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

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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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Personalised stem cell treatment may offer relief for progressive MS

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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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Cells that enable the sense of touch created from stem cells for the first time

UCLA Broad Stem Cell Research Center/Stem Cell Reports
Human embryonic stem cell-derived neurons (green) showing nuclei in blue. Left: with retinoic acid added. Right: with retinoic acid and BMP4 added, creating proprioceptive sensory interneurons (pink).

Researchers are the first to create sensory interneurons from stem cells

Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have, for the first time, coaxed human stem cells to become sensory interneurons — the cells that give us our sense of touch. The new protocol could be a step toward stem cell–based therapies to restore sensation in paralyzed people who have lost feeling in parts of their body.

The study, which was led by Samantha Butler, a UCLA associate professor of neurobiology and member of the Broad Stem Cell Research Center, was published today in the journal Stem Cell Reports.

Sensory interneurons, a class of neurons in the spinal cord, are responsible for relaying information from throughout the body to the central nervous system, which enables the sense of touch. The lack of a sense of touch greatly affects people who are paralyzed. For example, they often cannot feel the touch of another person, and the inability to feel pain leaves them susceptible to burns from inadvertent contact with a hot surface.

“The field has for a long time focused on making people walk again,” said Butler, the study’s senior author. “‘Making people feel again doesn’t have quite the same ring. But to walk, you need to be able to feel and to sense your body in space; the two processes really go hand in glove.”

In a separate study, published in September by the journal eLife, Butler and her colleagues discovered how signals from a family of proteins called bone morphogenetic proteins, or BMPs, influence the development of sensory interneurons in chicken embryos. The Stem Cell Reports research applies those findings to human stem cells in the lab.

When the researchers added a specific bone morphogenetic protein called BMP4, as well as another signaling molecule called retinoic acid, to human embryonic stem cells, they got a mixture of two types of sensory interneurons. DI1 sensory interneurons give people proprioception — a sense of where their body is in space — and dI3 sensory interneurons enable them to feel a sense of pressure.

The researchers found the identical mixture of sensory interneurons developed when they added the same signaling molecules to induced pluripotent stem cells, which are produced by reprogramming a patient’s own mature cells such as skin cells. This reprogramming method creates stem cells that can create any cell type while also maintaining the genetic code of the person they originated from. The ability to create sensory interneurons with a patient’s own reprogrammed cells holds significant potential for the creation of a cell-based treatment that restores the sense of touch without immune suppression.

Butler hopes to be able to create one type of interneuron at a time, which would make it easier to define the separate roles of each cell type and allow scientists to start the process of using these cells in clinical applications for people who are paralyzed. However, her research group has not yet identified how to make stem cells yield entirely dI1 or entirely dI3 cells — perhaps because another signaling pathway is involved, she said.

The researchers also have yet to determine the specific recipe of growth factors that would coax stem cells to create other types of sensory interneurons.

The group is currently implanting the new dI1 and dI3 sensory interneurons into the spinal cords of mice to understand whether the cells integrate into the nervous system and become fully functional. This is a critical step toward defining the clinical potential of the cells.

“This is a long path,” Butler said. “We haven’t solved how to restore touch but we’ve made a major first step by working out some of these protocols to create sensory interneurons.”

Learn more: UCLA scientists make cells that enable the sense of touch

 

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Stem cell therapy for dry age-related macular degeneration?

Mature iPSC-derived RPE cells are shown by super-resolution confocal microscopy. One primary cilium resides in the center of each cell. RPE cell borders are stained showing
tight junction markers. Credit: Ruchi Sharma, Ph.D., NEI.

Stem cell-derived retinal cells need primary cilia to support survival of light-sensing photoreceptors

Scientists at the National Eye Institute (NEI), part of the National Institutes of Health, report that tiny tube-like protrusions called primary cilia on cells of the retinal pigment epithelium (RPE)—a layer of cells in the back of the eye—are essential for the survival of the retina’s light-sensing photoreceptors. The discovery has advanced efforts to make stem cell-derived RPE for transplantation into patients with geographic atrophy, otherwise known as dry age-related macular degeneration (AMD), a leading cause of blindness in the U.S. The study appears in the January 2 Cell Reports.

“We now have a better idea about how to generate and replace RPE cells, which appear to be among the first type of cells to stop working properly in AMD,” said the study’s lead investigator, Kapil Bharti, Ph.D., Stadtman investigator at the NEI. Bharti is leading the development of patient stem cell-derived RPE for an AMD clinical trial set to launch in 2018.

In a healthy eye, RPE cells nourish and support photoreceptors, the cells that convert light into electrical signals that travel to the brain via the optic nerve. RPE cells form a layer just behind the photoreceptors. In geographic atrophy, RPE cells die, which causes photoreceptors to degenerate, leading to vision loss.

Bharti and his colleagues are hoping to halt and reverse the progression of geographic atrophy by replacing diseased RPE with lab-made RPE. The approach involves using a patient’s blood cells to generate induced-pluripotent stem cells (iPSCs), cells capable of becoming any type of cell in the body. iPSCs are grown in the laboratory and then coaxed into becoming RPE for surgical implantation.

Attempts to create functional RPE implants, however, have hit a recurring obstacle: iPSCs programmed to become RPE cells have a tendency to get developmentally stuck, said Bharti. “The cells frequently fail to mature into functional RPE capable of supporting photoreceptors. In cases where they do mature, however, RPE maturation coincides with the emergence of primary cilia on the iPSC-RPE cells.”

The researchers tested three drugs known to modulate the growth of primary cilia on iPSC-derived RPE. As predicted, the two drugs known to enhance cilia growth significantly improved the structural and functional maturation of the iPSC-derived RPE. One important characteristic of maturity observed was that the RPE cells all oriented properly, correctly forming a single, functional monolayer. The iPSC-derived RPE cell gene expression profile also resembled that of adult RPE cells. And importantly, the cells performed a crucial function of mature RPE cells: they engulfed the tips of photoreceptor outer segments, a pruning process that keeps photoreceptors working properly.

By contrast, iPSC-derived RPE cells exposed to the third drug, an inhibitor of cilia growth, demonstrated severely disrupted structure and functionality.

As further confirmation of their observations, when the researchers genetically knocked down expression of cilia protein IFT88, the iPSC-derived RPE showed severe maturation and functional defects, as confirmed by gene expression analysis. Tissue staining showed that knocking down IFT88 led to reduced iPSC-derived RPE cell density and functional polarity, i.e., cells within the RPE tissue pointed in the wrong direction.

Bharti and his group found similar results in iPSC-derived lung cells, another type of epithelial cell with primary cilia. When iPSC-derived lung cells were exposed to drugs that enhance cilia growth, immunostaining confirmed that the cells looked structurally mature.

The report suggests that primary cilia regulate the suppression of the canonical WNT pathway, a cell signaling pathway involved in embryonic development. Suppression of the WNT pathway during RPE development instructs the cells to stop dividing and to begin differentiating into adult RPE, according to the researchers.

The researchers also generated iPSC-derived RPE from a patient with ciliopathy, a disorder that causes severe vision loss due to photoreceptor degeneration. The patient’s ciliopathy was associated with mutations of cilia gene CEP290. Compared to a healthy donor, iPSC-derived RPE from the ciliopathy patient had cilia that were smaller. The patient’s iPSC-derived RPE also had maturation and functional defects similar to those with IFT88 knockdown.

Further studies in a mouse model of ciliopathy confirmed an important temporal relationship: Looking across several early development stages, the RPE defects preceded the photoreceptor degeneration, which provides additional insights into ciliopathy-induced retinal degeneration.

Learn more: NIH discovery brings stem cell therapy for eye disease closer to the clinic

 

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