̽��ֱ�� of Cambridge - Kevin Chalut

Cambridge scientists reverse ageing process in rat brain stem cells

Anonymous — Wed, 14 Aug 2019 17:01:45 +0000

̽��ֱ��results, published today in Nature, have far-reaching implications for how we understand the ageing process, and how we might develop much-needed treatments for age-related brain diseases.

As our bodies age, our muscles and joints can become stiff, making everyday movements more difficult. This study shows the same is true in our brains, and that age-related brain stiffening has a significant impact on the function of brain stem cells.

A multi-disciplinary research team, based at the Wellcome-MRC Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge, studied young and old rat brains to understand the impact of age-related brain stiffening on the function of oligodendrocyte progenitor cells (OPCs). These cells are a type of brain stem cell important for maintaining normal brain function, and for the regeneration of myelin – the fatty sheath that surrounds our nerves, which is damaged in multiple sclerosis (MS). ̽��ֱ��effects of age on these cells contributes to MS, but their function also declines with age in healthy people.

To determine whether the loss of function in aged OPCs was reversible, the researchers transplanted older OPCs from aged rats into the soft, spongy brains of younger animals. Remarkably, the older brain cells were rejuvenated, and began to behave like the younger, more vigorous cells.

To study this further, the researchers developed new materials in the lab with varying degrees of stiffness, and used these to grow and study the rat brain stem cells in a controlled environment. ̽��ֱ��materials were engineered to have a similar softness to either young or old brains.

To fully understand how brain softness and stiffness influences cell behavior, the researchers investigated Piezo1 – a protein found on the cell surface, which informs the cell whether the surrounding environment is soft or stiff.

Dr Kevin Chalut, who co-led the research, said: “We were fascinated to see that when we grew young, functioning rat brain stem cells on the stiff material, the cells became dysfunctional and lost their ability to regenerate, and in fact began to function like aged cells. What was especially interesting, however, was that when the old brain cells were grown on the soft material, they began to function like young cells – in other words, they were rejuvenated.”

“When we removed Piezo1 from the surface of aged brain stem cells, we were able to trick the cells into perceiving a soft surrounding environment, even when they were growing on the stiff material,” explained Professor Robin Franklin, who co-led the research with Dr Chalut. “What’s more, we were able to delete Piezo1 in the OPCs within the aged rat brains, which lead to the cells becoming rejuvenated and once again able to assume their normal regenerative function.”

Dr Susan Kohlhaas, Director of Research at the MS Society, who part funded the research, said: “MS is relentless, painful, and disabling, and treatments that can slow and prevent the accumulation of disability over time are desperately needed. ̽��ֱ��Cambridge team’s discoveries on how brain stem cells age and how this process might be reversed have important implications for future treatment, because it gives us a new target to address issues associated with aging and MS, including how to potentially regain lost function in the brain.”

This research was supported by the European Research Council, MS Society, Biotechnology and Biological Sciences Research Council, ̽��ֱ��Adelson Medical Research Foundation, Medical Research Council and Wellcome.

Niche stiffness underlies the ageing of central nervous system progenitor cells, M. Segel, B. Neumann, M. Hill, I. Weber, C. Viscomi, C. Zhao, A. Young, C. Agley, A. Thompson, G. Gonzalez, A. Sharma, S. Holmqvist, D. Rowitch, K. Franze, R. Franklin and K. Chalut is published in Nature.

New research reveals how increasing brain stiffness as we age causes brain stem cell dysfunction, and demonstrates new ways to reverse older stem cells to a younger, healthier state.

...when the old brain cells were grown on the soft material, they began to function like young cells – in other words, they were rejuvenated

Kevin Chalut

Mikey Segel

Aged rat brain stem cells grown on a soft surface (right) show more healthy, vigorous growth than similar aged brain stem cells grown on a stiff surface (left). ̽��ֱ��red marker shows brain stem cells, and the green marker indicates cell proliferation.

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Stem cell physical

lw355 — Fri, 10 Oct 2014 13:55:38 +0000

One of the many mysteries surrounding stem cells is how the constantly regenerating cells in adults, such as those in skin, are able to achieve the delicate balance between self-renewal and differentiation – in other words, both maintaining their numbers and producing cells that are more specialised to replace those that are used up or damaged.

“What all of us want to understand is how stem cells decide to make and maintain a body plan,” said Dr Kevin Chalut, a Cambridge physicist who moved his lab to the ̽��ֱ��’s Wellcome Trust-MRC Cambridge Stem Cell Institute two years ago. “How do they decide whether they’re going to differentiate or stay a stem cell in order to replenish tissue? We have discovered a lot about stem cells, but at this point nobody can tell you exactly how they maintain that balance.”

To unravel this mystery, both Chalut and another physicist, Professor Ben Simons, are bringing a fresh perspective to the biologists’ work. Looking at problems through the lens of a physicist helps them untangle many of the complex datasets associated with stem cell research. It also, they say, makes them unafraid to ask questions that some biologists might consider ‘heretical’, such as whether a few simple rules describe stem cells. “As physicists, we’re very used to the idea that complex systems have emergent behaviour that may be described by simple rules,” explained Simons.

What they have discovered is challenging some of the basic assumptions we have about stem cells.

One of those assumptions is that once a stem cell has been ‘fated’ for differentiation, there’s no going back. “In fact, it appears that stem cells are much more adaptable than previously thought,” said Simons.
By using fluorescent markers and live imaging to track a stem cell’s progression, Simons’ group has found that they can move backwards and forwards between states biased towards renewal and differentiation, depending on their physical position in the their host environment, known as the stem cell niche.

For example, some have argued that mammals, from elephants to mice, require just a few hundred blood stem cells to maintain sufficient levels of blood in the body. “Which sounds crazy,” said Simons. “But if the self-renewal potential of cells may vary reversibly, the number of cells that retain stem cell potential may be much higher. Just because a certain cell may have a low chance of self-renewal today doesn’t mean that it will still be low tomorrow or next week!”

Chalut’s group is also looking at the way in which stem cells interact with their environment, specifically at the role that their physical and mechanical properties might play in how they make their fate decisions. It’s a little-studied area, but one that could play a key role in understanding how stem cells work.
“If you go to the grocery store to buy an avocado, you’re not going to perform lots of chemistry on it in order to decide which is the best one: you’re going to pick it up and squeeze it,” said Chalut. “In essence, this is what we’re trying to do with stem cells.”

Chalut’s team is looking at the exact point where pluripotency – the ability to generate any other cell type in the body – arises in the embryo, and determining what role physical or mechanical signals play in generating this ‘ultimate’ stem cell state.

Using fluid pressure to squeeze the stem cells through a channel, as well as miniature cantilevers to push down on the cells, the researchers were able to observe and measure the mechanical properties of these master cells.

What they found is that the nuclei of embryonic stem cells display a bizarre and highly unusual property known as auxeticity. Most materials will contract when stretched. If you pull on an elastic band, the elastic will get thinner. If you squeeze a tennis ball, its circumference will get larger. However, auxetic materials react differently – squeeze them and they contract, stretch them and they expand.

“ ̽��ֱ��nucleus of an embryonic stem cell is an auxetic sponge – it can open up and soak up material when it’s pulled on and expel all that material when it’s compressed,” said Chalut. “But once the cells have differentiated, this property goes away.”

Auxeticity arises precisely at the point in a stem cell’s development that it needs to start differentiating, so it’s possible that the property exists so that the nucleus is able to allow entrance and space to the molecules required for differentiation.

“There’s a lot of discussion about what exactly it means to be pluripotent, and how pluripotency is regulated,” said Chalut. “Many different factors play a role, but we believe one of those factors may be a mechanical signal. This may also be the case in the developing embryo.”

By bringing together physics and biology, Simons and Chalut believe not only that some of the defining questions in embryonic and adult stem cell biology can be addressed, but also that new insights can be found into mechanisms of dysregulation in disease, cancer and ageing.

“One of the reasons that this bringing together of disciplines sometimes doesn’t work so well is that physicists don’t want to understand the biology and biologists don’t want to understand the physics,” said Chalut. “In a sense, biologists don’t know the physical questions to ask, and physicists don’t know the biological questions to ask. As a physicist, the main reason I wanted to move my lab to the Stem Cell Institute is I thought there was no point working in biology if I didn’t understand which questions to ask.”

“There’s a real effort being made to combine biology and physics much more than they have been in the past,” added Simons. “It takes a bit of a leap of faith to believe physics will enrich the field of biology, but I think it’s a very reasonable leap of faith. Scientific history is full of fields that have been enriched by people coming in and looking at an issue from different directions.”

Inset image: Kevin Chalut (left) and Ben Simons.

Looking at stem cells through physicists’ eyes is challenging some of our basic assumptions about the body’s master cells.

What all of us want to understand is how stem cells decide to make and maintain a body plan

Kevin Chalut

Effigos AG

Stem cells show auxeticity; the nucleus expands, rather than thins, when it's stretched

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Bulletproof nuclei? Stem cells exhibit unusual absorption property

cjb250 — Sun, 20 Apr 2014 17:00:00 +0000

̽��ֱ��property – known as auxeticity – is one which may have application as wide-ranging as soundproofing, super-absorbent sponges and bulletproof vests.

Most materials when stretched will contract. For example, if one pulls on an elastic band, the elastic itself will get thinner. ̽��ֱ��opposite is also true: squeeze a material and it will expand – for example, if one squeezes a tennis ball between both hands, the circumference around the ball gets larger. However, material scientists have begun to explore auxeticity, an unusual property which has the opposite effect – squeeze it and it will contract, stretch it and it will expand. This means that auxetic materials act as excellent shock absorbers or sponges, a fact that is being explored for various uses.

Until now, auxeticity has only been demonstrated in manmade materials and very rarely in nature, such as some species of sponge. But today, in a paper published in the journal Nature Materials, a team of ̽��ֱ�� of Cambridge researchers including biologists, engineers and physicists, report having observed auxeticity in the nuclei of embryonic stem cells, master cells within the body which can turn into any other type of cell.

Dr Kevin Chalut from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, who led the study, says: “This is a pretty bizarre finding and very unexpected. When the stem cell is in the process of transforming into a particular type of cell, its nucleus takes on an auxetic property, allowing it to ‘sponge up’ essential materials from its surrounding. This property has not, to my knowledge, been seen before at a cellular level and is highly unusual in the natural world.”

̽��ֱ��auxetic properties only appear in the stem cell’s nucleus when it is in the transition stage, changing from an embryonic, non-specific stem cell into a differentiated, tissue-specific cell, such as a heart tissue cell. Dr Chalut and colleagues treated the transitioning cell’s cytoplasm, the fluid surrounding the nucleus, with a coloured dye and found that when they stretched the nucleus, it absorbed the dye, suggesting that it had expanded to become porous. It is possible that it does so to absorb molecules from the cytoplasm or environment which would help the cell differentiate.

Auxetic materials are of great interest to material scientists and engineers and this new discovery may provide clues to different methods of manufacture. ̽��ֱ��vast majority of known auxetic materials are highly ordered, such as the auxetic honeycomb. However, some examples of disordered auxetic materials are known – for example, if one pulls both ends of a scrunched up ball of paper, the circumference around the ball expands. ̽��ֱ��nucleus of the transitional stem cell is likewise disordered.

“There is clearly a lot we can learn from nature,” adds Dr Chalut. “We are already seeing auxeticity explored for its super-absorption properties, but despite great technological effort, auxetic materials are still rare and there is still much to discover about them in order to manufacture them better. To overcome this, materials scientists can do what has become de rigueur in their discipline: they can learn from nature. Studying how auxeticity has evolved in nature will guide research into new ways to produce auxetic materials, which might have many diverse applications in our everyday life.”

Funding for the study was mainly provided by the Royal Society, the Wellcome Trust and the Medical Research Council.

Stem cells – the body’s master cells – demonstrate a bizarre property never before seen at a cellular level, according to a study published today from scientists at the ̽��ֱ�� of Cambridge.

This property has not, to my knowledge, been seen before at a cellular level and is highly unusual in the natural world

Kevin Chalut

Katrina Cole

Paper ball

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

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