Human cells take in less protein from a plant-based meat than from chicken

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Old skin cells reprogrammed to regain youthful function

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Young fibroblasts in the first image, the two are after 10 days, on the right with treatment, the last two are after 13 days, right with treatment. Red shows collagen production which has been restored. Credit: Fátima Santos, Babraham Institute

Research from the Babraham Institute has developed a method to “time jump” human skin cells by 30 years, turning back the aging clock for cells without losing their specialized function. Work by researchers in the Institute’s Epigenetics research program has been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. The research is published today in the journal eLife, and while this topic is still at an early stage of exploration, it could revolutionize regenerative medicine.

What is regenerative medicine?

As we age, our cells’ ability to function declines and the accumulates marks of aging. Regenerative biology aims to repair or replace cells including old ones. One of the most important tools in regenerative biology is our ability to create “induced” stem cells. The process is a result of several steps, each erasing some of the marks that make cells specialized. In theory, these stem cells have the potential to become any cell type, but scientists aren’t yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.

Turning back time

The new method, based on the Nobel Prize-winning technique scientists use to make stem cells, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialized cell function.

In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into which have the special ability to develop into any cell type. The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called “maturation phase transient reprogramming,” exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

Fibroblast cells migration as part of a wound healing assay. Credit: Fátima Santos, analysis by Hanneke Okkenhaug

Age isn’t just a number

To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of aging. As explained by Dr. Diljeet Gill, a postdoc in Wolf Reik’s lab at the Institute who conducted the work as a Ph.D. student, “Our understanding of aging on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved.”

Researchers looked at multiple measures of cellular age. The first is the , where chemical tags present throughout the genome indicate age. The second is the , all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.

The potential applications of this technique are dependent on the cells not only appearing younger, but functioning like young cells too. Fibroblasts produce collagen, a molecule found in bones, skin tendons and ligaments, helping provide structure to tissues and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. Researchers tested the partially rejuvenated cells by creating an artificial cut in a layer of cells in a dish. They found that their treated moved into the gap faster than older cells. This is a promising sign that one day this research could eventually be used to create cells that are better at healing wounds.

In the future, this research may also open up other therapeutic possibilities; the researchers observed that their method also had an effect on other genes linked to age-related diseases and symptoms. The APBA2 gene, associated with Alzheimer’s disease, and the MAF gene, with a role in the development of cataracts, both showed changes towards youthful levels of transcription.

The mechanism behind the successful transient reprogramming is not yet fully understood, and is the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in shaping cell identity might escape the reprogramming process.

Diljeet concluded, “Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of aging indicators in genes associated with diseases is particularly promising for the future of this work.”

Professor Wolf Reik, a group leader in the Epigenetics research program who has recently moved to lead the Altos Labs Cambridge Institute, said, “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of aging. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”

More information:
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming, eLife, 2022. DOI: 10.7554/eLife.71624

Journal information:

Old skin cells reprogrammed to regain youthful function (2022, April 7)
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Hexbyte Glen Cove How embryo cells gain independence

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With a so-called in-situ labeling, the cells from which the structures of the back develop are darkly marked in these zebrafish embryos. If the maternal proteins Sox19b and Pou5f3 are missing, as in the right embryo, the developmental programs no longer run correctly and the pattern changes. Credit: Daria Onichtchouk/ University of Freiburg /CIBSS

It happens in the first hours after fertilization: The cells of the early embryo begin to independently produce proteins, the building blocks for cells and organs. Their own, uniquely composed genetic material serves as the blueprint. In vertebrates, the starting signal for this process comes from three maternal proteins that bind to the DNA of the offspring. New findings from Dr. Meijiang Gao from a research team led by Dr. Daria Onichtchouk in the University of Freiburg’s Institute of Biology I now show, using a zebrafish model, how two of these three start proteins of the egg cell elicit their roles and how they act in further development. The findings were published in a study in the journal Nature Communications.

“We have shown how the proteins Pou5f3 and Sox19b function at different time points in and in different areas of the embryo,” says the biologist of the study’s integrative approach. She conducts her research at the University of Freiburg’s Cluster of Excellence CIBSS—Centre for Integrative Biological Signalling Studies, whose scientists are pursuing the goal of understanding signaling processes across scales. Prof. Dr. Jens Timmer und Markus Rosenblatt from the University of Freiburg’s Institute of Physics also participated in the study.

Important molecules for stem cell research

Similar human proteins, so-called homologues of Pou5f3 and Sox19b, are used in research to artificially produce stem from human skin cells. “The precise role of these factors in development is highly interesting for research and medicine for this reason as well,” says Onichtchouk.

To determine precisely what genes are controlled in what way by these two proteins and how they interact, the biologist and her team studied the development of zebrafish embryos. They induced mutations in the genes for Pou5f3 and Sox19b so that the fish would no longer produce these regulatory proteins. In this way, they succeeded in demonstrating that the two proteins have independent tasks. However, they both act on the DNA by binding to gene regulatory regions and making the genes freely accessible to the cellular machinery.

Gene control in sleep mode

In addition, the team discovered that Pou5f3 and Sox19b suppress late genetic programs. “They keep important processes in so that they do not start until later, when the appropriate step in development approaches,” describes Onichtchouk. “This concerns the genes responsible for the of the organs.” However, Pou5f3 and Sox19b appear to be the determining factors for the activation of the only on the ventral side of the embryo. On the dorsal side, they are ineffective. Onichtchouk wants to determine the reason for this: “We are curious to find out what takes over this function here and whether these proteins also originate from the mother.”

More information:
Meijiang Gao et al, Pluripotency factors determine gene expression repertoire at zygotic genome activation, Nature Communications (2022). DOI: 10.1038/s41467-022-28434-1

How embryo cells gain independence (2022, February 15)
retrieved 16 February 2022

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Hexbyte Glen Cove A 3D ink made of living cells for creating living structures

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Fig. 1: Schematics of the design strategy, production, and functional applications of microbial ink. a E. coli was genetically engineered to produce microbial ink by fusing α (knob) and γ (hole) protein domains, derived from fibrin to the main structural component of curli nanofibers, CsgA. Upon secretion, the CsgA-α and CsgA-γ monomers self-assemble into nanofibers crosslinked by the knob-hole binding interaction. b The knob and hole domains are derived from fibrin, where they play a key role in supramolecular polymerization during blood clot formation. c The protocol to produce microbial ink from the engineered protein nanofibers involves standard bacterial culture, limited processing steps, and no addition of exogenous polymers. Microbial ink was 3D printed to obtain functional living materials. Credit: DOI: 10.1038/s41467-021-26791-x

A team of researchers from Harvard University and Brigham and Women’s Hospital, Harvard Medical School, has developed a type of living ink that can be used to print living materials. In their paper published in the journal Nature Communications, the group describes how they made their ink and possible uses for it.

For several years, microbial engineers have been working to develop a means to create living materials for use in a wide variety of applications such as medical devices. But getting such materials to conform to desired 3D structures has proven to be a daunting task. In this new effort, the researchers have taken a new approach to tackling the problem—engineering Escherichia coli to produce a product that can be used as the basis for an ink for use in a 3D printer.

The work began by bioengineering the bacteria to produce living nanofibers. The researchers then bundled the fibers and added other ingredients to produce a type of living ink that could be used in a conventional 3D printer. Once they found the concept viable, the team bioengineered other microbes to produce other types of living fibers or materials and added them to the ink. They then used the ink to print 3D objects that had living components. One was a material that secreted azurin—an anticancer drug—when stimulated by certain chemicals. Another was a material that sequestered Bisphenol A (a toxin that has found its way into the environment) without assistance from other chemicals or devices.

The researchers believe that their concept suggests that producing such inks could be a self-creating proposition. Engineering could be added to the microbes to push them to produce carbon copies of themselves—the ink could literally be grown in a jar. They also state that it appears possible that the technique could be used to print renewable building that would not only grow but could self heal—a possible approach to building self-sustaining homes here on Earth, or on the moon or on Mars.

More information:
Anna M. Duraj-Thatte et al, Programmable microbial ink for 3D printing of living materials produced from genetically engineered protein nanofibers, Nature Communications (2021). DOI: 10.1038/s41467-021-26791-x

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A 3D ink made of living cells for creating living structures (2021, November 27)
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Hexbyte Glen Cove For stem cells, bigger doesn’t mean better

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Credit: CC0 Public Domain

MIT biologists have answered an important biological question: Why do cells control their size?

Cells of the same type are strikingly uniform in size, while cell size differs between different cell types. This raises the question of whether cell size is important for .

The new study suggests that cellular enlargement drives a decline in function of . The researchers found that , which are among the smallest cells in the body, lose their ability to perform their normal function—replenishing the body’s cells—as they grow larger. However, when the cells were restored to their usual size, they behaved normally again.

The researchers also found that blood stem cells tend to enlarge as they age. Their study shows that this enlargement contributes to stem cell decline during aging.

“We have discovered cellular enlargement as a new aging factor in vivo, and now we can explore if we can treat cellular enlargement to delay aging and aging-related diseases,” says Jette Lengefeld, a former MIT postdoc, who is now a principal investigator at the University of Helsinki.

Lengefeld is the lead author of the study, which appears today in Science Advances. The late Angelika Amon, an MIT professor of biology and member of the Koch Institute for Integrative Cancer Research, is the senior author of the study.

Outsized effects

It has been known since the 1960s that grown in a lab dish enlarge as they become senescent—a nondividing cellular state

that is associated with aging. Every time a cell divides, it can encounter DNA damage. When this happens, division is halted to repair the damage. During each of these delays, the cell grows slightly larger. Many scientists believed that this enlargement was simply a side effect of aging, but the Amon lab began to investigate the possibility that large cell size drives age-related losses of function.

Lengefeld studied the effects of size on stem cells—specifically, blood stem cells, which give rise to the blood cells of our body throughout life. To study how size affects these stem cells, the researchers damaged their DNA, leading to an increase in their size. They then compared these enlarged cells to other cells that also experienced DNA damage but were prevented from increasing in size using a drug called rapamycin.

After the treatment, the researchers measured the functionality of these two groups of stem cells by injecting them into mice that had their own blood stem cells eliminated. This allowed the researchers to determine whether the transplanted stem cells were able to repopulate the mouse’s blood cells.

They found that the DNA-damaged and enlarged stem cells were unable to produce new blood cells. However, the DNA-damaged stem cells that were kept small were still able to produce new blood cells.

In another experiment, the researchers used a genetic mutation to reduce the size of naturally occurring large stem cells that they found in older mice. They showed that if they induced those large stem cells to become small again, the cells regained their regenerative potential and behaved like younger stem cells.

“This is striking evidence supporting the model that size is important for functionality of stem cells,” Lengefeld says. “When we damage the stem cells’ DNA but keep them small during the damage, they retain their functionality. And if we reduce the size of large stem cells, we can restore their function.”

Keeping cells small

When the researchers treated mice with rapamycin, beginning at a young age, they were able to prevent blood stem cells from enlarging as the mice got older. Blood stem cells from those mice remained small and were able to build like young stem cells even in mice 3 years of age—an old age for a mouse.

Rapamycin, a drug that can inhibit cell growth, is now used to treat some cancers and to prevent organ transplant rejection, and has raised interest for its ability to extend lifespan in mice and other organisms. It may be useful in slowing down the enlargement of stem cells and therefore could have beneficial effects in humans, Lengefeld says.

“If we find drugs that are specific in making large blood stem cells smaller again, we can test whether this improves the health of people who suffer from problems with their blood system—like anemia and a reduced immune system—or maybe even help people with leukemia,” she says.

The researchers also demonstrated the importance of size in another type of stem cells—intestinal stem cells. They found that larger stem cells were less able to generate intestinal organoids, which mimic the structure of the intestinal lining.

“That suggested that this relationship between and function is conserved in stem , and that cellular size is a marker of stem cell function,” Lengefeld says.

More information:
Jette Lengefeld, Cell size is a determinant of stem cell potential during aging, Science Advances (2021). DOI: 10.1126/sciadv.abk0271.


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Hexbyte Glen Cove Researchers find how cells move while avoiding adhesion thumbnail

Hexbyte Glen Cove Researchers find how cells move while avoiding adhesion

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Cancer cells moving on glycoproteine strips: These strips act like splints, which allow to control and to study the movement of the cells better. Credit: Rädler Lab, Ludwig Maximilians Universität München

Cell velocity, or how fast a cell moves, is known to depend on how sticky the surface is beneath it, but the precise mechanisms of this relationship have remained elusive for decades. Now, researchers from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Ludwig Maximilians Universität München (LMU) have figured out the precise mechanics and developed a mathematical model capturing the forces involved in cell movement. The findings, reported in the journal Proceedings of the National Academy of Sciences (PNAS), provide new insight for developmental biology and potential cancer treatment.

Cell movement is a fundamental process, especially critical during development, when cells differentiate into their target cell type and then move to the correct tissue. Cells also move to repair wounds, while cancer cells crawl to the nearest blood vessel to spread to other parts of the body.

“The we developed can now be used by researchers to predict how different cells will behave on various substrates,” says Professor Martin Falcke, who heads MDC’s Mathematical Cell Physiology Lab and co-led the research. “Understanding these basic movements in precise detail could provide new targets to interrupt tumor metastasis.”

Teaming up to pin down

The finding comes thanks to experimental physicists at LMU teaming up with theoretical physicists at MDC. The experimentalists, led by Professor Joachim Rädler, tracked how quickly more than 15,000 moved along narrow lanes on a sticky surface, where the stickiness alternated between low and high. This allowed them to observe what happens as the cell transitions between stickiness levels, which is more representative of the dynamic environment inside the body.

Then Falcke and Behnam Amiri, co-first paper author and Ph.D. student in Falcke’s lab, used the large dataset to develop a mathematical equation that captures the elements shaping .

“Previous mathematical models trying to explain and motility are very specific, they only work for one feature or cell type,” Amiri says. “What we tried to do here is keep it as simple and general as possible.”

The approach worked even better than expected: The model matched the data gathered at LMU and held true for measurements about several other cell types taken over the past 30 years. “This is exciting,” Falcke says. “It’s rare that you find a theory explaining such a large spectrum of experimental results.”

Friction is key

When a cell moves, it pushes out its membrane in the direction of travel, expanding an internal network of actin filaments as it goes, and then peels off its back end. How fast this happens depends on adhesion bonds that form between the cell and the surface beneath it. When there are no bonds, the cell can hardly move because the actin network doesn’t have anything to push off against. The reason is friction: “When you are on ice skates you cannot push a car, only when there is enough friction between your shoes and the ground can you push a car,” Falcke says.

As the number of bonds increase, creating more friction, the cell can generate more force and move faster, until the point when it is so sticky, it becomes much harder to pull off the back end, slowing the cell down again.

The researchers investigated what happens when the front and rear ends of the cell experience different levels of stickiness. They were particularly curious to figure out what happens when it is stickier under the back end of the cell than the front, because that is when the cell could potentially get stuck, unable to generate enough force to pull off the back end.

This might have been the case if the adhesion bonds were more like screws, holding the cell to the substrate. At first, Falcke and Amiri included this type of “elastic” force in their model, but the equation only worked with friction forces.

“For me, the most challenging part was to wrap my mind around this mechanism working only with friction forces,” Falcke says, because there is nothing for the cell to firmly latch onto. But it is the friction-like forces that allow the cell to keep moving, even when bonds are stronger in the back than the front, slowly peeling itself off like scotch tape. “Even if you pull just a little with a weak force, you are still able to peel the tape off—very slowly, but it comes off,” Falcke says. “This is how the cell keeps itself from getting stuck.”

The team is now investigating how move in two dimensions, including how they make hard right and left turns, and U-turns.

More information:
Christoph Schreiber el al., On the adhesion–velocity relation and length adaptation of motile cells on stepped fibronectin lanes, PNAS (2020).

Researchers find how cells move while avoiding adhesion (2021, January 18)
retrieved 19 January 2021