Rejuvenating stem cells in the aging brain of mice improve the regeneration of injured or diseased areas in the brain

via University of Luxembourg

Scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg and from the German Cancer Research Center (DKFZ) have been able to rejuvenate stem cells in the brain of aging mice.

The revitalised stem cells improve the regeneration of injured or diseased areas in the brain of old mice. The researchers expect that their approach will provide fresh impetus in regenerative medicine and facilitate the development of stem cell therapies. Their results were published today in the journal “Cell”.

All cells making up our organs originate from stem cells. They divide and the resulting cells develop into specific tissue cells, forming the brain, lungs or bone marrow. With age, however, the stem cells of living organisms lose their ability to proliferate. Many of them lapse into a permanent state of quiescence.

In order to create as accurate as possible computational models of stem cell behaviour, the LCSB’s Computational Biology Group led by Prof. Antonio del Sol applied a novel approach. “Stem cells live in a niche where they constantly interact with other cells and extra-cellular components. It is extremely difficult to model such a plethora of complex molecular interactions on the computer. So we shifted perspective. We stopped thinking about what external factors were affecting the stem cells, and started thinking about what the internal state of a stem cell would be like in its precisely defined niche.”

The novel approach led to in a new computational model developed by Dr. Srikanth Ravichandran of the Computational Biology Group: “Our model can determine which proteins are responsible for the functional state of a given stem cell in its niche – meaning whether it will divide or remain in a state of quiescence. Our model relies on the information about which genes are being transcribed. Modern cell biology technologies enable profiling of gene expression at single cell resolution.”

It was previously unknown why most of the stem cells in the brain of old mice remain in a state of quiescence. From their computational model, the researchers at the LCSB identified a molecule called sFRP5 that keeps the neuronal stem cells inactive in old mice, and prevents proliferation by blocking the Wnt pathway crucial for cell differentiation.

A rejuvenation for stem cells

Then the long-standing expertise in neural stem cells of the collaborators at the German Cancer Research Center (DKFZ) came in: Studying stem cells first in a dish and then later directly in mice, they could experimentally validate the computational prediction. When neutralising the action of sFRP5, the quiescent stem cells did indeed start proliferating more actively. Thus, they were available again to be recruited for the regeneration processes in the aging brain. “With the deactivation of sFRP5, the cells undergo a kind of rejuvenation,” del Sol says: “As a result, the ratio of active to dormant stem cells in the brain of old mice becomes almost as favourable as in young animals.”

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases,” Antonio del Sol says. “We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.” This approach is not limited to studying the brain. It can also be used to model stem cells of other organs in the body. “The hope is that this will open avenues for regenerative medicine,” says del Sol.

Learn more: Scientists rejuvenate stem cells in the aging brain of mice

 

 

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The promise of stem cell technologies for treating Parkinson’s

Sections of rat brain transplanted with human cells in a preclinical model of PD are being prepared for analysis

Despite challenges, new advances in stem cell biology and genetic engineering show potential for better cell replacement therapies, say experts in a special supplement to JPD

Cell replacement may play an increasing role in alleviating the motor symptoms of Parkinson’s disease (PD) in future. Writing in an open access special supplement to the Journal of Parkinson’s Disease, experts describe how newly developed stem cell technologies could be used to treat the disease and discuss the great promise, as well as the significant challenges, of stem cell treatment.

The most common PD treatment today is based on enhancing the activity of the nigro-striatal pathway in the brain with dopamine-modulating therapies, thereby increasing striatal dopamine levels and improving motor impairment associated with the disease. However, this treatment has significant long-term limitations and side effects. Stem cell technologies show promise for treating PD and may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.

“We are in desperate need of a better way of helping people with PD. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” explained co-authors Claire Henchcliffe, MD, DPhil, from the Department of Neurology, Weill Cornell Medical College, and Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; and Malin Parmar, PhD, from the Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, Sweden. “If successful, using stem cells as a source of transplantable dopamine-producing nerve cells could revolutionize care of the PD patient in the future. A single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications.”

The authors have analyzed how newly developed stem cell technologies could be used to treat PD, and how clinical researchers are moving very quickly to translate this technology to early clinical trials. In the past, most transplantation studies in PD used human cells from aborted embryos. While these transplants could survive and function for many years, there were scientific and ethical issues: fetal cells are in limited supply, and they are highly variable and hard to quality control. Only some patients benefited, and some developed side effects from the grafts, such as uncontrollable movements called dyskinesias.

Recent strides in stem cell technology mean that quality, consistency, activity, and safety can be assured, and that it is possible to grow essentially unlimited amounts of dopamine-producing nerve cells in the laboratory for transplantation. This approach is now rapidly moving into initial testing in clinical trials. The choice of starting material has also expanded with the availability of multiple human embryonic stem cell lines, as well as the possibilities for producing induced pluripotent cells, or neuronal cells from a patient’s own blood or skin cells. The first systematic clinical transplantation trials using pluripotent stem cells as donor tissue were initiated in Japan in 2018.

“We are moving into a very exciting era for stem cell therapy,” commented Dr. Parmar. “The first-generation cells are now being trialed and new advances in stem cell biology and genetic engineering promise even better cells and therapies in the future. There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.”

“With several research groups, including our own centers, quickly moving towards testing of stem cell therapies for PD, there is not only a drive to improve what is possible for our patients, but also a realization that our best chance is harmonizing efforts across groups,” added Dr. Henchcliffe. “Right now, we are just talking about the first logical step in using cell therapies in PD. Importantly, it could open the way to being able to engineer the cells to provide superior treatment, possibly using different types of cells to treat different symptoms of PD like movement problems and memory loss.”

“This approach to brain repair in PD definitely has major potential, and the coming two decades might also see even greater advances in stem cell engineering with stem cells that are tailor-made for specific patients or patient groups,” commented Patrik Brundin, MD, PhD, Van Andel Research Institute, Grand Rapids, MI, USA, and J. William Langston, MD, Stanford Udall Center, Department of Pathology, Stanford University, Palo Alto, CA, USA, Editors-in-Chief of the Journal of Parkinson’s Disease. “At the same time, there are several biological, practical, and commercial hurdles that need circumventing for this to become a routine therapy.”

Learn more: Can We Repair the Brain? The Promise of Stem Cell Technologies for Treating Parkinson’s Disease

 

 

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The discovery of a new type of stem-cell has the potential to perform two functions at the same time and will mean better treatment or even cures for many diseases

via University of Queensland

University of Queensland researchers said the ability to provide two functions in one cell meant the cells could be used to regenerate or repair cell and tissue damage across a number of areas in the body.

This also means that arteries and veins could be created an engineer tissue to provide more effective treatments for a range of musculoskeletal and degenerative disorders including pulmonary fibrosis and heart disease.

This regenerative process is key to taking the next step in stem cell treatment.

For more details: Two in one: human placenta stem cells hold a dual benefit

 

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New stem cell work raises hopes for regenerative therapies that could heal currently intractable lung diseases

An image of an injured mouse lung partially regenerated by injected lung stem cells. The newly regenerated lung tissue is red, and the type-2 alveolar cells are green.
Massimo Nichane

Stanford scientists have found a cell that creates the two different compartments in the mouse lung. They hope their discovery could lead to better therapies for people with lung disease.

A researcher at the School of Medicine and his colleagues have succeeded in isolating mouse lung stem cells, growing them in large volumes and incorporating them into injured lung tissue in mice.

The work raises hopes for regenerative therapies that could heal currently intractable lung diseases.

A study describing the research was published online Nov. 6 in Nature MethodsKyle Loh, PhD, an investigator at the Stanford Institute for Stem Cell Biology and Regenerative Medicine, and Bing Lim, MD, PhD, an investigator at the Genome Institute of Singapore, share senior authorship. The lead author is Massimo Nichane, PhD, currently a research scientist at the Stanford stem cell institute.

The lungs are among the most vital organs of the body. In conjunction with the cardiovascular system, they allow air to travel to every cell and get rid of the waste products of respiration, such as carbon dioxide. For many people with end-stage lung diseases, the only option is lung transplantation.

“Scientists have previously had little success in putting new lung cells into damaged lung to regenerate healthy tissue,” Loh said. “We decided to see if we could do that in an animal model.”

The researchers started by working to improve on current knowledge of lung stem cells. The lung is divided into two compartments, Loh said: the airway, which allows for passage of air in and out of the lung; and the alveoli, where gases pass in and out of the blood. Other researchers had previously isolated one stem cell for the airway and another stem cell for the alveoli. Loh and his colleagues searched for and found a single lung stem cell that could create cells in both the airway and the alveoli. These multipotent lung stem cells were typified by their display of a protein marker called Sox9.

From one to 100 billion billion

Once they had isolated the stem cells, they were able to make them multiply dramatically. Each mouse lung stem cell that they start started with was able to grow into 100 billion billion lung stem cells over the course of six months. Previously, researchers had not had much success expanding any lung stem cell populations in the laboratory.

Finally, they injected the stem cells into mouse lungs that had been injured by a variety of toxins.  “What we saw was that these multipotent stem cells repaired the injured tissue and were able to differentiate into the many different kinds of cells that make up the healthy lung,” said Nichane.

“Our newfound ability to grow these mouse multipotent lung stem cells in a petri dish in very large numbers, and the cells’ ability to regenerate both lung airway and alveolar tissue, constitutes a first step towards future lung regenerative therapies,” Loh said. “Future work will focus on whether analogous multipotent stem cells can be found and cultivated from humans, which may open the way to eventually replenishing damaged lung tissue in the clinic.”

Learn more: Researchers find lung stem cell, heal lung injury in mice

 

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Personalised stem cell treatment may offer relief for progressive MS

via University of Cambridge

Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis (MS).

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

Luca Peruzzotti-Jametti

The study, led by researchers at the University of Cambridge, is a step towards developing personalised treatments based on a patient’s own skin cells for diseases of the central nervous system (CNS).

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord. Symptoms are unpredictable and include problems with mobility and balance, pain, and severe fatigue.

Key immune cells involved in causing this damage are macrophages (literally ‘big eaters’), which ordinarily serve to attack and rid the body of unwanted intruders. A particular type of macrophage known as microglia are found throughout the brain and spinal cord – in progressive forms of MS, they attack the CNS, causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that diseases of the CNS may be improved by the use of stem cell therapies. Stem cells are the body’s ‘master cells’, which can develop into almost any type of cell within the body. Previous work from the Cambridge team has shown that transplanting neural stem cells (NSCs) – stem cells that are part-way to developing into nerve cells – reduces inflammation and can help the injured CNS heal.

However, even if such a therapy could be developed, it would be hindered by the fact that such NSCs are sourced from embryos and therefore cannot be obtained in large enough quantities. Also, there is a risk that the body will see them as an alien invader, triggering an immune response to destroy them.

A possible solution to this problem would be the use of so-called ‘induced neural stem cells (iNSCs)’ – these cells can be generated by taking an adult’s skin cells and ‘re-programming’ them back to become neural stem cells. As these iNSCs would be the patient’s own, they are less likely to trigger an immune response.

Now, in research published in the journal Cell Stem Cell, researchers at the University of Cambridge have shown that iNSCs may be a viable option to repairing some of the damage caused by MS.

Using mice that had been manipulated to develop MS, the researchers discovered that chronic MS leads to significantly increased levels of succinate, a small metabolite that sends signals to macrophages and microglia, tricking them into causing inflammation, but only in cerebrospinal fluid, not in the peripheral blood.

Transplanting NSCs and iNSCs directly into the cerebrospinal fluid reduces the amount of succinate, reprogramming the macrophages and microglia – in essence, turning ‘bad’ immune cells ‘good’. This leads to a decrease in inflammation and subsequent secondary damage to the brain and spinal cord.

“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,” says Dr Stefano Pluchino, lead author of the study from the Department of Clinical Neurosciences at the University of Cambridge.

“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.”

The research team was led by Dr Pluchino, together with Dr Christian Frezza from the MRC Cancer Unit at the University of Cambridge, and brought together researchers from several university departments.

Dr Luca Peruzzotti-Jametti, the first author of the study and a Wellcome Trust Research Training Fellow, says: “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.”

Learn more: Study in mice suggests personalised stem cell treatment may offer relief for progressive MS

 

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