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Stem cell model offers first glimpse of early human embryonic development

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Stem cell model offers first glimpse of early human embryonic development


It’s one of life’s most defining moments — that crucial step in embryonic development, when an indistinct ball of cells rearranges itself into the orderly three-layered structure that sets the stage for all to come. Known as gastrulation, this crucial process unfolds in the third week of human development. “Gastrulation is the origin of our own individualization, the emergence of our axis,” says Rockefeller’s Ali Brivanlou. “It is the first moment that separates our heads from our behinds.”

Observing the molecular underpinnings of this pivotal event would go a long way toward helping scientists prevent miscarriages and developmental disorders. But studying human gastrulation has proven both technologically difficult and ethically complicated, and thus current approaches have had limited success in expanding our understanding of early human development. Now Brivanlou and colleagues have demonstrated how a stem cell model system known as a blastoid can allow the study of the nuances of human gastrulation in the presence of pre-implantation extra-embryonic cell types. Their study, published in Stem Cell Reports, describes the scientific and clinical potential of this new platform.

“Gastrulation was a tremendous black box. We had never seen ourselves at that stage,” Brivanlou says. “This moves us closer to understanding how we begin.”

A better blastocyst

Prior to implantation, an embryo is a ball of about 250 cells organized as a blastocyst. This elusive ball of cells was difficult to study directly, so scientists developed blastoids — stem-cell-based blastocyst models. Blastoids can be cloned, experimentally manipulated, and programmed, allowing scientists to study identical blastoids over and over again.

The question was whether blastoids could gastrulate in vitro. Unlike a blastocyst in vivo, which rolls around in the uterus until it attaches to maternal tissue, blastoids were good at modeling the ball of cells from which life emerges, but it remained unclear whether this in vitro model could model later stages of human development. That is, until Brivanlou developed a platform to allow blastoids to attach in vitro, and thereby progress toward gastrulation.

“We were then able to see epiblast symmetry breaking, marked by BRA expression, for the first time with the high molecular resolution,” says Riccardo De Santis, a research associate in the Brivanlou lab and lead author on the study. “This allowed us to start asking more detailed questions about the earliest moments of life.”

With this unprecedented clarity, the team directly observed two key moments in gastrulation: the first epiblast symmetry-breaking event and the emergence of the molecular markers of the primitive streak and mesoderm upon in vitro attachment.

The primitive streak is a structure that marks the beginning of gastrulation and lays the foundation for the three primary layers of the embryo. One of those layers, the mesoderm, forms during gastrulation and gives rise to muscles, bones, and the circulatory system. The team discovered that, as early as seven days after attachment, they were already able to use molecular markers to detect the earliest signature of a nascent primitive streak and mesodermal cells.

To confirm their findings, the team also compared the blastoid results with data from in vitro attached human embryos and demonstrated that blastoids express the same genes in vitro that a regular embryo would at that stage in vivo, a strong demonstration of the power of blastoids as models for human embryonic development. Further highlighting the power of the lab’s in vitro attached blastoid system, the team then used it to demonstrate that pathways that regulate the rise of the primitive streak and mesoderm in vivo also regulate blastoids symmetry breaking in vitro — all with nothing but stem-cell-derived blastoid models.

Along the way, the team also demonstrated that gastrulation in vitro can begin at day 12, earlier than once thought. “This will change textbooks,” Brivanlou says. “We’ve contributed to redefining the molecular signature and timing of the onset of gastrulation upon in vitro attachment.”

Therapeutic possibilities

The results demonstrate that blastoids, when combined with the Brivanlou lab’s unique attachment platform, are now capable of conveying insights into early human development that have long been inaccessible. De Santis envisions a future in which blastoid-based research leads to advancements in diagnosing and treating developmental disorders, or offers insights into potential causes of early miscarriages during gastrulation.

“Many couples can’t have babies because the embryo doesn’t attach properly, and many miscarriages occur in the first few weeks of pregnancy,” De Santis explains. “We now have a model system that can help us understand the molecular mechanism that defines whether a pregnancy will be successful or not.” In the near future, De Santis hopes to combine this method with machine learning to help predict pregnancy outcomes and the trajectories of developmental disorders by observing how model blastoids built with particular genetic makeups fare in vitro.

“A better understanding of gastrulation — and the ability to study it with a reliable model system — impacts everything from survival of the fetus to autism to neurodegeneration.”



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Early dark energy could resolve cosmology’s two biggest puzzles

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A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.

One puzzle in question is the “Hubble tension,” which refers to a mismatch in measurements of how fast the universe is expanding. The other involves observations of numerous early, bright galaxies that existed at a time when the early universe should have been much less populated.

Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.

Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.

The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.

You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”

The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.

Big city lights

Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.

But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.

“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”

For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.

Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.

Galaxy skeleton

The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.

“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”

The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.

Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.

The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.

“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”

“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”

We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”

This research was supported, in part, by NASA and the National Science Foundation.



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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions

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A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.

It is well known that plants release volatile organic compounds (VOCs) into the atmosphere when damaged by herbivores. These VOCs play a crucial role in plant-plant interactions, whereby undamaged plants may detect warning signals from their damaged neighbours and prepare their defences. “Reactive plant VOCs undergo oxidative chemical reactions, resulting in the formation of secondary organic aerosols (SOAs). We wondered whether the ecological functions mediated by VOCs persist after they are oxidated to form SOAs,” said Dr. Hao Yu, formerly a PhD student at UEF, but now at the University of Bern.

The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.

“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.

“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.

The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.



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Folded or cut, this lithium-sulfur battery keeps going

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Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.

Sulfur has been suggested as a material for lithium-ion batteries because of its low cost and potential to hold more energy than lithium-metal oxides and other materials used in traditional ion-based versions. To make Li-S batteries stable at high temperatures, researchers have previously proposed using a carbonate-based electrolyte to separate the two electrodes (an iron sulfide cathode and a lithium metal-containing anode). However, as the sulfide in the cathode dissolves into the electrolyte, it forms an impenetrable precipitate, causing the cell to quickly lose capacity. Liping Wang and colleagues wondered if they could add a layer between the cathode and electrolyte to reduce this corrosion without reducing functionality and rechargeability.

The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.

After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.

The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.



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