Astrocytes are star-shaped glial cells with many functions which include providing nutrient support to neurons, helping repair damage to nervous system tissue, regulating connectivity of brain circuits, participating in inflammatory signaling, and helping to regulate blood flow across the blood-brain barrier. They are a crucial component of brain function, but are often overlooked in research and drug development. However, researchers from the New York Stem Cell Foundation (NYSCF) Research Institute say they have created astrocytes from stem cells and show that in disease-like environments these helpful cells can turn into neuron killers.
Their study, “CD49f Is a Novel Marker of Functional and Reactive Human iPSC-Derived Astrocytes,” is published in Neuron.
New methods for investigating human astrocytes were needed, given their critical role in the central nervous system. Most studies of astrocytes have been done in mouse models, but it has been shown that many aspects of human astrocyte function are not fully captured by mouse models. “The field needed a reliable method for making human astrocytes from stem cells so that we can better investigate how they may be contributing to neurodegenerative diseases,” explained Valentina Fossati, PhD, study author and a senior research investigator at the NYSCF Research Institute. “Previously, drugs that failed have not specifically targeted astrocytes. Now, drugs targeting astrocyte malfunctions can be identified using patient cells.”
Fossati’s team built on their previously published protocols for converting stem cells into glial cells such as microglia and oligodendrocytes to identify a protein marker, CD49f, which is expressed in astrocytes and can be used to isolate them from mixed cell populations in a lab dish or the human brain.
“We were excited to see that our stem cell-derived astrocytes isolated with CD49f behaved the way typical astrocytes do: they take up glutamate, respond to inflammation, engage in phagocytosis—which is like ‘cell eating’—and encourage mature firing patterns and connections in neurons,” said Fossati.
The team also confirmed that CD49f is present in astrocytes found in human brain tissue. “We looked at human brain tissue samples from both a healthy donor and a patient with Alzheimer’s disease and found that these astrocytes also expressed CD49f—suggesting that this protein is a reliable indicator of astrocyte identity in both health and disease,” said Fossati.
The team then turned their attention to how these astrocytes begin to misbehave in disease. Recent work from Shane Liddelow, PhD, a coauthor on the study and assistant professor of neuroscience and physiology and of ophthalmology at the NYU Grossman School of Medicine, found that astrocytes can “go rogue,” becoming toxic to the neurons they typically support.
“We observed in mice that astrocytes in inflammatory environments take on a reactive state, actually attacking neurons rather than supporting them,” explained Liddelow. “We found evidence of reactive astrocytes in the brains of patients with neurodegenerative diseases, but without a human stem cell model, it wasn’t possible to figure out how they were created and what they are doing in patients’ brains.”
Fossati’s team exposed healthy stem cell-derived astrocytes to inflammation—essentially mimicking the environment of the brain in neurodegenerative diseases—collected their byproducts, and then exposed these secretions to healthy neurons. “What we saw in the dish confirmed what Liddelow saw in mice: the neurons began to die,” said Fossati. “Observing this ‘rogue astrocyte’ phenomenon in a human model of disease suggests that it could be happening in actual patients and opens the door for new therapeutics that intervene in this process.”
“We can now create stem cells from any individual and see in the dish how astrocytes play a role in diseases like multiple sclerosis, Parkinson’s, and Alzheimer’s,” stated NYSCF CEO Susan L. Solomon, JD. “This will shed new light on the devastating process of neurodegeneration, pointing us towards effective treatments for this growing group of patients.”
The team also noted that stem cell-derived astrocytes exposed to inflammation lost their typical astrocyte functions and took on a constricted star-shape. “Along with secreting a toxin that kills neurons, we also saw that stem cell-derived astrocytes in disease-like environments simply do not perform their typical jobs as well, and that could lead to neuronal dysfunction,” noted Fossati. “For example, since they do not take up glutamate properly, too much glutamate is likely left around the neurons, which could cause a neuron to atrophy, and that’s something we can potentially target in new therapies.”
These findings provide a new method for researchers to explore mechanisms of disease and offer hope toward treating neurodegenerative diseases.
“I’m looking forward to using our new system to further explore the intricacies of astrocyte function in Alzheimer’s, multiple sclerosis, Parkinson’s, and other diseases,” stated Fossati. “We have already seen intriguing behaviors that may explain how neurodegeneration occurs, and I am hopeful that this work will point us toward new treatment opportunities for these patients.”