Connect with us

TOP SCEINCE

Brain ‘assembloids’ mimic human blood-brain barrier

Published

on

Brain ‘assembloids’ mimic human blood-brain barrier


In a pioneering achievement, a research team led by experts at Cincinnati Children’s have developed the world’s first human mini-brain that incorporates a fully functional blood-brain barrier (BBB).

This major advance, published May 15, 2024, in Cell Stem Cell, promises to accelerate the understanding and improved treatment of a wide range of brain disorders, including stroke, cerebral vascular disorders, brain cancer, Alzheimer’s disease, Huntington disease, Parkinson’s disease, and other neurodegenerative conditions.

“Lack of an authentic human BBB model has been a major hurdle in studying neurological diseases,” says lead corresponding author Ziyuan Guo, PhD, “Our breakthrough involves the generation of human BBB organoids from human pluripotent stem cells, mimicking human neurovascular development to produce a faithful representation of the barrier in growing, functioning brain tissue. This is an important advance because animal models we currently use in research do not accurately reflect human brain development and BBB functionality.”

What is the blood-brain barrier?

Unlike the rest of our bodies, blood vessels in the brain feature an extra lining of tightly packed cells that sharply limit the size of molecules that can pass from the bloodstream into the central nervous system (CNS).

A properly functioning barrier maintains brain health by preventing the entry of harmful substances while allowing essential nutrients to reach the brain. However, that same barrier also prevents many potentially helpful medicines from reaching the brain. Also, several neurological disorders are caused, or worsened, when the blood-brain barrier forms improperly or begins breaking down.

Significant differences between human and animal brains have resulted in many hopeful new drugs that were developed relying heavily on animal models to fail later when tested in human study participants.

“Now, through stem cell bioengineering, we have developed an innovative platform based on human stem cells that allows us to study the intricate mechanisms governing BBB function and dysfunction. This provides unprecedented opportunities for drug discovery and therapeutic intervention,” Guo says.

Overcoming a long-running challenge

Research teams worldwide have been racing to develop brain organoids — tiny, growing 3D structures that mimic the early steps of brain formation. Unlike cell types grown flat in a lab dish, organoid cells are connected. They self-assemble into spherical forms. Their cells “talk” to each other like human cells normally do during fetal development.

Cincinnati Children’s has been a leader in developing other types of organoids, including the world’s first functional intestine, stomach and esophagus organoids. But until now, no research center had succeeded at making a brain organoid that features the special barrier lining found in human brain blood vessels.

The research team calls their new model “BBB assembloids.” Their name reflects the advance that made the breakthrough possible. These assembloids combine two distinct types of organoids: brain organoids that replicate human brain tissue and blood vessel organoids that mimic vascular structures.

The combination process began with brain organoids measuring 3 to 4 millimeters in diameter and blood vessel organoids about 1 millimeter in diameter. Over the course of about a month, these separate structures fused into a single sphere measuring slightly more than 4 millimeters in diameter (about 1/8 of an inch, or roughly the size of a sesame seed).

These integrated organoids recreate many of the complex neurovascular interactions observed in the human brain, but they are not complete models of the brain. For example, the tissue does not contain immune cells and there are no connections to the rest of the body’s nervous system.

Research teams at Cincinnati Children’s have shown other successes at merging and layering organoids from different cell types to form more complex “next generation” organoids. Those successes helped inform the new brain organoid work.

Importantly, the BBB assembloids can be grown using neurotypical human stem cells or stem cells from people with specific brain diseases, thus reflecting gene variants and other conditions that can lead to a malfunctioning blood-brain barrier.

Initial proof of concept

To demonstrate the potential utility of the new assembloids, the researcher team used a line of patient-derived stem cells to make assembloids that accurately replicated key features of a rare brain condition called a cerebral cavernous malformation.

This genetic disorder, which is characterized by dysfunctional blood-brain barrier integrity, results in clusters of abnormal blood vessels in the brain that often resemble raspberries in their appearance. The disorder significantly increases risk of stroke.

“Our model accurately recapitulated the disease phenotype, offering new insights into the underlying molecular and cellular pathology of cerebral vascular disorders,” Guo says.

Potential applications

The co-authors envision a variety of potential uses of BBB assembloids:

  • Personalized Drug Screening: Patient-derived BBB assembloids could serve as avatars to tailor therapies for patients based on their unique genetic and molecular profiles.
  • Disease Modeling: A number of neurovascular disorders, including rare and genetically complex conditions, lack good model systems for research. Success at making BBB assembloids could accelerate development of human brain tissue models for more conditions.
  • High-Throughput Drug Discovery: Scaling up assembloid production could allow more accurate, and more rapid analysis of whether potential brain medications can effectively cross the BBB.
  • Environmental Toxin Testing: Often based heavily on animal model systems, BBB assembloids could help evaluate the toxic effects of environmental pollutants, pharmaceuticals, and other chemical compounds.
  • Immunotherapy Development: Through investigating the role of the BBB in neuroinflammatory and neurodegenerative diseases, the new assembloids could support delivering immune-based therapies to the brain.
  • Bioengineering and Biomaterials Research: Biomedical engineers and materials scientists will likely benefit from having a lab model of the BBB to test novel biomaterials, drug delivery vehicles, and tissue engineering strategies.

“Overall, BBB assembloids represent a game-changing technology with broad implications for neuroscience, drug discovery, and personalized medicine,” Guo says.

About the study

In addition to Guo, the co-first authors of the study were: Lan Dao, MS, and Lu Lu, PhD, from Cincinnati Children’s; Tianyang Xu from UC San Diego; and Zhen You from the Mayo Clinic. Co-corresponding authors were Sheng Zhong, PhD, from UC San Diego and L. Frank Huang, PhD, from the Mayo Clinic.

Co-authors from Cincinnati Children’s also included Avijite Kumer Sarkar, PhD, Hui Zhu, PhD, George Yoshida, BA, Yifei Miao, PhD, Sarah Mierke, MD, Srijan Kalva, Mingxia Gu, MD, PhD, and Sudhakar Vadivelu, MD. The Single Cell Genomics Facility at Cincinnati Children’s and the NIH NeuroBioBank also provided key support to the research.

Guo and Dao have a pending patent application (“Vascularized brain organoids having a CCM-like feature and methods of making and use,” U.S. Application no. 63/510,463) related to this research. Zhong is a founder of Genemo, Inc.



Source link

Continue Reading
Click to comment

Leave a Reply

TOP SCEINCE

New drug shows promise in clearing HIV from brain

Published

on

By

Brain ‘assembloids’ mimic human blood-brain barrier


An experimental drug originally developed to treat cancer may help clear HIV from infected cells in the brain, according to a new Tulane University study.

For the first time, researchers at Tulane National Primate Research Center found that a cancer drug significantly reduced levels of SIV, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.

Published in the journal Brain, this discovery marks a significant step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.

“This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication,” said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center. “By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment.”

Antiretroviral therapy (ART) is an essential component of successful HIV treatment, maintaining the virus at undetectable levels in the blood and transforming HIV from a terminal illness into a manageable condition. However, ART does not completely eradicate HIV, necessitating lifelong treatment. The virus persists in “viral reservoirs” in the brain, liver, and lymph nodes, where it remains out of reach of ART.

The brain has been a particularly challenging area for treatment due to the blood-brain barrier — a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. In addition, cells in the brain known as macrophages are extremely long-lived, making them difficult to eradicate once they become infected.

Infection of macrophages is thought to contribute to neurocognitive dysfunction, experienced by nearly half of those living with HIV. Eradicating the virus from the brain is critical for comprehensive HIV treatment and could significantly improve the quality of life for those with HIV-related neurocognitive problems.

Researchers focused on macrophages, a type of white blood cell that harbors HIV in the brain. By using a small molecule inhibitor to block a receptor that increases in HIV-infected macrophages, the team successfully reduced the viral load in the brain. This approach essentially cleared the virus from brain tissue, providing a potential new treatment avenue for HIV.

The small molecule inhibitor used, BLZ945, has previously been studied for therapeutic use in amyotrophic lateral sclerosis (ALS) and brain cancer, but never before in the context of clearing HIV from the brain.

The study, which took place at the Tulane National Primate Research Center, utilized three groups to model human HIV infection and treatment: an untreated control group, and two groups treated with either a low or high dose of the small molecule inhibitor for 30 days. The high-dose treatment lead to a notable reduction in cells expressing HIV receptor sites, as well as a 95-99% decrease in viral DNA loads in the brain .

In addition to reducing viral loads, the treatment did not significantly impact microglia, the brain’s resident immune cells, which are essential for maintaining a healthy neuroimmune environment. It also did not show signs of liver toxicity at the doses tested.

The next step for the research team is to test this therapy in conjunction with ART to assess its efficacy in a combined treatment approach. This could pave the way for more comprehensive strategies to eradicate HIV from the body entirely.

This research was funded by the National Institutes of Health, including grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, and was supported with resources from the Tulane National Primate Research Center base grant of the National Institutes of Health, P51 OD011104.



Source link

Continue Reading

TOP SCEINCE

Chemical analyses find hidden elements from renaissance astronomer Tycho Brahe’s alchemy laboratory

Published

on

By

Brain ‘assembloids’ mimic human blood-brain barrier


In the Middle Ages, alchemists were notoriously secretive and didn’t share their knowledge with others. Danish Tycho Brahe was no exception. Consequently, we don’t know precisely what he did in the alchemical laboratory located beneath his combined residence and observatory, Uraniborg, on the now Swedish island of Ven.

Only a few of his alchemical recipes have survived, and today, there are very few remnants of his laboratory. Uraniborg was demolished after his death in 1601, and the building materials were scattered for reuse.

However, during an excavation in 1988-1990, some pottery and glass shards were found in Uraniborg’s old garden. These shards were believed to originate from the basement’s alchemical laboratory. Five of these shards — four glass and one ceramic — have now undergone chemical analyses to determine which elements the original glass and ceramic containers came into contact with.

The chemical analyses were conducted by Professor Emeritus and expert in archaeometry, Kaare Lund Rasmussen from the Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark. Senior researcher and museum curator Poul Grinder-Hansen from the National Museum of Denmark oversaw the insertion of the analyses into historical context.

Enriched levels of trace elements were found on four of them, while one glass shard showed no specific enrichments. The study has been published in the journal Heritage Science.

“Most intriguing are the elements found in higher concentrations than expected — indicating enrichment and providing insight into the substances used in Tycho Brahe’s alchemical laboratory,” said Kaare Lund Rasmussen.

The enriched elements are nickel, copper, zinc, tin, antimony, tungsten, gold, mercury, and lead, and they have been found on either the inside or outside of the shards.

Most of them are not surprising for an alchemist’s laboratory. Gold and mercury were — at least among the upper echelons of society — commonly known and used against a wide range of diseases.

“But tungsten is very mysterious. Tungsten had not even been described at that time, so what should we infer from its presence on a shard from Tycho Brahe’s alchemy workshop?,” said Kaare Lund Rasmussen.

Tungsten was first described and produced in pure form more than 180 years later by the Swedish chemist Carl Wilhelm Scheele. Tungsten occurs naturally in certain minerals, and perhaps the element found its way to Tycho Brahe’s laboratory through one of these minerals. In the laboratory, the mineral might have undergone some processing that separated the tungsten, without Tycho Brahe ever realizing it.

However, there is also another possibility that Professor Kaare Lund Rasmussen emphasizes has no evidence whatsoever — but which could be plausible.

Already in the first half of the 1500s, the German mineralogist Georgius Agricola described something strange in tin ore from Saxony, which caused problems when he tried to smelt tin. Agricola called this strange substance in the tin ore “Wolfram” (German for Wolf’s froth, later renamed to tungsten in English).

“Maybe Tycho Brahe had heard about this and thus knew of tungsten’s existence. But this is not something we know or can say based on the analyses I have done. It is merely a possible theoretical explanation for why we find tungsten in the samples,” said Kaare Lund Rasmussen.

Tycho Brahe belonged to the branch of alchemists who, inspired by the German physician Paracelsus, tried to develop medicine for various diseases of the time: plague, syphilis, leprosy, fever, stomach aches, etc. But he distanced himself from the branch that tried to create gold from less valuable minerals and metals.

In line with the other medical alchemists of the time, he kept his recipes close to his chest and shared them only with a few selected individuals, such as his patron, Emperor Rudolph II, who allegedly received Tycho Brahe’s prescriptions for plague medicine.

We know that Tycho Brahe’s plague medicine was complicated to produce. It contained theriac, which was one of the standard remedies for almost everything at the time and could have up to 60 ingredients, including snake flesh and opium. It also contained copper or iron vitriol (sulphates), various oils, and herbs.

After various filtrations and distillations, the first of Brahe’s three recipes against plague was obtained. This could be made even more potent by adding tinctures of, for example, coral, sapphires, hyacinths, or potable gold.

“It may seem strange that Tycho Brahe was involved in both astronomy and alchemy, but when one understands his worldview, it makes sense. He believed that there were obvious connections between the heavenly bodies, earthly substances, and the body’s organs. Thus, the Sun, gold, and the heart were connected, and the same applied to the Moon, silver, and the brain; Jupiter, tin, and the liver; Venus, copper, and the kidneys; Saturn, lead, and the spleen; Mars, iron, and the gallbladder; and Mercury, mercury, and the lungs. Minerals and gemstones could also be linked to this system, so emeralds, for example, belonged to Mercury,” explained Poul Grinder-Hansen.

Kaare Lund Rasmussen has previously analyzed hair and bones from Tycho Brahe and found, among other elements, gold. This could indicate that Tycho Brahe himself had taken medicine that contained potable gold.



Source link

Continue Reading

TOP SCEINCE

Nitrogen emissions have a net cooling effect: But researchers warn against a climate solution

Published

on

By

Brain ‘assembloids’ mimic human blood-brain barrier


An international team of researchers has found that nitrogen emissions from fertilisers and fossil fuels have a net cooling effect on the climate. But they warn increasing atmospheric nitrogen has further damaging effects on the environment, calling for an urgent reduction in greenhouse gas emissions to halt global warming.

Published today in Nature, the paper found that reactive nitrogen released in the environment through human activities cools the climate by minus 0.34 watts per square metre. While global warming would have advanced further without the input of human-generated nitrogen, the amount would not offset the level of greenhouse gasses heating the atmosphere.

The paper was led by the Max Planck Institute in Germany and included authors from the University of Sydney. It comes one day after new data from the European Union’s Copernicus Climate Change Service indicated that Sunday, 21 July was the hottest day recorded in recent history.

The net cooling effect occurs in four ways:

  • Short-lived nitrogen oxides produced by the combustion of fossil fuels pollute the atmosphere by forming fine suspended particles which shield sunlight, in turn cooling the climate;

  • ammonia (a nitrogen and hydrogen-based compound) released into the atmosphere from the application of manure and artificial fertilisers has a similar effect;

  • nitrogen applied to crops allows plants to grow more abundantly, absorbing more CO2 from the atmosphere, enabling a cooling effect;

  • nitrogen oxides also play a role in the breakdown of atmospheric methane, a potent greenhouse gas.

The researchers warned that increasing atmospheric nitrogen was not a solution for combatting climate change.

“Nitrogen fertilisers pollute water and nitrogen oxides from fossil fuels pollute the air. Therefore, increasing rates of nitrogen in the atmosphere to combat climate change is not an acceptable compromise, nor is it a solution,” said Professor Federico Maggi from the University of Sydney’s School of Civil Engineering.

Sönke Zaehle from the Max Planck Institute said: “This may sound like good news, but you have to bear in mind that nitrogen emissions have many harmful effects, for example on health, biodiversity and the ozone layer. The current findings, therefore, are no reason to gloss over the harmful effects, let alone see additional nitrogen input as a means of combatting global warming.”

Elemental nitrogen, which makes up around 78 percent of the air, is climate-neutral, but other reactive nitrogen compounds can have direct or indirect effects on the global climate — sometimes warming and at other times cooling. Nitrous oxide (N2O) is an almost 300 times more potent greenhouse gas than CO2. Other forms of nitrogen stimulate the formation of ozone in the troposphere, which is a potent greenhouse gas and enhances global warming.

Professor Maggi said the research was important as it helped the team gain an understanding of the net-effect of the distribution of nitrogen emissions from agriculture.

“This work is an extraordinary example of how complex interactions at planetary scales cannot be captured with simplistic assessment tools. It shows the importance of developing mathematical models that can show the emergence of nonlinear — or unproportional — effects across soil, land, and atmosphere,” he said.

“Even if it appears counter-intuitive, reactive nitrogen introduced in the environment, mostly as agricultural fertilisers, can reduce total warming. However, this is minor compared with the reduction in greenhouse gas emissions required to keep the planet within safe and just operational boundaries.

“New generation computational tools are helping drive new learnings in climate change science, but understanding is not enough — we must act with great urgency to reduce greenhouse gas emissions.”

Gaining a holistic understanding of the impacts of nitrogen

The scientists determined the overall impact of nitrogen from human sources by first analysing the quantities of the various nitrogen compounds that end up in soil, water and air.

They then fed this data into models that depict the global nitrogen cycle and the effects on the carbon cycle, for example the stimulation of plant growth and ultimately the CO2 and methane content of the atmosphere. From the results of these simulations, they used another atmospheric chemistry model to calculate the effect of man-made nitrogen emissions on radiative forcing, that is the radiant energy that hits one square metre of the Earth’s surface per unit of time.



Source link

Continue Reading

Trending