University of Cambridge researchers find reprogramming skin cells could help multiple sclerosis patients

PUBLISHED: 23:53 07 March 2018 | UPDATED: 00:04 08 March 2018

Dr Luca Peruzzotti-Jametti, a Wellcome Trust Research Training Fellow at the University of Cambridge

Dr Luca Peruzzotti-Jametti, a Wellcome Trust Research Training Fellow at the University of Cambridge

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Turning patient’s own skin cells into brain stem cells might help repair MS damage, study suggests

Dr Stefano Pluchino, from the Department of Clinical Neurosciences at the University of CambridgeDr Stefano Pluchino, from the Department of Clinical Neurosciences at the University of Cambridge

Research led by the University of Cambridge has suggested that reprogramming a patient’s own skin cells could provide a route to repairing the damage caused by multiple sclerosis.

Scientists across a number of university departments carried out a study in mice, which showed that turning skin cells into brain stem cells, then transplanting them back into the body, helped reduce the inflammation associated with the disease.

The research is an important step towards developing personalised treatments based on a patient’s skin cells for diseases of the central nervous system.

Stem cell therapies are a promising avenue for tackling such conditions. They employ a stem cell’s ability to become almost any type of cell in the human body.

Damage is caused to nerve cells by progressive forms of multiple sclerosis, which attacks the central nervous system and causes chronic inflammation.

It is the body’s own immune system that strikes, damaging the protective sheath around nerve fibres, which is known as myelin.

This disrupts messages sent around the brain and spinal cord, causing a range of symptoms that can include problems with mobility and balance, pain, severe fatigue, muscle spasms and vision problems.

Induced neural stem cells could be used to create personalised treatments for patients with chronic inflammatory diseases, University of Cambridge researchers sayInduced neural stem cells could be used to create personalised treatments for patients with chronic inflammatory diseases, University of Cambridge researchers say

The autoimmune disease affects about 100,000 people in the UK – and two to three times as many women as men. More than eight out of 10 are diagnosed with the ‘relapsing remitting’ type, during which symptoms worsen over a period of time, then slowly improve for a spell. There are several therapies to help during this phase.

Within 15-20 years of diagnosis, about half of those diagnosed with the condition go on to develop a secondary progressive form of the disease which does not have any effective treatment.

The key immune cells involved are known as macrophages, which means ‘big eaters’. They normally gobble up unwanted intruders in the body, but in MS patients one particular type of macrophage known as microglia – found throughout the brain and spinal cord – attacks the central nervous system.

The Cambridge team has previously shown that transplanting neural stem cells (NSCs) – which are stem cells part-way to developing into nerve cells – reduces inflammation and can help the central nervous system to heal.

But if this was to be developed into a therapy, it would be hampered by the lack of availability of such NSCs. These cells are sourced from embryos and therefore not available in large quantities.

There is also the potential that the body’s immune system would consider the cells to be invaders and mount an immune response to destroy them.

A solution to both of these challenges could come in the form of induced neural stem cells, or iNSCs. These can be generated in the lab by taking an adult’s skin cells and reprogramming them back to become neural stem cells. The risk of an immune response to these cells is significantly reduced as the iNSCs would be the patient’s own cells.

Dr Stefano Pluchino, lead author of the study from the Department of Clinical Neurosciences at the University of Cambridge, said: “Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS. This is particularly promising as these cells should be more readily obtainable than conventional neural stem cells and would not carry the risk of an adverse immune response.”

In their paper, published in the journal Cell Stem Cell, the researchers used mice manipulated to develop MS and discovered it leads to significantly increased levels of succinate. This small metabolite sends signals to macrophages and microglia, prompting them into causing inflammation, but only in cerebrospinal fluid, not in the peripheral blood.

They found that transplanting NSCs and iNSCs directly into the cerebrospinal fluid reduced the amount of succinate, reprogramming the macrophages and microglia.

The immune cells that had been attacking the body were restored to being useful once more, leading to a decrease in inflammation and subsequent secondary damage to the brain and spinal cord.

Dr Pluchino led the research team with Dr Christian Frezza, from the MRC Cancer Unit at the University of Cambridge.

Dr Luca Peruzzotti-Jametti, the first author of the study and a Wellcome Trust Research Training Fellow, said: “We made this discovery by bringing together researchers from diverse fields including regenerative medicine, cancer, mitochondrial biology, inflammation and stroke and cellular reprogramming. Without this multidisciplinary collaboration, many of these insights would not have been possible.”

Now based on Cambridge Biomedical Campus, Dr Peruzzotti-Jametti began his career studying medicine at the University Vita-Salute San Raffaele, Milan. He worked in Switzerland, Denmark, and Sweden before coming to Cambridge.

“My research sets out to understand how progression works in MS by studying how inflammation is maintained in the brains of patients, and to develop new treatments aimed at preventing disease progression,” he said. “My hope is that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS.

“Cambridge has been the best place to do my research due to the incredible concentration of scientists who pursue novel therapeutic approaches using cutting-edge technologies.

“I am very thankful for the support I received in the past years from top notch scientists. Being in Cambridge has also helped me to compete for major funding sources and my work would not have been possible without the support of the Wellcome Trust.

“I wish to continue working in this exceptional environment where so many minds and efforts are put together in a joint cause for the benefit of those who suffer.”

The research was funded by Wellcome, the European Research Council, the Medical Research Council, Italian Multiple Sclerosis Association, Congressionally-Directed Medical Research Programs, the Evelyn Trust and the Bascule Charitable Trust.

The laboratories reprogramming skin and blood cells

It might sound like science fiction – or a form of genetic alchemy – but laboratories around Cambridge are now routinely reprogramming human cells, and then offering them for sale.

One such company is Axol Bioscence, based at Chesterford Research Park.

“We are using Nobel Prize-winning technology and introducing some special stem-cell related genes into very easily accessible cells, such as blood cells, skins cells and now urine-derived cells and kidney cells,” Dr Yichen Shi told the Cambridge Independent.

“We convert these easily accessible cells into embryonic stem cell-like cells. We call them induced pluripotent stem cells (iPSCs).”

Axol Bioscience makes high quality neural cells and cardiac muscle cells, among others, from these embryonic stem cell-like cells, and sells them via its website for researchers to use.

Dr Shi likens the process to wiping a computer, then launching new programmes on it.

Another company in the field is Elpis Biomed, a university spin-out that launched last year with backing from heavyweight investors.

Its synthetic biology approach could be a game-changer for the industry, cutting the time taken to create mature brain cells from 100-120 days to just 20.

Scientific founder Dr Mark Kotter said: “It entails getting genetic information into the cell. The cleanest way to do this is to use a gene editing approach because you then know exactly how many copies of the information you have inserted.

“We are using the precision of gene editing to make sure there is no effect on the cell.

“It’s a platform technology and more and more research shows it’s applicable to all cell types.”

The technology is helping Elpis to create pure, mature and highly consistent batches of human cell types that can be used in research, toxicology and drug development.

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