Nature | Autologous Ileum Organ Transplantation for Short Bowel Syndrome

Written by Xueyue | Qi small intestine is the main organ for nutrient absorption, and the epithelial tissue of the small intestine has the characteristics of expressing specific nutrient transporters in specific areas.

After the small intestine is surgically removed due to diseases and other reasons, if it is unable to adapt to the remaining small intestine tissue, it will lead to short bowel syndrome (SBS), the patient’s malabsorption of nutrients, the body wasting, and relying on total parenteral nutrition (total parenteral nutrition, TPN) Survival.

Small bowel transplantation is still the only method used to treat SBS.

However, severe allogeneic rejection can reduce the survival rate of patients and the long-term effect of this treatment.

Therefore, the development of new transplantation methods is a top priority.

Organoid technology can effectively expand the area of ​​intestinal epithelial tissue in vitro.
Several studies have combined organoid and tissue engineering technology to construct organ-like structures.

The small intestine is highly vascularized and has a complex circulatory system connected with surrounding organs.
The nervous system and muscle tissue are also essential for the absorption of nutrients.

Therefore, rebuilding the entire small intestine, including the complex lymphatic vascular system, remains a huge challenge.

Recently, Toshiro Sato's team from Keio University in Japan published an article titled An organoid-based organ-repurposing approach to treat short bowel syndrome in Nature.

The study used the structural similarity of the epithelial cells of the small intestine and colon, and used organ transplantation to replace the colon epithelium with the small intestinal epithelium, resulting in a "small intestinalized colon" (small intestinalized colon SIC).
SIC can be vascularized and can form a lymphatic structure to guide the colon.
The formation of the structure of the small intestine.

The authors first transplanted human small intestine organoids onto the surface of the colon of immunodeficient mice.

The results show that xenotransplantation of ileal organoids will construct the villi structure of small intestinal epithelial tissue, and the reconstructed villi structure will express proteins related to nutrient transport.

Because the graft spontaneously formed the villi structure of the small intestine, the author began to explore what factors promoted the formation of villi.

The author has developed a culture system that can make small intestine organoids form a 2D plane structure with a polarization plane.

Constant stimulus in the polarization plane.
Through this experiment, the author found that mechanical force is an important factor in stimulating the formation of villi structure.

Next, the author used rats to verify the above findings, because the rats allowed the author's team to perform surgical operations to observe the SIC reconstruction.

The author first imitated human short bowel syndrome with rats, which is similar to the phenomenon in humans.
If 3 cm of the terminal ileum is retained, it can effectively improve the survival of rats after surgery and reduce the occurrence of intestinal failure, while retaining 4 cm of jejunum in the human body Can not produce similar effects.

Next, the author performed a complete jejunoileectomy on the rats and transplanted ileal organs at the ileocecal valve.

The results showed that the mortality rate associated with surgery was less than 30%, and the transplantation rate was nearly 100%.

In situ hybridization and immunohistochemistry showed the presence of LGR5+ stem cells and their main differentiated cell types in SIC, including intestinal epithelial cells responsible for the absorption of nutrients.

In order to observe the therapeutic effect of SIC, the authors first confirmed the same transplantation rate of the two groups of rats transplanted with colon organs and ileal organs through organoids with bioluminescence.

The rats transplanted with colon organoids were almost dead within two weeks, while the weight loss in the ileal organ transplantation group was relieved and the survival rate was improved.

The implanted area of ​​organoids in rats with a long survival period increased significantly.

It shows the importance of effective and stable implantation of organoids for the therapeutic effect.

Further analysis of the structure of the small intestine shows that SIC can play the function of the small intestine and reshape the structure of lymphatic vessels.
SIC can also maintain the muscular tissue under the regulation of neural circuits and the innervation of autonomic nerves.

Comparing the changes of intestinal flora, the flora of rats transplanted with ileal organoids is similar to that of mice with 3 cm ileum, which indicates that ileal organoids also play an important role in shaping the intestinal flora.

The study used organ remodeling methods to treat short bowel syndrome, provided conceptual support for autologous organoid regenerative medicine, and made a milestone contribution to overcome the gap between in vitro stem cells and clinical transformation.

Original link: https://doi.
org/10.
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