Stem Cell Therapy for Stroke: Progress and Challenges

Post by Shahin Khodaei

What's the science?

A stroke is a serious medical condition where blood flow to a part of the brain is reduced, causing the death of brain cells and impairments in movement, speech, or cognition in survivors. The majority of strokes are ischemic strokes, meaning that blood supply is disrupted because of a blockage in blood vessels. Currently, the only FDA-approved treatments for ischemic stroke involve removing the blockage either mechanically or pharmacologically to restore normal blood supply, however, this treatment is only effective within a few hours of the stroke onset. Finding new treatments that can be effective at later time points is critical. This week in Brain, Rust and colleagues published a review paper on one such treatment strategy: stem cell therapy for long-term treatment of ischemic stroke.

What happens in ischemic stroke?

When blood supply to a brain region is interrupted, millions of neurons and billions of synapses quickly die. Beyond the damage to neurons, stroke causes massive local and systemic inflammation and significant damage to the blood-brain barrier (BBB), which regulates what substances enter and exit the brain. These changes all have lasting negative consequences on brain function. Over the subsequent days and weeks, neurons can also die off in distant brain regions anatomically connected to the stroke site.

After a stroke, the brain’s built-in neuroplasticity processes kick in. Some new neurons and synapses may be created, and surviving brain regions start to take on some of the functions of the brain areas lost in the stroke. In addition, new blood vessels form around the site of the stroke, and the support cells in the brain are able to partially restore the BBB. All these mechanisms lead to some degree of functional recovery in patients – this plasticity window peaks during the first 3 months and gradually weakens 6-12 months after stroke.

How can stem cell therapy help?

Given that many neurons die in a stroke, a treatment strategy that replaces the lost cells using stem cells is an intuitive concept. Preclinical studies using animal models have shown that using stem cells after stroke may be therapeutic in two ways. One is the replacement of lost cells, where stem cells turn into brain cells and integrate into the existing neuronal networks to restore function. However, this form of direct integration is rather limited, because newly formed neurons and cells often have a short lifespan. Instead, emerging studies show that transplanted stem cells support the brain’s built-in plasticity processes, leading to beneficial effects. These include reducing the massive inflammatory response that follows a stroke, the repair and remodeling of blood vessels, and the repair of neural circuits. Both cell replacement and support processes were reported following stem cell transplant in a recent preclinical study by Rust’s team. Using a mouse model, transplanting cells 7 days after stroke caused increased neuronal plasticity, blood vessel repair and remodeling, and improved motor function. These transplanted cells developed into neurons and other brain cells that survived for at least five weeks and cross-talked with surrounding stroke tissue to activate plasticity and regeneration processes.

Clinical trials using stem cells after stroke started two decades ago, and have shown that this approach is safe, without significant negative effects. However, in terms of effectiveness, these clinical trials have found mixed results. Rust and colleagues suggest that findings from preclinical studies can teach us how to more effectively use stem cells in a clinical setting. For example, to increase the lifespan of stem cells, preclinical studies have treated the cells pharmacologically and genetically before transplanting them into the brain – a similar approach may be used in clinical trials in the future to possibly increase the effectiveness of stem cell therapy.

What's the bottom line?

Stem cell therapies have been recognized as one of the most promising approaches to help survivors of stroke. Unfortunately, clinical trials using this strategy have not shown consistent improvements for patients thus far. Rust and colleagues argue that our growing understanding of the mechanisms of stem cell therapy from preclinical studies can help improve the effectiveness of this approach for patients, ultimately leading to better treatment for stroke.

Access the original scientific publication here.

Focused Ultrasound for the Treatment of Parkinson’s Disease

Post by Natalia Ladyka-Wojcik

A primer on motor symptoms in Parkinson’s disease

Parkinson’s disease (PD) is a complex neurodegenerative disorder that affects over 10 million people globally, typically in individuals aged 60 years or older. PD affects a central brain area called the basal ganglia, leading to a range of motor, cognitive, and sleep changes. A particularly affected region of the basal ganglia is a crescent-shaped cell mass in the brain stem called the substantia nigra. The neurons in this tiny region produce the neurotransmitter dopamine and play a big role in planning and controlling body movement. In PD, these neurons begin to die off and hallmark motor symptoms of PD such as tremor, rigidity, and slowness of movement tend to emerge when about 80% of dopamine is lost.

Dopamine is critical for stimulating receptors in one of the basal ganglia called the striatum, which works with the substantia nigra to send signals between the spinal cord and the brain. If striatum receptors aren’t sufficiently stimulated, other portions of the basal ganglia may also be over- or under-stimulated: the hallmark tremors associated with PD result from overstimulation whereas rigidity and slowness of movement result from understimulation. Perhaps unsurprisingly, patients with PD report that the severity and frequency of these symptoms significantly decrease their quality of life, highlighting the importance of targeted treatment for these symptoms.

Current challenges in treating Parkinson’s disease symptoms

Traditionally, PD treatments have largely relied on medications, which aim to either preserve dopamine in the brain by preventing its breakdown, increase dopamine release, or mimic dopamine altogether. Although clinical research has made great strides in developing effective medications for PD, these medications tend to work better in the early stages of the disease. Moreover, some of these medications can cause unwanted side effects, including hallucinations, nausea, depression, and even obsessive behavior. Given these considerations, research has turned to exciting new avenues for treating PD by leveraging advanced therapeutic technologies. Here, we’ll survey two major technologies to better understand the future of PD treatment: (1) deep brain stimulation, and (2) focused ultrasound.

Deep brain stimulation for Parkinson’s disease

Deep brain stimulation (DBS) is a surgical therapy that addresses the movement symptoms of PD but can also help improve other non-motor symptoms including changes in sleep. In the U.S., it is approved by the Food and Drug Administration and is especially effective in individuals with severe tremors. In DBS surgery, electrodes are inserted into the basal ganglia and then a pacemaker-like implant is placed either under the collarbone or in the abdomen. This implant delivers electrical neurostimulation to the basal ganglia which the patient controls with a remote. On average, DBS patients with optimal drug therapy require lower medication doses compared to a control group receiving only optimal drug therapy. Importantly, DBS patients also show slowed progression of tremor symptoms. The future of DBS as a therapy for PD holds much promise, with larger randomized control studies to investigate DBS efficacy underway by the Food and Drug Administration.

Focused ultrasound: A cutting-edge therapy for Parkinson’s tremors

When imagining what neurosurgery is like, you might visualize the surgical incisions needed for neurosurgeons to access the brain. However, focused ultrasound therapy is a new noninvasive approach: beams of ultrasonic energy are used to precisely and accurately target deep brain structures with thermal lesions without damaging surrounding healthy tissue. This technique massively reduces risks of infection or brain bleeding compared to traditional surgery and does not require any external implants to be placed in the patient’s body. Neurosurgeons typically use magnetic resonance imaging (MRI) to guide the ultrasound beams to the desired location in the patient’s brain, ensuring that thermal lesions are done accurately. On average, patients show marked improvements in motor symptoms of PD, especially tremor, although some negative side effects have been reported. In the future, some scientists hope that focused ultrasound technology can even be used to disrupt the blood-brain barrier, a selective semi-permeable membrane that defends the brain from external substances and can sometimes prevent medication from successfully reaching the brain. This means that in addition to directly manipulating dysfunctional brain signaling, focused ultrasound may also help PD medications be even more effective.

What’s the bottom line?

Every year 90,000 people are diagnosed with PD in the United States alone, and it is the second-most common neurodegenerative disease after Alzheimer’s dementia. PD is associated with progressive symptoms, especially related to motor skills, which are managed by available medications only to a certain degree of efficacy. New technologies, including DBS and focused ultrasound, provide exciting new avenues for the treatment of PD.

References +

Hacker, M. L., Turchan, M., Heusinkveld, L. E., Currie, A. D., Millan, S. H., Molinari, A. L., Konrad, P. E., Davis, T. L., Phibbs, F. T., Hedera, P., Cannard, K. R., Wang, L., & Charles, D. (2020). Deep brain stimulation in early-stage Parkinson disease. Neurology, 95(4), e393–e401.

Moosa, S., Martínez‐Fernández, R., Elias, W. J., Del Alamo, M., Eisenberg, H. M., & Fishman, P. S. (2019). The role of high‐intensity focused ultrasound as a symptomatic treatment for Parkinson's disease. Movement Disorders, 34(9), 1243-1251.

Rahman, S., Griffin, H. J., Quinn, N. P., & Jahanshahi, M. (2008). Quality of life in Parkinson’s disease: The relative importance of the symptoms. Movement Disorders, 23(10), 1428–1434.

Whitney, C. M. (2007). Medications for Parkinsonʼs Disease. The Neurologist, 13(6), 387–388.

How Transplanting Microglia Could Fight Age-Related Disease

Post by Anastasia Sares

The takeaway

Microglia are an important type of support cell in the brain. While mice brains without microglia can develop normally, they become severely compromised in old age. Restoring microglia can help prevent these age-related diseases in mice, paving the way for similar therapies in humans.

What's the science?

When it comes to neuroscience research, neurons are often the stars of the show. However, the brain has essential supporting actors. Cells like microglia and oligodendrocytes have a variety of roles, like aiding neuronal growth and signaling. Without the aid of these cells, neurons couldn’t do what they do. For example, microglia prune and sometimes devour other cells if they’re not pulling their weight, while oligodendrocytes wrap around the axons of neurons like the plastic around a power cord, insulating them and making the signal travel faster. They are important to the integrity of the white matter in the brain, where information is transported across long distances between different parts of the cortex. However, we still don’t fully understand the importance of these supporting cells. For example, even without the genes needed for functional microglia, some mice seem to grow and develop normally. So, what’s going on here?

This week in Neuron, Munro and colleagues showed that while mice can develop normally without microglia, their brain health takes a sharp turn for the worse in old age. However, these effects can be reversed by transplanting microglia into the brains of mice without them.

How did they do it?

This study focused on genetically modified mice that lacked a specific portion of a gene (Csf1r) that is important for microglia to form. These mice have fairly normal development, with normal levels of most other brain cells and normal performance on behavioral tests. The authors used a technique called RNA sequencing to understand how cells acted differently without microglia present. RNA is a messenger molecule carrying instructions from a cell’s DNA, a crucial step in determining which genes get made into proteins in a given cell. Different cells need different kinds of proteins depending on their function, and the cells' needs can change over time. By seeing what kinds of RNA are around in a cell, researchers can tell if the cell is functioning normally or not.

The authors collected cells from the brains of these mice and tracked RNA expression in young, adult, and elderly mice with and without their microglia to see how this expression changed as the mice were aging. They also performed other tests on the mouse brains, including scanning them with high-resolution magnetic resonance imaging (MRI), so they could detect overall changes in brain structure.

Finally, the researchers tried an intervention: they transplanted microglia into the brains of the mice who couldn’t produce them. They tracked these mice in the same way as the other two groups.

What did they find?

In young mice who were missing their microglia, the RNA profiles of most other brain cells looked normal. One exception was the oligodendrocytes, which had subtle signs of abnormal activity.

As the mice lacking microglia aged, they had increasing neurological health problems. The oligodendrocyte’s RNA profiles became even more abnormal, and other cells started showing signs of stress, producing RNA related to injury, infection, and disease. The decline could also be seen in MRI, with white matter degrading faster over time in the mice without microglia. MRI measures showed that blood flow to the thalamus was particularly affected, and the authors discovered large calcium deposits in the thalamic brain regions of these aged mice. This means that microglia play an important role in maintaining the brain’s white matter and blood flow in old age, especially in the thalamus. Interestingly, when mice without microglia received transplanted ones, they aged normally.

What's the impact?

This study shows that while microglia might not be crucial for brain development (at least in mice), they are important for helping maintain continued functioning in old age. The recovery of mice who received microglia transplants is exciting because similar therapies could be developed for humans with microglial abnormalities, potentially preventing age-related degeneration and increasing longevity and quality of life.

Access the original scientific publication here.