidneys, also known as kidney organoids in the lab. Ultimately, the utility of these mini-kidney tissues will depend on how effectively they mature and replicate a normal kidney and we are currently working toward improving the structure, size and function of these organoids.
Further understanding the genetic pathways involved in the formation and maturation of each cell type during kidney development will help us better replicate normal development in a dish.
We expect this research to be revolutionary to kidney disease treatment options via two avenues: one is through patient-derived disease modelling and drug screening approaches that further our understanding of kidney diseases and lead us toward new treatment options; the second is through the regeneration of kidney tissue for transplant or the development of artificial kidneys,
Modelling kidney disease in a dish using patient-derived stem cells and drug screening
One key area of our kidney research focuses on creating stem cells from patients and recreating their kidney tissue or mini kidney organoids in our laboratories. This allows us to recreate and study their disease more closely–this method of research is called disease modelling.
If we can determine a genetic cause for the disease by studying a patient’s tissue in the laboratory, we now have the gene-editing capability and technology to correct mutations found in that patient’s genome. By comparing a patient’s genetically mutated and corrected cell lines, we can better understand a disease’s cause and progression, which informs our understanding of any potential preventative measures, tests for that disease, development of new treatments and hopefully cures.
We are also investigating whether mini-kidneys can screen for drugs that cause damage to kidney tissue or relieve the underlying causes of kidney disease.
Understanding how nephron stem cells are maintained and characterised
The kidney is a tricky organ for regenerative treatment options. A kidney has millions of functional units called ‘nephrons’ which develop from kidney stem cells in utero.
Once a child is born, no further nephrons can be created within the kidney, regardless of any damage or disease that may impact their ability to function properly. In our laboratory, we have recently discovered a method of recreating these kidney stem cells, which has enabled us to create mini-kidney ‘organoids’.
We are continuing to learn how these stem cells can be best maintained in order to improve our development of kidney organoids for regenerative treatment options, drug screening and disease modelling applications.
Other projects
- Screening for novel treatments for congenital nephrotic syndrome
- Screening for novel treatments for Autosomal recessive
polycystic kidney disease ( ARPKD) - Tissue scale-up for transplantation
- Evaluation of connectivity and vascularisation at transplantation
- Integrating collecting duct tissue into kidney organoids
- Optimisation of nephron patterning and maturation
- Evaluation of the impact of macrophages on kidney morphogenesis
Funding
- Novo Nordisk Foundation
- Medical Research Future Fund Stem Cell Therapies Mission
- Medical Research Future Fund Genomic Health Futures Mission
- National Health & Medical Research Council of Australia
- PKD Australia and PKD USA
- Department of Jobs Precincts and Regions, Victorian State Government
- National Institutes of Health, USA
Collaborations
- Leiden University Medical Center, The Netherlands
- Prof. Anton J Rabelink
- University of Pennsylvania, USA
- Dr. Alexander Hughes
- Dr. Lukasz Bujacz
- The Royal Children’s Hospital, Melbourne
- Dr. Cathy Quinlan
- Dr. Thomas Forbes
- Dr. Sue White
Featured publications
Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. 2021.
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