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Stem cell transplantation can reverse stroke damage, researchers report.

Its beneficial effects include regeneration of neurons and restoration of motor functions, marking a milestone in the treatment of brain disorders.

One in four adults suffer a stroke in their lifetime, leaving around half of them with residual damage such as paralysis or speech impairment because internal bleeding or a lack of oxygen supply kill brain cells irreversibly. No therapies currently exist to repair this kind of damage.

“That’s why it is essential to pursue new therapeutic approaches to potential brain regeneration after diseases or accidents,” says Christian Tackenberg, the scientific head of division in the neurodegeneration group at the University of Zurich (UZH) Institute for Regenerative Medicine.

Neural stem cells have the potential to regenerate brain tissue, as a team led by Tackenberg and postdoctoral researcher Rebecca Weber has now shown in two studies they conducted in collaboration with a group headed by Ruslan Rust from the University of Southern California.

“Our findings show that neural stem cells not only form new neurons, but also induce other regeneration processes,” Tackenberg says.

The studies employed human neural stem cells, from which different cell types of the nervous system can form. The stem cells were derived from induced pluripotent stem cells, which in turn can be manufactured from normal human somatic cells. For their investigation, the researchers induced a permanent stroke in mice, the characteristics of which closely resemble manifestation of stroke in humans. The animals were genetically modified so that they would not reject the human stem cells.

One week after stroke induction, the research team transplanted neural stem cells into the injured brain region and observed subsequent developments using a variety of imaging and biochemical methods.

“We found that the stem cells survived for the full analysis period of five weeks and that most of them transformed into neurons, which actually even communicated with the already existing brain cells,” Tackenberg says.

The researchers also found other markers of regeneration: new formation of blood vessels, an attenuation of inflammatory response processes and improved blood-brain barrier integrity.

“Our analysis goes far beyond the scope of other studies, which focused on the immediate effects right after transplantation,” Tackenberg explains. Fortunately, stem cell transplantation in mice also reversed motor impairments caused by stroke. Proof of that was delivered in part by an AI-assisted mouse gait analysis.

When he was designing the studies, Tackenberg already had his sights set on clinical applications in humans. That’s why, for example, the stem cells were manufactured without the use of reagents derived from animals. The Zurich-based research team developed a defined protocol for that purpose in collaboration with the Center for iPS Cell Research and Application (CiRA) at Kyoto University. This is important for potential therapeutic applications in humans.

Another new insight discovered was that stem cell transplantation works better when it is performed not immediately after a stroke but a week later, as the second study verified. In the clinical setting, that time window could greatly facilitate therapy preparation and implementation.

Despite the encouraging results of the studies, Tackenberg warns that there is still work to be done.

“We need to minimize risks and simplify a potential application in humans,” he says.

Tackenberg’s group, again in collaboration with Ruslan Rust, is currently working on a kind of safety switch system that prevents uncontrolled growth of stem cells in the brain. Delivery of stem cells through endovascular injection, which would be much more practicable than a brain graft, is also under development. Initial clinical trials using induced stem cells to treat Parkinson’s disease in humans are already underway in Japan, Tackenberg reports.

“Stroke could be one of the next diseases for which a clinical trial becomes possible,” Tackenberg says.

The first study appears in Nature Communications. The second appears in Advanced Science.

Source: University of Zurich

A new study reveals that small cell lung cancer likely begins in basal stem cells rather than in neuroendocrine cells, marking a major shift in the understanding of this aggressive disease that is often associated with smoking.

For decades, scientists have thought small cell lung cancer (SCLC) begins in specialized lung cells known as neuroendocrine cells. The study—led by Duke scientists and published in the journal Nature—shows basal cells (which have the ability to regenerate multiple lung cell types) can give rise to tumors in both the classic neuroendocrine form and a tuft-like form.

The tuft-like form is associated with poor patient outcomes and resistance to current therapies. By pinpointing that basal cells can form both tumor states, researchers can now explore strategies to prevent the disease before it evades the immune system and spreads.

“This discovery reshapes our understanding of how small cell lung cancer begins,” says the study’s senior author, Trudy G. Oliver, professor in the pharmacology and cancer biology department at Duke University School of Medicine.

“Our models, for the first time, reflect the full complexity of the disease,” Oliver says, “allowing us to study and target its most dangerous forms.”

Using genetically engineered mice, 3D tumor organoids, and the largest-available dataset of human SCLC tumors (at 944 samples), researchers also discovered the tuft-like tumors were only triggered when genetic changes were introduced into basal cells—not neuroendocrine cells—suggesting a fundamental shift in how scientists understand the disease.

“We used a technique called lineage barcoding that allowed us to tag individual cells and track how they evolve over time,” says the study’s first author, Abbie S. Ireland, graduate student in the Molecular Cancer Biology program at Duke University School of Medicine.

“This revealed that small cell lung cancer cells can shapeshift through a process called cell fate plasticity,” Ireland says, “which helps explain why the disease resists treatment and could provide new approaches for how we might block their transition into aggressive cancer.”

The researchers say this discovery creates the first accurate lab models of the most treatment-resistant tuft-like form of SCLC. The models, in combination with new foundational understanding, allow for advancement in the study of early detection and targeted therapies.

“We now have the tools to explore how the immune system interacts with these basal cells before they transform into aggressive cancer. That opens the door to therapies that could stop the disease before it even starts,” says Oliver.

Funding for the research came from the Duke Science and Technology Scholar initiative, the National Institutes of Health through National Cancer Institute grants, and the Cancer Center Support Grant.

Source: Duke University

Excess fat in brain immune cells weakens defenses against Alzheimer’s. Blocking fat storage restored their ability to fight disease.

For many years, scientists believed that fat in the brain had little connection to neurodegenerative diseases. Purdue University researchers are now challenging that view.

Their study, published in Immunity, demonstrates that an accumulation of fat in microglia, the brain’s immune cells, weakens their disease-fighting capacity. The discovery points toward new therapeutic strategies in lipid biology that could support microglial activity and improve neuronal health in conditions such as Alzheimer’s. The work was led by Gaurav Chopra, the James Tarpo Jr. and Margaret Tarpo Professor of Chemistry and (by courtesy) of Computer Science at Purdue.

Looking beyond plaques and tangles

Most Alzheimer’s treatments in development aim at the disease’s main hallmarks: amyloid beta protein plaques and tau protein tangles. Chopra, however, is directing attention to the unusually fat-laden cells found around damaged areas of the brain.

In earlier research published in Nature, Chopra and colleagues showed that astrocytes—cells that provide support to neurons—release a fatty acid that becomes toxic to brain cells under disease conditions. Another collaborative study with the University of Pennsylvania, also published in Nature the previous year, connected age-related mitochondrial dysfunction in neurons to fat buildup in glial cells, highlighting a key risk factor for neurodegeneration.

“In our view, directly targeting plaques or tangles will not solve the problem; we need to restore function of immune cells in the brain,” Chopra said. “We’re finding that reducing accumulation of fat in the diseased brain is the key, as accumulated fat makes it harder for the immune system to do its job and maintain balance. By targeting these pathways, we can restore the ability of immune cells like microglia to fight disease and keep the brain in balance, which is what they’re meant to do.”

Chopra’s team worked in collaboration with researchers at Cleveland Clinic led by Dimitrios Davalos, assistant professor of molecular medicine. Chopra is also the director of Merck-Purdue Center and a member of the Purdue Institute for Integrative Neuroscience; the Purdue Institute for Drug Discovery; the Purdue Institute of Inflammation, Immunology and Infectious Disease; and the Regenstrief Center for Healthcare Engineering.

Chopra’s work is part of Purdue’s presidential One Health initiative, which brings together research on human, animal, and plant health. His research supports the initiative’s focus on advanced chemistry, where Purdue faculty study complex chemical systems and develop new techniques and applications.

Fat droplets as drivers of disease

Over a century ago, Alois Alzheimer documented unusual features in the brain of a patient with the condition later named after him. These included protein plaques, tangles, and cells packed with lipid droplets. For many years, such lipid deposits were regarded as mere by-products of the disease.

Chopra and his colleagues, however, have uncovered strong evidence linking fats in microglia and astrocytes—two types of glial cells that support neurons—to neurodegeneration. Based on these findings, Chopra proposes a “new lipid model of neurodegeneration,” referring to these accumulations as “lipid plaques” since they differ in form from typical spherical droplets.

“It is not the lipid droplets that are pathogenic, but the accumulation of these droplets is bad. We think the composition of lipid molecules that accumulate within brain cells is one of the major drivers of neuroinflammation, leading to different pathologies, such as aging, Alzheimer’s disease, and other conditions related to inflammatory insults in the brain. The specific composition of these lipid plaques may define particular brain diseases,” Chopra said.

Microglia impaired by lipid accumulation

The Immunity paper focuses on microglia, the “bona fide immune cells of the brain,” which clear out debris, such as misfolded proteins like amyloid beta and tau, by absorbing and breaking them down through a process called phagocytosis. Chopra’s team examined microglia in the presence of amyloid beta and asked a simple question: What happens to microglia when they come into contact with amyloid beta?

Images of brain tissue from people with Alzheimer’s disease showed amyloid beta plaques surrounded by microglia. Microglia located within 10 micrometers of these plaques contained twice as many lipid droplets as those farther away. These lipid droplet-laden microglia closest to the plaques cleared 40% less amyloid beta than ordinary microglia from brains without disease.

How fatty acids become trapped

In their investigation into why microglia were impaired in Alzheimer’s brains, the team used specialized techniques and found that microglia in contact with plaques and disease-related inflammation produced an excess of free fatty acids. While microglia normally use free fatty acids as an energy source — and some production of these fatty acids is even beneficial — Chopra and his team discovered the microglia closest to amyloid beta plaques convert these free fatty acids to triacylglycerol, a stored form of fat, in such large quantities that they become overloaded and immobilized by their own accumulation. The formation of these lipid droplets depends on age and disease progression, becoming more prominent as Alzheimer’s disease advances.

By tracing the complex series of steps microglia use to convert free fatty acids to triacylglycerol, the research team zeroed in on the final step of this pathway. They found abnormally high levels of an enzyme called DGAT2 catalyzes the final step of converting free fatty acids to triacylglycerol. They expected to see equally high levels of the DGAT2 gene — since the gene must be copied to produce the protein — but that was not the case. The enzyme accumulates because it is not degrading as quickly as it normally would, rather than being overproduced. This accumulation of DGAT2 causes microglia to divert fatty acids into long-term storage and fat accumulation instead of using them for energy or repair.

Restoring microglial function

“We showed that amyloid beta is directly responsible for the fat that forms inside microglia,” Chopra said. “Because of these fatty deposits, microglial cells become dysfunctional — they stop clearing amyloid beta and stop doing their job.”

Chopra said the researchers don’t yet know what causes the DGAT2 enzyme to persist. However, in their search for a remedy, the team tested two molecules: one that inhibits DGAT2’s function and another that promotes its degradation. The degradation of the DGAT2 enzyme was ultimately beneficial to reduce fat in the brains, improve function of microglia and their ability to eat amyloid-beta plaques, and improve markers of neuronal health in Alzheimer’s disease animal models.

“What we’ve seen is that when we target the fat-making enzyme and either remove or degrade it, we restore the microglia’s ability to fight disease and maintain balance in the brain — which is what they’re meant to do,” Chopra said.

“This is an exciting finding that reveals how a toxic protein plaque directly influences how lipids are formed and metabolized by microglial cells in Alzheimer’s brains,” said Priya Prakash, a first co-author of the study. “While most recent work in this area has focused on the genetic basis of the disease, our research paves the way for understanding how lipids and their pathways within the brain’s immune cells can be targeted to restore their function and combat the disease.”

“It’s incredibly exciting to connect fat metabolism to immune dysfunction in Alzheimer’s,” said Palak Manchanda, the other first co-author. “By pinpointing this lipid burden and the DGAT2 switch that drives it, we reveal a completely new therapeutic angle: Restore microglial metabolism and you may restore the brain’s own defense against disease.”

References:

“Neurotoxic reactive astrocytes induce cell death via saturated lipids” by Kevin A. Guttenplan, Maya K. Weigel, Priya Prakash, Prageeth R. Wijewardhane, Philip Hasel, Uriel Rufen-Blanchette, Alexandra E. Münch, Jacob A. Blum, Jonathan Fine, Mikaela C. Neal, Kimberley D. Bruce, Aaron D. Gitler, Gaurav Chopra, Shane A. Liddelow and Ben A. Barres, 6 October 2021, Nature.
DOI: 10.1038/s41586-021-03960-y

“Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease” by Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Jitika Rajpoot, Victoria Wendt, Ahad Hossain, Prageeth R. Wijewardhane, Caitlin E. Randolph, Yihao Chen, Sarah Stanko, Nadia Gasmi, Anxhela Gjojdeshi, Sophie Card, Jonathan Fine, Krupal P. Jethava, Matthew G. Clark, Bin Dong, Seohee Ma, Alexis Crockett, Elizabeth A. Thayer, Marlo Nicolas, Ryann Davis, Dhruv Hardikar, Daniela Allende, Richard A. Prayson, Chi Zhang, Dimitrios Davalos and Gaurav Chopra, 19 May 2025, Immunity.
DOI: 10.1016/j.immuni.2025.04.029

“Senescent glia link mitochondrial dysfunction and lipid accumulation” by China N. Byrns, Alexandra E. Perlegos, Karl N. Miller, Zhecheng Jin, Faith R. Carranza, Palak Manchandra, Connor H. Beveridge, Caitlin E. Randolph, V. Sai Chaluvadi, Shirley L. Zhang, Ananth R. Srinivasan, F. C. Bennett, Amita Sehgal, Peter D. Adams, Gaurav Chopra and Nancy M. Bonini, 5 June 2024, Nature.
DOI: 10.1038/s41586-024-07516-8

Funding: U.S. Department of Defense, NIH/National Institute of Neurological Disorders and Stroke, NIH/National Institute of Mental Health, NIH/National Institutes of Health, NIH/National Institute on Aging

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