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Imagine yourself painting a forest while all you have to the artist is a leaf and a piece of bark, as opposed to a living and growing tree as a model. Seeing how the pieces fit together can make all the difference.
This is the level of advancement in organoid science that Cincinnati Children's researchers have achieved with the results published today in the journal Nature. Instead of cultivating human mini-organs independently in separate laboratory dishes, a team led by Takanori Takebe, MD, has successfully grown a connected set of three organs: the liver, pancreas and bile ducts.
Organoids, developed from stem cells, are tiny 3D formations of human tissue that actually fulfill the functions of several types of cells found in real size organs. The organoid experts at Cincinnati Children & # 39; s have already developed intestines with villi that absorb nutrients, gastrointestinal organoids producing digestive acids, and so on.
Human organoids alone are already a sophisticated research tool. But this advance allows scientists to study together how human tissue works. This major breakthrough could begin to reduce the need for drug studies in animals, dramatically accelerate the concept of precision medicine and eventually lead to the production of transplantable tissues in laboratories.
"Connectivity is the most important part of that," says Takebe. "What we have done is to design a tissue production method in the pre-forming phase of the organs so that they can develop naturally.We maximize our ability to make multiple organs in the same way as the body."
A 5-year quest reaches a key goal
Takebe, 32, joined Cincinnati Children & # 39; s in 2016 and holds a dual position at the Tokyo Medical and Dental University (TMDU) in Japan. He graduated from medicine in 2011 and plans to become a liver transplant surgeon. But as he discovered the gap between supply and demand for donor organs, Takebe shifted the focus to focus on organ procurement.
In previous research, Takebe has demonstrated a method for producing large amounts of "buds" of the liver, an early form of an organoid liver. He has also developed liver organelles that reflect pathological conditions such as steatohepatitis, a dangerous form of liver scarring and inflammation that occurs in some obese people.
To date, his work has been praised by the Imperial Prince of Japan, who awarded Takebe an honor in 2018 from the Japan Society for the Promotion of Science. Discover the magazine Takebe's organoid work was also ranked # 5 in the list of Top 100 Scientific Achievements in 2013.
But Takebe says this project is his most important job to date.
"We noted this point in the organ differentiation some time ago, but it took five years to adjust the cropping system to allow this development," said Takebe.
How three proto-organs grow up in concert
The most difficult parts of the process were the first steps. Takebe worked for many hours with colleagues at Cincinnati Children's, including first author Hiroyuki Koike, PhD, currently at Nippon Medical School in Japan, to perfect the process. They started with human skin cells, reconverting them into primitive stem cells, and then guiding and pushing these stem cells to form two "spheroids" of cells at a very early stage, loosely called the anterior intestine and the Medium intestine.
These balls of cells are formed very early in embryonic development. In humans, they form late in the first month of pregnancy. In mice, they are formed in only 8.5 days. Over time, these spheres merge and become organs that eventually become the digestive tract.
The growth of these spheroids in the laboratory was a complex process that required the use of the right ingredients at the right time. Once they were mature enough – a timekeeping step that required a lot of work to be located – the easiest part appeared.
The team simply placed the spheroids next to each other in a special laboratory dish. The cells were suspended in a gel commonly used to support organoid growth, and then placed on a thin membrane covering a carefully mixed batch of growth medium.
"From there, the cells knew what to do," says Takebe.
The laboratory team simply watched the cells of each spheroid begin to transform by meeting on the border between the two. They converted and mutually transformed themselves into more specialized cells that could be seen to change color thanks to the chemical labels that the laboratory team had attached to the cells.
Soon, the fused and changing spheres multiplied to give birth to new groups of cells belonging to specific organs. Over a period of 70 days, these cells continued to multiply into more refined and distinct cell types. In the end, the mini organoids started treating bile acids as they digested and filtered the food.
"It was completely unexpected.We thought that we should add ingredients or other factors to move this process forward," Koike said. "Not trying to control this biological process has led us to this success."
What does this advance mean?
Aaron Zorn, PhD, director of the Center for Stem Cell and Organoid Medicine (CuSTOM) at Cincinnati Children & # 39; s, says this breakthrough will be helpful in many ways.
"The real breakthrough here was to be able to create an integrated organ system," says Zorn. "From the research point of view, it is an unprecedented opportunity to study normal human development."
However, Takebe and his colleagues have only been able to grow these organoids until now.
For the long-term hope of developing organ tissues large enough to be useful for human transplantation, Mr. Takebe said that further work was needed. He and his colleagues have already begun to look for ways to add immune cells to the cell lines needed to form blood vessels, connective tissue, and so on.
But for research and diagnostic purposes, this discovery may have more immediate implications.
In precision medicine, physicians are beginning to use genomic data and other information to determine precisely which treatments would best suit patients with a critical illness, at what dose and with the least amount of disease. possible side effects.
A living "gut" composed of several organs would provide scientists with a powerful tool to study precisely how genetic variations and other factors affect the development of organs during pregnancy, and to develop better-targeted drugs to treat diseases. diseases after birth.
A connected system of "generic" human organoids would offer much more information than three organoids in disconnected dishes. Cultivating a set of intestinal organoids for a specific patient could enable even more accurate diagnosis and personalized treatment.
"Current approaches to regenerative liver medicine suffer from the lack of bile duct connectivity," says Takebe. "Although much work remains to be done before we can begin clinical trials on humans, our multi-organoid transplant system is about to solve this problem and could one day provide a lifelong healing cure for patients with liver disease. "
A day maybe not so far
Takebe and his colleagues have already announced a step towards a practical application.
The team has already developed a set of intestinal organoids lacking the HES1 gene. It is one of many known genes that play a major role in triggering biliary atresia, a disease that destroys the bile duct system, resulting in liver failure and the death, unless a transplant can not be provided. This disease is the leading cause of liver transplantation in children.
The new study shows how the absence of HES1 harms the intestinal organ organs. If scientists can find a way to compensate for this genetic variation, they may be able to find a drug or cell transplant that would preserve bile function in the newborn and possibly avoid the need for a difficult liver transplant. get.
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