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Bypassing stem cells

Auteur: Nienke Beintema | Publicatiedatum:

Pascale Guillot, keynote speaker at the Figon Dutch Medicines Days, heads a London group that is revolutionising stem cell research. ‘It is not the stem cells themselves but their chemical products that have immense clinical potential. So why not focus on these molecules instead?’

Bone marrow, skin, umbilical cord blood, or fetal tissue: finding the ideal source of stem cells has been tantalising scientists around the world. Their quest has been characterised by trade-offs and ethical controversy. Embryonic stem cells are still considered scientifically ideal, as they are pluripotent: they have the ability to develop into all cell types. Generating embryos solely for science, however, is considered questionable in terms of ethics. Next best are fetal stem cells. Although not pluripotent, they still retain the ability to develop into many different lineages, making them ideal candidates for use in regenerative medicine. However, coming from the tissues of terminated pregnancies, they too represent a contentious source. Adult stem cells, next in line, are readily available but are not as plastic as fetal stem cells and they age faster in culture.

Stem cells can be rejuvenated, or reprogrammed, to regain the ability to function as younger cells again and resemble embryonic stem cells. However, cellular reprogramming to pluripotency traditionally involves using viruses to insert new DNA into the genome. In short, stem cells are a proverbial can of worms.

Nevertheless, 2012 saw a significant breakthrough. The group headed by French scientist Pascale Guillot at University College London – keynote speaker at the Dutch Medicines Days – presented promising results with amniotic fluid stem cells. These fetal cells can be found in the fluid surrounding the fetus in the womb.

These stem cells had been discovered a decade earlier. What was new in 2012?

‘Amniotic fluid stem cells, or AFSCs, are not pluripotent. While their plasticity is intermediate between that of embryonic stem cells and adult stem cells they can be reprogrammed to become pluripotent again. We developed a method to rejuvenate AFSCs by using a chemical, called  valproic acid, which alters the epigenetics of the cell. In other words, it can reactivate genes that have been switched off during the cells’ development. This was the first evidence that you can revert human cells to pluripotency without using viruses and foreign genetic material.’

What are the advantages of using AFSCs, compared to stem cells from other sources?

‘For one thing, it opens the possibility of treating babies with their own fetal stem cells or with the fetal stem cells from another healthy baby, even before they are born.

‘You can treat babies with their own fetal stem cells’

These cells can be obtained relatively easily during pregnancy, during a routine procedure called amniocentesis – often performed anyway, for prenatal testing. Secondly, AFSCs don’t trigger an immune response in another person.’

What is the main potential application of AFSCs?

‘Most of our research focuses on counteracting bone loss, for instance in diseases like brittle bone disease and juvenile osteoporosis – but also in people who are immobilised, who travel in space for prolonged periods of time, or who experience bone problems due to menopause or ageing in general. Our research shows that AFSCs stimulate bone regeneration. But we also showed that they can decrease brain inflammation in neonates.’

This all sounds very promising. Then why are stem cell therapies developing so slowly?

‘I don’t necessarily agree with that. There’s a lot going on, and very quickly as well. More than 250 clinical trials are in progress using human mesenchymal stem cells for different applications. Some stem cells are available on the shelf already, for example MAPC stem cells (multipotent adult progenitor cells, Ed.). And there is an ongoing clinical trial to treat brittle bone disease with fetal stem cells. But I think there’s a huge gap between what the public knows and what’s actually going on. Negative sentiments surrounding fetal cells are still dominating the public debate.’

What should be done about that negative reputation?

‘We are doing our best to communicate our results to the general public with the help of charity organisations and their websites. But most importantly, I think we need to show through our research the enormous potential of uncontroversial stem cells, like AFSCs. We need to show that stem cells have this unique ability to boost the cellular metabolism of the recipient.’

Is that how they work? It is not the stem cells themselves that become, say, bone cells?

‘Exactly. Stem cells are little factories of chemicals, for instance growth factors. It is those chemicals that stimulate a person’s own bone cells to step up their performance. Stem cells release these growth factors in small vesicles.

‘We want to produce these factors synthetically’

We are now studying those vesicles and their contents in order to understand how they work exactly. It’s not an easy task because these vesicles contain a huge amount of different chemicals and we suspect that they work in interaction. And also that they trigger cascades of reactions in the recipient’s cells. Only if we understand this chemistry in more detail can we try to mimic these vesicles and produce these chemicals synthetically. Then we would no longer have to use stem cells at all. I think that will be a reality within the next 3 to 5 years.’

And 10 to 15 years from now?

‘Then we’ll definitely know which factors are responsible for regenerating specific  tissues or reducing inflammation. And we’ll better understand the mechanisms by which stem cells work. We’ll be able to produce most of these factors synthetically. Ideally, we would use them to treat all kinds of pathologies – and to promote healthy ageing.’

People will become older?

‘Not necessarily. Lifespan is one thing – and I don’t know if our approach can affect that – but quality of life is something entirely different.  Are you healthy and active, doing the things that you love – or do you spend your days crippled in a wheelchair? All this focus on living longer… A better quality of life is very big in itself. I have always had that in mind; from the moment I knew I wanted to be a scientist.’ 

 

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