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Stem Cells in Focus

Ramping up Discovery with Kidney Organoids

By Maya Chaddah | April 4, 2014
Expert Contributor: Melissa Little, PhD

Although they conjure up images of science fiction, organoids are actually the quirky new name for mini, lab-grown models of human organs. Scientists are using pluripotent stem cells – the master cells that make any cell in the body – to create small buds of brain, thymus, liver, intestine, eye or kidney tissue that replicate some of the functions we find in these organs.

There was great excitement in 2013 when Australian scientist, Prof. Melissa Little, at The University of Queensland’s Institute for Molecular Bioscience in Brisbane, Australia saw tiny buds of tissue growing in a dish that looked like embryonic kidneys. Originally a cancer geneticist, she had spent years studying the genes and pathways that lead to the formation of Wilm’s tumor, a kidney cancer found in children. As the connections between abnormal kidney formation during development and kidney dysfunction in children became apparent, she began exploring new ways to help individuals with kidney disease.

In the 15 years since Prof. Little started focusing on kidney development, renal disease and repair, the rates of chronic kidney disease have skyrocketed globally, due in large part to conditions like diabetes, hypertension (high blood pressure), glomerulonephritis (immune-mediated disease) and cardiovascular disease. Although the adult kidney can repair some damage – for example, after a night of excessive alcohol, a period of dehydration, rapid blood loss, or exposure to chronic toxins – it cannot grow new nephrons, which are vital to its function, after we are born. So chronic kidney damage takes its toll and ultimately leaves individuals on dialysis or awaiting kidney transplants, which are in very short supply.

The kidney is a very complex organ, comprised of 250,000 to 2 million nephrons that filter the blood (about 5 cups/minute), resorb nutrients and excrete waste. Each nephron is shaped like the head of a wrench leading into a long convoluted tube that bends and winds. Blood is filtered at the head of the wrench and different points along the tube take back what the body needs – ions, amino acids and water. The tube then dumps what the body doesn’t want into a large pipe called the ‘collecting duct,’ which funnels the waste to the bladder for excretion. Any condition that repeatedly affects the ability of the nephrons to filter the blood can lead to a build-up of kidney damage over time.

Prof. Little’s team was keen to understand kidney development in humans. Because the adult human kidney cannot make new nephrons, they attempted to replicate the process by which nephrons develop in the human embryo, using cultured cells grown in the laboratory. This involved identifying the conditions under which embryonic stem cells – derived from the earliest unspecialized cells in an embryo – can be coaxed to make mesoderm, the layer of cells in the early embryo with the potential to make kidney cells. From there, they developed a very tight, quality controlled method for reproducibly making nephron progenitors, the cells which make nephrons, as well as early nephrons and collecting duct cells.

What Prof. Little’s team finds amazing is how exactly these types of cells, the nephrons and their progenitors and collecting duct cells, self-assemble into three dimensional structures outside the body, in a totally artificial lab environment. She likens the mystery to when animals are born and immediately just know how to stand up and go to their mothers. The kidney organoids her team can grow right now are only tiny buds of tissue, much smaller than normal kidneys and less complicated, but clearly with the same kinds of cells found in an embryo making a kidney. The next steps are to keep pushing the kidney organoids down the developmental pathway that ends with fully functional organs, and then to investigate whether the nephrons could do their job if given a blood supply.

Prof. Little sees a few ways that functional kidney organoids could open new avenues of discovery in the near future:

  1. Kidney organoids are made with human cells, so they mimic early human kidney development more closely than mouse models, allowing researchers to better study the organ and its diseases
  2. Kidney organoids promise a more patient-specific way to model what goes wrong in disease. If researchers are able to accurately and quickly replicate the types of mutations found in particular patients, they can better treat them (eventually leading to more directed treatments)
  3. Kidney organoids could become test beds for assessing whether experimental drugs are toxic to the kidney – lack of adequate testing models is one of the main reasons that drug development fails and incurs such enormous costs

Because the kidney is such a large, complex organ, it is unlikely that scientists will be able to grow life-sized kidneys for the purpose of transplantation. But in the distant future, even tiny kidney organoids might provide enough functional filtration to benefit patients. There is still a long, long way to go, but just being able to make kidneys organoids is bringing scientists like Melissa Little one step closer to helping people with chronic kidney disease.

 

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