19 May 2011

Australians achieve kidney stem cell world-first

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With their wizardly power to conjure up any type of body tissue, embryonic stem cells promise spare parts for ailing bodies. But it turns out that some cell types are easier to produce than others.
kidney stem cells

Researchers have developed stem cells from kidney tissue. Shown here is a developing kidney with glomeruli (red) and the connecting branches (green). Credit: Sharon Ricardo, Monash Immunology and Stem Cell lab

MELBOURNE: With their wizardly power to conjure up any type of body tissue, embryonic stem cells promise spare parts for ailing bodies. But it turns out that some cell types are easier to produce than others.

Making brain or retina cells, for instance, has been fairly straightforward. Not so for kidney cells: the route to making them seems obstructed by twists and turns.

That’s been frustrating for kidney researchers trying to generate replacement cells for the tens of thousands of patients who suffer terminal kidney failure each year.

Now researchers at Monash Immunology and Stem Cell laboratories at Melbourne’s Monash University, say they have found a detour which may shorten the path to producing kidney cells.

Winding back the clock

Instead of starting with embryonic stem cells derived from surplus human embryos, they started with mature human kidney cells and wound back their developmental clock to a more embryonic state.

These cells, known as induced pluripotent stem cells or iPS cells have similar properties to embryonic stem cells – they multiply without limits and produce different types of cells.

But the researchers are hoping they will also retain a memory of their origins and find their own way back on the convoluted route to becoming kidney cells.

“We think these kidney iPS cells will be better at making kidney tissue,” says Sharon Ricardo, one of the authors of the paper which was published in this month’s issue of the Journal of the American Society for Nephrology.

Tailor-made cells

When Japanese researchers first reported making iPS cells from human skin cells in 2007, it seemed like an answer to researchers’ prayers. Generating embryonic stem cells from spare embryos is not only technically difficult, researchers faced huge resistance from powerful groups to stymie the research.

By contrast, the iPS cell method produced cells that seemed to have the same power as embryonic stem cells but was a lot easier – it just required ferrying four new genes into a skin cell via a retrovirus.

And no embryos were involved so no-one had to fret about whether souls were being destroyed. Another great advantage was that since iPS cells were made from a person’s skin cells, they could be tailor-made for a patient, eliminating concerns of tissue rejection.

By contrast, stem cells from a donated embryo would have a different tissue type to the patient that received them – so just like any organ transplant, tissue-matching and anti-rejection drugs would be needed.

Cell returns to its native state

But last year researchers reported a drawback to the iPS cells. They were not as pluripotent (able to make any tissue) as embryonic stem cells: they appeared to retain a strong ‘epigenetic’ memory of the cell type they originated from.

In practice that meant that an iPS cell made from a skin cell would rather turn back into skin than any other tissue.

That was a disappointing result if you want to make different tissues from skin iPS cells. But for Ricardo and co-author Andrew Laslett, it signalled a new opportunity.

If they could make iPS cells from kidney cells, they might not only get a cell with the ability to multiply like a stem cell but also one that would, like a homing pigeon, return to its native state.

Slotting into diseased kidney

Ricardo had access to kidney tissue from human biopsies but this tissue was a collage of some 26 different cell types.

She had to choose a single type of cell to transform into a stem cell and ultimately settled on the mesangial cell – a cell that plays the key role in filtering wastes and is also the one most often damaged in kidney disease.

The researchers’ meticulous work succeeded in producing the world’s first kidney-derived iPS cells.

Now they plan to put them to work. If they can produce copious amounts of healthy mesangial ‘filtering’ cells, they might be able to slot them back into a diseased kidney – rather like replacing the charcoal filter on your water purifier.

Unmasking causes of disease

They also plan to make kidney iPS cells from patients with inherited kidney diseases such as polycystic kidney disease and Alport disease. These cells in turn will provide human cell models to unmask how these diseases develop and search for drugs that can derail the process.

Last year researchers at the Salk Institute in San Diego used a similar approach with iPS cells made from the skin cells of children with Rett’s syndrome (a form of autism). When they triggered these cells to form brain cells, they discovered they made sparse connections, a result not seen when iPS cells were produced from healthy children.

Other kidney researchers have welcomed the step forward. “This is an exciting development for this field of medicine. It opens the door to studies that may teach us about the nature of the problem in patients with kidney disease and screening for drugs that might help,” commented Melissa Little at the University of Queensland.

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