Morphology of TESI in the mouse model. (A) Four weeks after implantation, the tissue-engineered intestine formed a sphere about twice the size of the initial implanted polymer (arrow). (B) Hematoxylin and eosin staining at low magnification demonstrates a large amount of continuous mucosa lining the lumen of the TESI. (C) At higher magnification, the mucosa of the TESI is composed of a simple columnar epithelium forming crypt and villus structures. Goblet cells, along the crypt and villus axis, and Paneth cells, at the base of the crypts, can be identified. Scale bar: 40.0 μm. TESI, tissue-engineered small intestine.
Researchers at The Saban Research Institute of Children’s Hospital Los Angeles have successfully created a tissue-engineered small intestine in mice that replicates the intestinal structures of natural intestine—a necessary first step toward someday applying this regenerative medicine technique to humans.
Tissue engineering, which promises to rebuild or replace injured or failing body parts, has seen some major advancements in recent months, with biological scaffolds used to create new bones in rabbits and regrown muscle in humans.
Tissue-engineered small intestine (TESI) has successfully been used to rescue Lewis rats after massive small bowel resection. In this study, we transitioned the technique to a mouse model, allowing investigation of the processes involved during TESI formation through the transgenic tools available in this species. This is a necessary step toward applying the technique to human therapy. Multicellular organoid units were derived from small intestines of transgenic mice and transplanted within the abdomen on biodegradable polymers. Immunofluorescence staining was used to characterize the cellular processes during TESI formation. We demonstrate the preservation of Lgr5- and DcamKl1-positive cells, two putative intestinal stem cell populations, in proximity to their niche mesenchymal cells, the intestinal subepithelial myofibroblasts (ISEMFs), at the time of implantation. Maintenance of the relationship between ISEMF and crypt epithelium is observed during the growth of TESI. The engineered small intestine has an epithelium containing a differentiated epithelium next to an innervated muscularis. Lineage tracing demonstrates that all the essential components, including epithelium, muscularis, nerves, and some of the blood vessels, are of donor origin. This multicellular approach provides the necessary cell population to regenerate large amounts of intestinal tissue that could be used to treat short bowel syndrome.
Working in the laboratory, the research team took samples of intestinal tissue from mice. This tissue was comprised of the layers of the various cells that make up the intestine — including muscle cells and the cells that line the inside, known as epithelial cells. The investigators then transplanted that mixture of cells within the abdomen on biodegradable polymers or “scaffolding.”
What the team wanted to happen did — new, engineered small intestines grew and had all of the cell types found in native intestine. Because the transplanted cells had carried a green label, the scientists could identify which cells had been provided — and all of the major components of the tissue-engineered intestine derived from the implanted cells. Critically, the new organs contained the most essential components of the originals.
“What is novel about this research is that this tissue-engineered intestine contains every important cell type needed for functional intestine. For children with intestinal failure, we are always looking for long-term, durable solutions that will not require the administration of toxic drugs to ensure engraftment. This tissue-engineered intestine, which has all of the critical components of the mature intestine, represents a truly exciting albeit preliminary step in the right direction,” said Henri Ford, MD, Vice President and Surgeon-in-Chief at Children’s Hospital Los Angeles.
“We demonstrated that we are providing all of the important cells—the muscle, nerve, epithelium, and some of the blood vessels,” noted Frédéric Sala, PhD, lead author. “All of these are critical to proper functioning of the tissue, and now we know their origins.” Next up are additional tissue-growing experiments—each one of which may bring that much closer the prospects of clinical testing and a solution for babies in need.
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