However, despite extensive efforts, regenerative therapies involving PSCs still have many hurdles to overcome. One being the formation of tumors (via the process of tumorigenesis) after the transplantation of PSCs. Once the PSCs differentiate into a specific type for stem cell therapy, there is a high probability of tumor formation after differentiated stem cells are introduced to the target organ. For the success of PSC-based therapies, the need of the hour is to minimize the risk of tumorigenesis by identifying potentially problematic cells in cultures, prior to transplantation.

Against this backdrop, a research team led by Atsushi Intoh and Akira Kurisaki from Nara Institute of Science and Technology, Japan, has recently achieved a breakthrough discovery regarding stem cell therapy and tumorigenesis. “Our findings present advancements that could bridge the gap between stem cell research and clinical application,” says Intoh, talking about the potential of their findings. Their study was published in Stem Cells Translational Medicine and focuses on a membrane protein called EPHA2, which was previously found to be elevated in PSCs prior to differentiation by the team.

Through several experiments involving both mouse and human stem cell cultures, the researchers gained insights into the role of EPHA2 in preserving the potency of PSCs to develop into several cell types. They found that EPHA2 in stem cells is co-expressed with OCT4 — a transcription factor protein which controls the expression of genes which are critically involved in the differentiation of embryonic stem cells. Interestingly, when the EPHA2 gene was knocked down from the cells, cultured stem cells spontaneously differentiated. These results suggest that EPHA2 plays a central role in keeping stem cells in an undifferentiated state.

The researchers thus theorized that EPHA2-expressing stem cells, which would fail to differentiate, might be responsible for tumorigenesis upon transplantation into the target organ.

To test this hypothesis, the researchers prepared PSC cultures and artificially induced their differentiation into liver cells. Using a magnetic antibody targeting EPHA2, they extracted EPHA2-positive cells from a group of cultures prior to transplantation into mice. Interestingly, the formation of tumors in mice receiving transplants from cultures from which EPHA2 had been removed was vastly suppressed.

Taken together, these results point to the importance of EPHA2 in emerging stem cell-based therapies. “EPHA2 conclusively emerges as a potential marker for selecting undifferentiated stem cells, providing a valuable method to decrease tumorigenesis risks after stem cell transplantation in regenerative treatments,” remarks Kurisaki.

Further in-depth studies on this protein may lead to the development of protocols that make PSCs safer to use. Luckily, however, these findings pave the way towards a future where we will be able to finally restore damaged organs and even overcome degenerative conditions.

“You can’t even tell what it is, let alone which animal it came from,” said John Moretti, a doctoral student at the UT Jackson School of Geosciences who led research. “It’s like a geode. It’s ugly on the outside, and the treasure is all inside.”

The research was published in the May issue of The Anatomical Record.

The fossil looks like a lumpy, rounded rock with a couple of exposed teeth that are a little worse for wear, having been submerged and tumbled along the floor of the Gulf of Mexico for thousands of years before washing up on a beach. But when the fossil was X-rayed at the Jackson School’s University of Texas Computed Tomography Lab, Moretti saw there was more to the fossil that met the eye: a hidden canine tooth that had not yet erupted from the jaw bone.

It was just what Moretti needed to identify the fossil as belonging to a Homotherium, a genus of large cat that roamed much of the Earth for millions of years. Because this specific cat wasn’t fully grown when it died, its distinctive saber-like canine tooth had not fallen into its permanent position. Nestled inside the jaw, the tooth was protected from the elements.

“Had that saber tooth been all the way erupted and fully in its adult form, and not some awkward teenage in-between stage, it would have just snapped right off,” Moretti said. “It wouldn’t have been there, and we wouldn’t have that to use as evidence.”

Homotherium spanned across habitats in Africa, Eurasia and the Americas. It was a large, robust cat about the size of a jaguar, with an elongated face, lanky front legs, and a sloping back that ended in a bobtail. Their serrated canine teeth were covered by large gum flaps, similar to domestic dogs today.

Their fossils have been found in several areas of Texas, but this fossil shows for the first time that the big cat roamed the now-submerged continental shelf that connects Texas and Florida. Scientists hypothesize that this stretch of land was a Neotropical corridor. Animals such as capybaras and giant armadillos that wouldn’t have ventured farther north used this strip of humid grassland to move from Mexico to Texas to Florida.

The discovery that Homotherium lived along this corridor gives scientists a small glimpse into the ecology of this landscape during the Late Pleistocene, Moretti said. Big carnivores such as these cats helped shape the broader animal community, tamping down prey-animal populations and influencing regional biodiversity.

The fossil specimen was discovered more than 60 years ago on McFaddin Beach, south of Beaumont, by Russell Long, a professor at Lamar University, but was donated by U.S. Rep. Brian Babin, a former student of Long’s who worked for 38 years as a dentist. Babin said that his training in paleontology and dentistry helped him recognize that what seems like a strange rock at first glance is actually an upper jaw bone and teeth.

“Without question, my professional knowledge and what I’ve learned as a dentist helped me in that regard,” he said.

The research is part of a larger initiative on McFaddin Beach fossils started in 2018 by William Godwin, curator at the Sam Houston State University Natural Science Museum and a co-author of the study. Co-authors also include Deanna Flores, Christopher J. Bell, Adam Hartstone-Rose, and Patrick J. Lewis. The research was funded by UT, Sam Houston State University and North Carolina State University.

“Previous observations have suggested that some massive star clusters (globular clusters) host an intermediate-mass black hole (IMBH),” Fujii explains the motivation for the research project. “An IMBH is a black hole with a mass of 100-10000 solar masses. So far, there has been no strong theoretical evidence to show the existence of IMBH with 1000-10,10.1126/science.adi4211000 solar masses compared to less massive (stellar mass) and more massive (supermassive) ones.”

Birthing nests might conjure up images of warmth and tranquility. Not so with stars. Globular star clusters form in turmoil. The differences in density first cause stars to collide and merge. As the stars continue to merge and grow, the gravitational forces grow with them. The repeated stellar collisions in the dense, central region of globular clusters are called runaway collisions. They can lead to the birth of very massive stars with more than 1000 solar masses. These stars could potentially evolve into IMBHs. However, previous simulations of already-formed clusters suggested that stellar winds blow away most of their mass, leaving them too small. To investigate whether IMBHs could “survive,” researchers needed to simulate a cluster while it was still forming.

“Star cluster formation simulations were challenging because of the simulation cost,” Fujii says. “We, for the first time, successfully performed numerical simulations of globular cluster formation, modeling individual stars. By resolving individual stars with a realistic mass for each, we could reconstruct the collisions of stars in a tightly packed environment. For these simulations, we have developed a novel simulation code, in which we could integrate millions of stars with high accuracy.”

In the simulation, the runaway collisions indeed led to the formation of very massive stars that evolved into intermediate-mass black holes. The researchers also found that the mass ratio between the cluster and the IMBH matched that of the observations that originally motivated the project.

“Our final goal is to simulate entire galaxies by resolving individual stars,” Fujii points to future research. “It is still difficult to simulate Milky Way-size galaxies by resolving individual stars using currently available supercomputers. However, it would be possible to simulate smaller galaxies such as dwarf galaxies. We also want to target the first clusters, star clusters formed in the early universe. First clusters are also places where IMBHs can be born.”

That could pose a threat to biodiversity in waterways around the world and increase the amount of carbon in Earth’s atmosphere, potentially exacerbating climate change.

Published in Science, the study is the first to combine a global experiment and predictive modeling to illustrate how human impacts to waterways may contribute to the global climate crisis.

“Everyone in the world needs water,” said Krista Capps, co-author of the study and an associate professor in UGA’s Odum School of Ecology and Savannah River Ecology Laboratory. “When human activities change the fundamental ways rivers work, it’s concerning. Increases in decomposition rates may be problematic for the global carbon cycle and for animals, like insects and fish, that live in streams because the food resources they need to survive will disappear more quickly, lost to the atmosphere as carbon dioxide.”

Global warming, urbanization, increased nutrients altering global carbon cycle

Rivers and streams play a key role in the global carbon cycle by storing and decomposing large amounts of leaves, branches and other plant matter.

Typically, the process would go something like this: Leaf falls into river. Bacteria and fungi colonize the leaf. An insect eats the bacteria and fungi, using the carbon stored in the leaf to grow and make more insects. A fish eats the insect.

The study found that this process is changing in areas of the world impacted by humans.

Rivers impacted by urbanization and agriculture are changing how quickly leaf litter decomposes.

And when the process speeds up, that insect doesn’t have a chance to absorb the carbon from the leaf. Instead, the carbon is released into the atmosphere, contributing to greenhouse gas pollution and ultimately disrupting the food chain.

“When we think of greenhouse gas emissions, we tend to think of tailpipes and factories,” said Scott Tiegs, co-author of the study and a professor of biological sciences at Oakland. “But a lot of carbon dioxide and methane comes from aquatic ecosystems. This process is natural. But when humans add nutrient pollution like fertilizer to fresh waters and elevate water temperatures, we increase the decomposition rates and direct more CO2 into the atmosphere.”

Reducing human impact could improve water quality, help fight climate change

The researchers collected field data from 550 rivers across the globe, collaborating with more than 150 researchers in 40 countries.

Based on that data, the scientists generated one of the first estimates of decomposition rates in rivers and streams throughout the world, including understudied areas such as the tropics.

The authors compiled the data into a free online mapping tool that shows how fast different kinds of leaves decompose in local waterways.

Using predictive modeling, the researchers also identified environmental factors responsible for increased decomposition rates, such as higher temperatures and increased nutrient concentrations.

“Both of these factors are impacted by human activities,” said David Costello, co-author of the study and an associate professor at Kent State. “Reducing human impacts on decomposition will keep more carbon in rivers, preventing it from entering the atmosphere as carbon dioxide and contributing to climate change.”

The study was co-authored by John Paul Schmidt, from UGA’s Odum School of Ecology; Christopher J. Patrick, Virginia Institute of Marine Science; Jennifer J. Follstad Shah, University of Utah; Carrie J. LeRoy, The Evergreen State College; and the CELLDEX Consortium.

In a study published last month in Nature Communications, researchers from Tokyo Medical and Dental University (TMDU) have revealed that growing donor skin in another species yields surprisingly robust and functional skin grafts.

The gold standard for treating burn wounds is autologous skin grafting, a process in which sheets of skin containing both the epidermis (the outer layer) and the dermis (the deeper layer) are transferred from other parts of the patient’s body to cover the wounded area. However, for large wounds it can be difficult to harvest enough skin from the limited donor sites. Split-thickness grafts that contain mostly epidermis with only some of dermis can be used to cover larger areas, but they do not include features like hair and sweat glands, and are more prone to shrinkage and scarring.

“As alternatives to autologous skin grafts, artificial skin substitutes including cultured epidermis and reconstituted skins have been developed,” says the lead author of the study Dr. Hisato Nagano. “These options are inferior, though, as cultured epidermis can only be used for shallow wounds, and the engraftment rate of reconstituted skins is low.”

To provide proof-of-concept for a new way to produce autologous skin grafts, the researchers generated skin grafts by introducing a mutation into mouse fetuses that made them unable to grow mature epidermis. These fetuses were then injected with mouse stem cells and allowed to develop normally until birth, when their skin growth was analyzed.

“The results were very surprising,” explains Dr. Naoaki Mizuno, the corresponding author. “Not only were the chimeric mice born covered with large patches of skin derived from the injected cells, but these patches also survived up to 3 months when grafted onto mature mice, and even grew fur.”

Intriguingly, injecting the same mutated mouse embryos with human skin cells yielded similar results: as the mice developed in utero, they grew sheets of human skin that mimicked the structure and organization of mature epidermis.

“Our findings suggest that semi-autologous skin grafts containing hair follicles and other skin appendages can be generated in vivo and engrafted successfully,” says Dr. Hiromitsu Nakauchi, senior author.

Given that mouse embryos can only grow small amounts of skin, the next step would be to scale up the process to larger animals with a longer gestation period to generate large human skin grafts. This approach, which involves generating only skin tissue, could help avoid ethical concerns about using human-animal chimeras to produce organs for medical use.

The 2020 Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuelle Charpentier for developing a groundbreaking yet simple way to edit DNA, the “blueprint” of living organisms. While their discovery opened new avenues for research, the accuracy of the method and safety concerns about “cutting” both strands of DNA limited its use for gene therapy treatments. As such, research has been underway to develop tools that do not have these drawbacks.

The prime editing system is one such tool, a molecule complex consisting of two components. One component is the prime editor, which combines a SpCas9 protein, used in the first CRISPR-Cas gene editing technology, and a reverse transcriptase, an enzyme that transcribes RNA into DNA. The second component is the prime editing guide RNA (pegRNA), a modified guide RNA that identifies the target sequence within the DNA and encodes the desired edit. In this complex, the prime editor works like a “word processor,” accurately replacing genomic information. The tool has already been successfully implemented in living cells of organisms such as plants, zebrafish, and mice. However, precisely how this molecule complex executes each step of the editing process has not been clear, mostly due to a lack of information on its spatial structure.

“We became curious about how the unnatural combination of proteins Cas9 and reverse transcriptase work together,” says Shuto, the first author of the paper.

The research team used cryogenic electron microscopy, an imaging technique that makes observations possible at a near-atomic scale. The method required samples to be in glassy ice to protect them from the potential damage by the electron beams, posing some additional challenges.

“We found the prime editor complex to be unstable under experimental conditions,” explains Shuto. “So, it was very challenging to optimize the conditions for the complex to stay stable. For a long time, we could only determine the structure of Cas9.”

Finally overcoming the challenges, the researchers succeeded in determining the three-dimensional structure of the prime editor complex in multiple states during reverse transcription on the target DNA. The structures revealed that the reverse transcriptase bound to the RNA-DNA complex that formed along the “part” of the Cas9 protein associated with DNA cleavage, the splitting of a single strand of the double helix. While performing the reverse transcription, the reverse transcriptase maintained its position relative to the Cas9 protein. The structural and biochemical analyses also indicated that the reverse transcriptase could lead to additional, undesired insertions.

These findings have opened new avenues for both basic and applied research. So, Shuto lays out the next steps.

“Our structure determination strategy in this study can also be applied to prime editors composed of a different Cas9 protein and reverse transcriptase. We want to utilize the newly obtained structural information to lead to the development of improved prime editors.”