Researchers at Cincinnati Children Cincinnati Children's Hospital Medical Center recently reported a significant development in their multi-year project to develop a more accurate model for gastrointestinal disease research.
They have successfully created a sophisticated "next-generation" intestinal organoid with the essential components of a working immune system.
An engineer from CNRS (French Reseach Institut Center) anaesthetises a mouse before introducing in its uterus an embryo with stem cells to set a genetically modified line, on February 9, 2012, at the Centre d'Immunologie de Marseille-Luminy (CIML).
The team said that the first in vivo organoid of any kind, such as heart, stomach, liver, and many more, to include a functioning immune system.
The research began with the development of intestine organoids using a novel technique developed in 2011 by specialists at Cincinnati Children's Center for Stem Cell & Organoid Medicine (CuSTOM).
The team was the first in the world to create an organoid from induced pluripotent stem cells (iPSCs), a type of stem cell created from adult human cells rather than fetal tissue. Since then, the center has accomplished several significant accomplishments, such as creating the first-ever esophagus and stomach organoids.
"Humanized Mice"
The tiny organoid spheres had grown to a few millimeters in size after 28 days of growth on a dish. The organoids were then inserted into an immunosuppressed mouse to prevent the rejection of the human tissue.
In this study, the team employed "humanized" mice that had been genetically altered to suppress their immune systems, allowing human immune cells to function in place.
This enabled scientists to analyze the role of the immune system during development.
The organoids were implanted into mice via delicate surgery, placing them under a membrane covering their kidneys. After that, the organoids continued to expand, eventually reaching a diameter of around 1 cm or roughly the size of a pea.
The team gathered organoids at 12, 16, and 20 weeks to examine the types of cells they held. They discovered that the human immune cells, including CD45+ cells and significant cell clusters known as gut-associated lymphoid tissue (GALT) structures, had moved from the humanized mice into the organoids.
"Organoids are Remarkable"
According to corresponding author Michael Helmrath, they found that immune cells from the humanized mouse migrated to the organoid. They also saw the same types of cells after the sequences of development seen in humans.
The scientists also verified that humanized tissues could only create functioning M cells, a crucial class of immunological signaling cells, when they were exposed to particular bacterial antigens.
To accomplish this, small developing intestines had to be exposed to fragments of E. coli bacteria, typically present in the human intestine. After the exposure, the organoid tissue was triggered to release antibodies.
"When we started this project, we did not know if implanting intestinal organoids in humanized mice would work, since it had never been done before," Carine Boufi, one of the study's authors, said in a statement.
"When we got the first results, we saw the infiltration of immune cells in the organoids and I thought that the host mouse was rejecting the organoid. But after further analysis, we found that the immune cells were actually organized and later developed into an immune tissue comparable to a human intestine. Organoids are remarkable."
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Future Applications
The first uses for these upgraded organoids will likely be as research platforms to understand better the several immune-mediated illnesses that affect the digestive system.
In the long run, researchers want to replicate their accomplishment in mice with bigger animal hosts that can create more human organoid tissue. If they are successful, lab-grown organ tissues may someday act as live patches to aid in the self-healing of damaged organs before needing full organ transplantation.
The full findings of the study were published in Nature Biotechnology.
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