Stem cell-derived organs help better understand and treat disease

MCRI researchers are using cutting-edge stem cell techniques to help treat young patients with kidney disease, and offering hope that one day stem cell-derived kidneys could be used as transplants.

Looking for better options for young patients

Not that many years ago, Charlotte Matthews would have died soon after she was born. Charlotte has congenital nephrotic syndrome, a condition which caused her kidneys to leak a vital protein, making them ineffective

Drugs and surgery kept her alive while she waited for a transplant, but these treatments come with devastating side effects. It’s a painful life for children like Charlotte until they receive life-saving transplants, but it is the best available.

Murdoch Children’s Research Institute’s (MCRI) stem cell medicine and kidney researchers are looking for a better way.

Charlotte’s syndrome was caused by a specific genetic mutation, so MCRI Stem Cell researchers have modelled her disorder in the lab and looked for ways to grow the specific part of the kidney her own body was unable to, called the glomerulus, the kidney’s waste filtering unit.

By studying children like Charlotte, MCRI can develop drugs that will transform the lives of other children like her – and the millions of adults who have less severe disease worldwide.

MCRI researchers want to move kidney disease management towards personalised, stem cell-driven medicine for people across the globe. And they’re inching closer toward that goal each day. 

Charlotte Matthews, 4, is having dialysis to treat her kidney disease. She had one kidney removed when she was a baby and now relies on dialysis to survive, as she waits for a transplant, but is doing great. MCRI researchers have taken cells from her to create a 3D model of the disease to test new treatments. Charlotte Matthews with mother Jessica Taylor. Picture: Jason Edwards

Patient specific mini kidneys

MCRI’s stem cell experts broke new ground in 2018, spearheading research in which stem cells derived from a young patient were grown into two sets of living mini kidneys; one with her kidney disease and another which corrected the gene mutation.

Alex suffers from Mainzer-Saldino Syndrome, a rare genetic condition causing vision loss and kidney failure. Following her diagnosis, MCRI researchers took a skin biopsy from Alex to create stem cells and turn them into kidney tissue. The findings proved the lab-grown tissue can be used to study inherited kidney disease.

The idea is that, one day, the gene corrected kidney-tissue could be transplanted back into the patient from whom it was derived.

The discovery showed the unparalleled value of modelling a patient’s own tissue from stem cells, compared against traditional mouse models of disease.

Using gene editing to correct mutations

Led by MCRI Cell Biology Theme Director, Professor Melissa Little, the group demonstrated that gene editing could correct the mutation and stop the disease developing in the mini kidney.

“Following this result, we wanted to understand how we can use models made from a patient’s stem cells to better understand their disease and find the most appropriate drugs for treatment.”

Professor Little

Disease models created from a patient’s own cells are already helping researchers better understand conditions and develop more precise treatments. But creating enough identical organ models to meet the needs of research teams is a slow and laborious task.

Getting the results faster with the Disease Modelling and Drug Discovery Facility

The MCRI Disease Modelling and Drug Discovery Facility, led by Dr Alejandro Hidalgo, aims to speed up the production line, allowing for increased scale and precision to test new medications and deliver tailor-made treatments.

The Hon Greg Hunt MP visits MCRI to tour the Stem Cell Based Disease Modelling Facility

“With researcher clinicians working across MCRI and The Royal Children’s Hospital we have the invaluable opportunity to work with patients in the clinic and then apply that real world learning within our stem cell labs.”

Dr Hidalgo

Due to funding support received from the Stafford Fox Medical Research Foundation the team have built and equipped those facilities to an industry-leading world standard.

The facility has centralised and enhanced MCRI’s ability to use stem cells models across the eight focus disease areas of kidney, heart, blood, immune system, brain, muscle, reproductive development, and bone and cartilage disorders.

“We have experts working across many of the body’s organs and tissues, making us the largest group of researchers in Australia generating stem cells from a patient’s blood or skin cells.”

Professor Little

3D bioprinting tiny kidneys

In 2020, MCRI researchers reached another milestone when they used a 3D bioprinter to create hundreds of identical tiny human kidneys in the laboratory. This cutting-edge research raised hopes that human tissue printing will one day allow those with end-stage kidney failure to receive a bioprinted kidney instead of waiting for a donor kidney transplant.

MCRI Stem Cell researchers printed the kidneys using a stem cell paste that is fed into a 3D printer. The paste is like a “bioink” to create artificial living tissue in a dish. The mini-kidneys range from as small as a grain of rice to the size of a fingernail, and fully resemble a regular-sized kidney, with hundreds of tiny tubes and blood vessels that form the organ’s filtering structures called nephrons.

The findings of the research were published in Nature Materials. A key part of the study was to test the cells’ response to aminoglycosides, a class of antibiotics that commonly damage the kidneys, as a proof of concept for testing drug toxicities in these assays.

Professor Little said, “Generating stem cells from a patient with a genetic kidney disease, and then growing mini kidneys from them, paves the way for tailoring treatment plans specific to each patient, which could be extended to a range of kidney diseases.”

There is a massive increase in the number of people suffering from kidney disease, but only one in four patients will receive a transplant. That means three in four live on dialysis, an extremely difficult way to live.

“The mortality rate is very high and the quality of life is extremely low,” Professor Little said. “Also, dialysis is still risky as it’s effectively giving you only about 10 per cent of normal renal function. Our hope is that we will find something that is substantially better than dialysis and potentially able to be delivered to the three out of four who can’t find a matched transplant.”

How COVID-19 changed the landscape

SARS-CoV-2 brought a new set of challenges in February 2020. With growing evidence that COVID damages organs beyond lungs, MCRI’s stem cell researchers turned their focus to coronavirus.

The MCRI-led study on the effects of COVID on different organs received a Victorian Government funding boost in 2021 to further its research focus to include emerging strains, long-term symptoms and potential links between the virus and unborn children.

The additional research will build on the MCRI-led project that uses human stem cells to better understand the effects of the virus on different organ systems including the lungs, heart, kidneys, brain, immune system and blood vessels, to support the development of targeted treatments.

The scientists from MCRI, The Doherty InstituteWalter and Eliza Hall Institute of Medical Research and Monash University will now include placental tissue to gain greater insight into the effects of coronavirus on the placenta and potential transfer of the virus to the fetus.

The funding will also see the team investigate cellular mechanisms leading to lingering ‘long COVID’ issues such as fatigue and ongoing breathing problems and analyse international variants to understand the impacts of more infectious strains.

An Australian first

This is the first time research of this kind has been done in Australia, with MCRI one of only a few facilities worldwide able to study the effect of the virus on every major human organ.

Using cutting edge stem cell processing equipment, which recreates human tissues infected with COVID-19, the project has already identified issues with the heart muscle as a result of the virus disrupting oxygen supply.

The Stafford Fox Medical Research Foundation Stem Cell Based Disease Modelling Facility at MCRI also provides capacity to perform rapid drug screening to allow rapid evaluation of emerging COVID-19 treatments.

Professor Little said, “this collaborative program will increase our understanding of disease pathology, identify underlying risk factors, change clinical care to protect the patient from severe complications, facilitate the development of targeted treatment options and better prepare us for the next pandemic.”