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Human intestinal model from stem cells grown in culture and transplanted into mice

A research group has built a better model for studying the human small intestine by growing intestinal tissue from human stem cells and then successfully transplanting it into the mouse kidney capsule, where it performs digestive functions and responds to the physiological environment. To date, scientists have had limited options available for studying the human intestine under physiological conditions similar to the human body. Mouse models and human cells in laboratory culture fall short in terms of simulating what happens to the human intestine inside the body. By building on a previous advance that created three-dimensional mini-intestines, or “organoids,” from human stem cells, researchers have now produced a more accurate model for studying the human intestine. First, they grew human stem cells in laboratory cell culture with a special mix of growth factors for about 5 weeks to allow them time to form hollow, intestine-like organoids. They were able to use different types of human stem cells to form the organoids, including embryonic stem cells approved for NIH research and “induced pluripotent stem cells” made from an adult human cell type called a fibroblast. The organoids were then transplanted into an immune-deficient breed of mice, which would not reject the human tissue, by placing them under the kidney capsule, a layer of connective tissue covering each kidney. In more than 130 transplant procedures performed, over 90 percent were successful. Transplants were allowed to grow and mature inside the mice for 6 weeks before they were collected. After collection, the transplants were seen to have grown 50- to 100-fold and exhibited signs of mature human intestinal tissue, particularly similar to the small intestine, including a diversity of differentiated intestinal cell types, appropriate intestinal structures and layers, and functions such as maintaining the intestinal barrier, producing digestive enzymes, and absorbing nutrients. The transplanted tissue’s maturation outstripped that of tissue grown for the same time period inside a culture dish. The researchers also tested the advantages of this model for studying human intestinal responses in a physiological (whole-body) system. Surgical removal of a portion of the intestine is known to stimulate some compensatory growth of the remaining intestine through factors present in the circulation. The researchers either surgically removed part of the intestine or performed a sham surgery in mice that had previously been transplanted with the human intestinal organoids for 6 weeks, then examined the effect on the transplant. The mice with the intestinal surgery had more robust growth in the transplanted intestinal organoids than the transplants in mice receiving the sham surgery, highlighting the transplanted intestinal organoids’ responsiveness to physiological signals. This study has created the first functional, in vivo model of human small intestine generated from stem cells. This unique model can be used to study more complex contributors to human intestinal function and disease than was possible before. In the future, the technology could be used for further research toward a goal of generating personalized human intestinal tissue, using organoids from induced pluripotent stem cells in particular, as a treatment for diseases such as short bowel syndrome.


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