The filamentary structure of hydrogen gas in which galaxies form, known as the cosmic web, is one of the major predictions of the model of the Big Bang and of galaxy formation. Until now, all that was known about the web was limited to a few specific regions, particularly in the direction of quasars, whose powerful radiation acts like car headlights, revealing gas clouds along the line of sight. However, these regions are poorly representative of the whole network of filaments where most galaxies, including our own, were born. Direct observation of the faint light emitted by the gas making up the filaments was a holy grail which has now been attained by an international team headed by Roland Bacon, CNRS researcher at the Centre de Recherche Astrophysique de Lyon (CNRS/Université Lyon 1/ENS de Lyon).

The team took the bold step of pointing ESO’s Very Large Telescope, equipped with the MUSE instrument coupled to the telescope’s adaptive optics system, at a single region of the sky for over 140 hours. Together, the two instruments form one of the most powerful systems in the world. The region selected forms part of the Hubble Ultra-Deep Field, which was until now the deepest image of the cosmos ever obtained. However, Hubble has now been surpassed, since 40% of the galaxies discovered by MUSE have no counterpart in the Hubble images.

After meticulous planning, it took eight months to carry out this exceptional observing campaign. This was followed by a year of data processing and analysis, which for the first time revealed light from the hydrogen filaments, as well as images of several filaments as they were one to two billion years after the Big Bang, a key period for understanding how galaxies formed from the gas in the cosmic web. However, the biggest surprise for the team was when simulations showed that the light from the gas came from a hitherto invisible population of billions of dwarf galaxies spawning a host of stars (3). Although these galaxies are too faint to be detected individually with current instruments, their existence will have major consequences for galaxy formation models, with implications that scientists are only just beginning to explore.

Notes:

(1) MUSE, which stands for Multi Unit Spectroscopic Explorer, is a 3D spectrograph designed to explore the distant Universe. The construction of the instrument was led by the Centre de Recherche Astrophysique de Lyon (CNRS/Université Claude Bernard-Lyon 1/ENS de Lyon).

(2) Other French laboratories involved: Laboratoire d’Astrophysique de Marseille (CNRS/Aix-Marseille Université/CNES), Institut de Recherche en Astrophysique et Planétologie (CNRS/Université Toulouse III — Paul Sabatier/CNES).

(3) Until now, theory predicted that the light came from the diffuse cosmic ultraviolet background radiation (very weak background radiation produced by all the galaxies and stars) which, by heating the gas in the filaments, causes them to glow.

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Hanna, who is in the Institute’s Molecular Genetics Department, explains that much of what is known about mammalian embryonic development today comes either from observing the process in non-mammals like frogs or fish that lay transparent eggs, or by obtaining static images from dissected mouse embryos and adding them together. The idea of growing early embryos outside the uterus has been around since before the 1930s, he adds, but experiments based on these proposals had limited success and the embryos tended to be abnormal.

Hanna’s team decided to renew that effort in order to advance the research in his lab, which focuses on the way the development program is enacted in embryonic stem cells. Over seven years, through trial and error, fine-tuning and double-checking, his team came up with a two-step process in which they were able to grow normally developing mouse embryos outside the uterus for six days — around a third of their 20-day gestation — by which time the embryos already had a well-defined body plan and visible organs. “To us, that is the most mysterious and the most interesting part of embryonic development, and we can now observe it and experiment with it in amazing detail,” say Hanna.

The research was led by Alejandro Aguilera-Castrejon, Dr. Bernardo Oldak, the late Dr. Rada Massarwa and Dr. Noa Novershtern in Hanna’s lab and Dr. Itay Maza, a former student of Hanna’s now in the Rambam Health Care Campus of the Technion — Israel Institute of Technology.

For the first step, which lasted around two days, the researchers started with several-day old mouse embryos — right after they would have implanted in the uterus. At this stage the embryos were balls consisting of 250 identical stem cells. These were placed on a special growth medium in a laboratory dish and the team got the balls to attach to this medium as they would to the uterine wall. With this step, they succeeded in duplicating the first stage of embryonic development, in which the embryo doubles and triples in size, as it differentiates into three layers: inner, middle and outer.

Beyond two days, as the embryos entered the next developmental stage — the formation of organs from each of the layers — they needed additional conditions. For this second step, the scientists placed the embryos in a nutrient solution in tiny beakers, setting the beakers on rollers that kept the solutions in motion and continually mixed. That mixing seems to have helped keep the embryos, which were growing without maternal blood flow to the placenta, bathed in the nutrients. In addition to carefully regulating the nutrients in the beakers, the team learned in further experiments to closely control the gases, oxygen and carbon dioxide — not just the amounts, but the gas pressure as well.

To check whether the developmental processes they were observing throughout the two steps were normal, the team conducted careful comparisons with embryos removed from pregnant mice in the relevant time period, showing that both the separation into layers and the organ formation were all but identical in the two groups. In subsequent experiments, they inserted into the embryos genes that labeled the growing organs in fluorescent colors. The success of this attempt suggested that further experiments with this system involving various genetic and other manipulations should produce reliable results. “We think you can inject genes or other elements into the cells, alter the conditions or infect the embryo with a virus, and the system we demonstrated will give you results consistent with development inside a mouse uterus,” says Hanna.

“If you give an embryo the right conditions, its genetic code will function like a pre-set line of dominos, arranged to fall one after the other,” he adds. “Our aim was to recreate those conditions, and now we can watch, in real time, as each domino hits the next one in line.” Among other things, explains Hanna, the method will lower the cost and speed up the process of research in the field of developmental biology, as well as reducing the need for lab animals.

In fact, the next step in Hanna’s lab will be to see if they can skip the step of removing embryos from pregnant mice. He and his team intend to try to create artificial embryos made from stem cells for use in this research. Among other things, they hope to put their new method to work to answer such questions as why so many pregnancies fail to implant, why the window for implantation is so short, how stem cells gradually lose their “stemness” as differentiation progresses and what conditions in gestation may later lead to developmental disorders.

Video: https://www.youtube.com/watch?v=tNb2npuiF3Q

If confirmed in humans, these new heart valves could prevent the need for repeated valve replacement surgeries in thousands of children born each year with congenital heart defects. The valves can also be stored for at least six months, which means they could provide surgeons with an “off the shelf” option for treatment.

The study was published today in Science Translational Medicine, an interdisciplinary medical journal by the American Association for the Advancement of Science (AAAS). The valve-making procedure has also been patented and licensed to the University of Minnesota startup company Vascudyne, Inc. (Stillwater, Minn.).

“This is a huge step forward in pediatric heart research,” said Robert Tranquillo, the senior researcher on the study and a University of Minnesota professor in the Departments of Biomedical Engineering and the Department of Chemical Engineering and Materials Science. “This is the first demonstration that a valve implanted into a large animal model, in our case a lamb, can grow with the animal into adulthood. We have a way to go yet, but this puts us much farther down the path to future clinical trials in children. We are excited and optimistic about the possibility of this actually becoming a reality in years to come.”

Currently, researchers have not been able to develop a heart valve that can grow and maintain function for pediatric patients. The only accepted options for these children with heart defects are valves made from chemically treated animal tissues that often become dysfunctional due to calcification and require replacement because they don’t grow with the child. These children will often need to endure up to five (or more) open heart surgeries until a mechanical valve is implanted in adulthood. This requires them to take blood thinners the rest of their lives.

In this study, Tranquillo and his colleagues used a hybrid of tissue engineering and regenerative medicine to create the growing heart valves. Over an eight-week period, they used a specialized tissue engineering technique they previously developed to generate vessel-like tubes in the lab from a post-natal donor’s skin cells. To develop the tubes, researchers combined the donor sheep skin cells in a gelatin-like material, called fibrin, in the form of a tube and then provided nutrients necessary for cell growth using a bioreactor.

The researchers then used special detergents to wash away all the sheep cells from the tissue-like tubes, leaving behind a cell-free collagenous matrix that does not cause immune reaction when implanted. This means the tubes can be stored and implanted without requiring customized growth using the recipient’s cells.

The next step was to precisely sew three of these tubes (about 16 mm in diameter) together into a closed ring. The researchers then trimmed them slightly to create leaflets to replicate a structure similar to a heart valve about 19 mm in diameter.

Video: https://www.youtube.com/watch?v=zpRbFsAVofA

“After these initial steps, it looked like a heart valve, but the question then became if it could work like a heart valve and if it could grow,” Tranquillo said. “Our findings confirmed both.”

This second generation of tri-tube valves were implanted into the pulmonary artery of three lambs. After 52 weeks, the valve regenerated as its matrix became populated by cells from the recipient lamb, and the diameter increased from 19 mm to a physiologically normal valve about 25 mm. The researchers also saw a 17 to 34 percent increase in the length of the valve leaflets as measured from ultrasound images. In addition, researchers showed that the tri-tube valves worked better than current animal-derived valves with almost none of the calcification or blood clotting that the other valves showed after being implanted in lambs of the same age.

“We knew from previous studies that the engineered tubes have the capacity to regenerate and grow in a growing lamb model, but the biggest challenge was how to maintain leaflet function in a growing valved conduit that goes through 40 million cycles in a year,” said Zeeshan Syedain, the lead researcher on the study and a University of Minnesota senior research associate in Tranquillo’s lab. “When we saw how well the valves functioned for an entire year from young lamb to adult sheep, it was very exciting.”

https://www.youtube.com/watch?v=rme9CZgRgsg

Tranquillo said the next steps are to implant the tri-tube valve directly into the right ventricle of the heart to emulate the most common surgical repair and then start the process of requesting approval from the U.S. Food and Drug Administration (FDA) for human clinical trials over the next few years.

“If we can get these valves approved someday for children, it would have such a big impact on the children who suffer from heart defects and their families who have to deal with the immense stress of multiple surgeries,” Tranquillo said. “We could potentially reduce the number of surgeries these children would have to endure from five to one. That’s the dream.”

In addition to Tranquillo and Syedain, the research team included Bee Haynie (independent contractor); University of Minnesota researchers Sandra L. Johnson and Greeshma Thrivikraman (biomedical engineering), James Berry, Richard Bianco, John P. Carney, and Matthew Lahti (experimental surgical services); Jirong Li (mechanical engineering); and Ryan C. Hill and Kirk C. Hansen (University of Colorado Anschutz Medical Campus).

The research was funded by the National Institutes of Health (R01 HL107572).

To read the full research paper entitled “Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs,” visit the Science Translational Medicine website.