MND stem cell study identifies TDP-43 astrocytes as not toxic to motor neurones

Funded by the MND Association, international researchers have used stem cell technology to learn more about the relationship between motor neurones and their support cells.

These findings highlight the potential of stem cell technology as a tool to create new human ‘in a dish’ cellular models of disease to learn more about the causes of MND.

Prof Siddharthan Chandran and Sir Prof Ian Wilmut at University of Edinburgh looking at a stem cell image

The research group included MND Association funded researchers Prof Siddharthan Chandran and Sir Prof Ian Wilmut from University of Edinburgh, Prof Chris Shaw from King’s College London and Prof Tom Maniatis from Columbia University in America.

This important finding was published in the scientific journal PNAS on 11 February 2013. This new finding follows on from previous work published by this research group in 2012 where they demonstrated the proof of principle of creating human motor neurones with MND in a dish.

Why we need an astrocyte model of MND

Astrocytes, so called because of their star-like appearance, normally act as neurone support cells to nourish and protect motor neurones. They act with motor neurones to ensure that they can continue to function.

From previous studies, we know that when these cells begin to dysfunction, they can become toxic to motor neurones to contribute to MND. Finding out why astrocytes can cause motor neurones to degenerate is an issue of ongoing debate – we recently gave an update on this from the International Symposium.

Being able to grow human astrocytes in a laboratory dish is of importance to be able to learn more about the relationship between astrocytes and motor neurones in MND.

Creating human astrocytes in a dish

Using cutting-edge stem cell technology, the research group reprogrammed skin cells into astrocytes in a laboratory dish. The skin cells were donated by people with MND who have a family history of the disease caused by known mistakes in a gene called TDP-43.

Led by Prof Chandran and colleagues, the research group aimed to identify whether these cells would develop the ‘hallmarks’ of MND in a laboratory dish.

By studying the characteristics of these human astrocytes with faults in the TDP-43 gene, the research group identified that they shared the same qualities as cells affected by MND. The astrocytes had increased levels of TDP-43 found in areas where it isn’t usually found – outside of the control centre of the cell. They also found that the astrocytes didn’t survive as long as astrocytes created from skin cells of people that didn’t have MND.

This means that the human astrocytes created by Prof Chandran and colleagues using stem cell technology develop MND-like characteristics. This new model can be used to study how motor neurones develop the disease in a system that is directly relevant to people living with MND.

Answering whether faulty astrocytes affect healthy motor neurones

The next question that this research group wanted to answer was whether these faulty astrocytes had an effect on healthy motor neurones.

By growing faulty TDP-43 astrocytes with healthy motor neurones, the research group identified that the survival of motor neurones was not adversely affected.

This was surprising as other research groups have shown that when astrocytes have faults in the SOD1 gene (which cause one in five cases of MND with a family history) that motor neurones are compromised, even if the motor neurones were originally healthy.

TDP-43 is found within tangled lumps in over 90% of cases of MND (irrespective of whether it was caused by an inherited genetic mistake). However, when MND is caused by SOD1, TDP-43 is not found in these tangled lumps. This important difference could be leading to the key difference in whether astrocytes become toxic to contribute to causing MND.

These findings will of course need to be verified by an independent research group to determine that they are valid, but the results suggests that SOD1 and TDP-43 could be causing havoc in motor neurones in slightly different ways, both avenues leading to MND.

Our Director of Research Development, Dr Brian Dickie comments: “From a therapeutic perspective this is important because it means that specific treatments targeted at astrocytes may only be relevant and effective, in specific subsets of patients who will have to be carefully selected for drug trials.”

References:

Our news release on this finding.

March 2012 finding: Association-funded stem cell study achieves milestone

Serio A et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. PNAS 2013

Mixing with the media

Brian with Profs Chandran and Wilmut

It’s Friday afternoon and I’m just back from a press briefing in London, where we were unveiling an exciting new stem cell research programme. I’ve just realised that we’ve put a press embargo on until Monday, so this won’t be posted until Monday morning – otherwise I’ll be breaking our own embargo…..

The press briefing was held in the Science Media Centre  . The SMC plays a vital role in bringing scientists and the media together, to assist with the accuracy of reporting of scientific issues in the public eye. We’ve developed a very good relationship with them, having held several press conferences at the SMC offices over the years. They were having a frenetic time of it this morning – not only were they setting up our press conference, but they were also dealing with the story of Craig Ventner creating a ‘man-made’ bacterium, which was all over the papers (“Dr God creates artificial life in lab”, was the none-too subtle heading in my morning paper).

‘Dr God’ probably had an impact on the number of journalists in attendance, as many were still out and about following up other reporting angles, but we still managed to attract quite a few of the top science correspondents from TV and radio (BBC, Channel 4) newspapers (Telegraph, Times, Daily Mail) medical press (BMJ) as well as the Press Association (which ensures that the story will go out on the newswire).

By the time I arrived, two of the researchers involved in the project (Prof Siddarthan Chandran and Prof Ian Wilmut from Edinburgh University) were already there. It was straight into the press briefing, where Siddarthan led off by setting out the background to the research programme, for the assembled reporters. Recent advances in stem cell research mean that researchers are now able to model human MND in the lab. Siddarthan explained the promise that research using induced pluripotential stem cells holds for advancing our understanding of MND and for developing methods for the efficient screening potential therapeutic compounds. This is a field that is moving quickly – less than a couple of years ago, the idea that a skin cell could be turned back into a stem cell and then into a motor neuron, would have graced the pages of a Sci-Fi magazine rather than a medical journal.

Prof Ian Wilmut explained in more detail how the stem cells are created in the Edinburgh lab and I followed up by outlining how the other research teams in this initiative, led by Prof Chris Shaw (King’s College London) and Prof Tom Maniatis (Columbia University, New York) would analyse how the cells react under healthy conditions and also under conditions that mimic the damaging cellular environment that occurs in the brain and spine of people with MND. A key message that all three of us put across the importance of international collaboration – if we are going to crack this disease, we have to ensure that the best researchers in the world are working together on the big questions.

You could tell it was a collection of science reporters in the room by the high percentage of intelligent questions – not something you always get when discussing science with the media. Hopefully this press briefing will be the first of many as this and complementary MND research programmes around the world, start to gather pace.

PS – Monday morning. Quite a bit of press coverage, some accurate (well done The Scotsman!) some not quite on the button, but all helping to raise awareness of MND!