1: An organoid-based organ-repurposing approach to treat short bowel syndrome.

Nature.
2021; 592(7852): 99-104. doi: 10.1038/s41586-021-03247-2.

Sugimoto S, Kobayashi E, Fujii M, Ohta Y, Arai K, Matano M, Ishikawa K, Miyamoto K, Toshimitsu K, Takahashi S, Nanki K, Hakamata Y, Kanai T, Sato T.

Small bowel transplantation, the only curative treatment for severe cases of short bowel syndrome caused by massive resection of the small intestine, is performed in very few cases due to problems such as strong rejection compared to other organs and donor shortages. Although expectations are high for regenerative medicine, it has been impossible to create an entire small intestine with its complex structure, including functions like digestion, absorption, and peristalsis, as well as its epithelium, stroma, lymphatic and vascular systems, nerves, and muscle layers. Focusing on the similarity between the large and small intestines below the submucosal layer, we have developed a technique to "small-intestinalize" the colon by stripping its epithelium and replacing it with small intestine-derived organoids. Leveraging the discovery that flow is crucial for its maturation, we successfully demonstrated the proof-of-concept in rats, using the small-intestinalized colon to treat short bowel syndrome. This technology, which can be applied to human-sized intestines and repurposes a patient's own existing organ into another needed organ, is a step forward in realizing rejection-free organ transplantation through regenerative medicine. It is also expected to serve as a research method that will lead to a better understanding of the pathophysiology of various small intestinal diseases.

(Shinya Sugimoto, 88th graduate, The Sakaguchi Laboratory (Organoid Medicine) / Department of Gastroenterology and Hepatology; Toshiro Sato, 76th graduate;

Eiji Kobayashi, equivalent to 61st graduate, Department of Organ Fabrication, Bridgestone Chair)

Immunity .

2021 Mar 9;54(3):514-525.e6. doi: 10.1016/j.immuni.2021.02.015.

Mikami Y, Philips RL, Sciumè G, Petermann F, Meylan F, Nagashima H, Yao C, Davis FP, Brooks SR, Sun HW, Takahashi H, Poholek AC, Shih HY, Afzali B, Muljo SA, Hafner M, Kanno Y, O'Shea JJ.

Intestinal immunity normally functions as a defense mechanism against infectious diseases caused by pathogenic bacteria and viruses, as well as against cancer cells. However, it has a dual nature, as an excessive immune response can cause inflammatory bowel disease (IBD). Among immune cells, helper T cells that produce high levels of interleukin (IL)-17 (Th17 cells), which were identified relatively recently, are particularly abundant in the intestinal tract. However, their function has not been fully understood, with some reports suggesting they are responsible for enteritis, while others indicate they have a suppressive effect on it.

In this study, we first examined intestinal Th17 cells using single-cell RNA sequencing. We found that what was previously categorized as "Th17 cells" is actually a collection of diverse populations, including cell groups that induce enteritis and those that suppress it. We newly identified two types of microRNAs (miR-221/222) as factors that balance these populations. These findings are expected to lead to a better understanding of the pathophysiology of diseases like IBD and colorectal cancer, and to the development of new therapeutic methods.

(Yohei Mikami, 85th graduate, Department of Gastroenterology and Hepatology)

Lancet Psychiatry .

2021 May;8(5):387-404. doi: 10.1016/S2215-0366(21)00039-0.

Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU.

Schizophrenia is a chronic, relapsing disorder characterized by positive symptoms such as hallucinations and delusions, and negative symptoms such as emotional blunting and avolition. In the acute phase, positive symptoms become prominent, but they often resolve with treatment. However, as relapses recur, negative symptoms can worsen and social functioning declines, making relapse prevention crucial. The greatest risk factor for relapse is discontinuation of antipsychotic medication. Although continuous use of antipsychotics is necessary, many patients have poor medication adherence. Long-acting injectable antipsychotics (LAIs), which eliminate the need for daily oral medication with injections every 2 to 12 weeks, are considered a useful treatment option. However, their use has been debated, as randomized controlled trials (RCTs) have not always shown a significant difference from oral medications in preventing hospitalization or relapse. This paper is a large-scale meta-analysis comparing LAIs and oral medications for the maintenance treatment of schizophrenia. The analysis included not only RCTs but also cohort studies and pre-post studies (which verify effects before and after the introduction of LAIs), incorporating patient data from a total of 137 studies and 397,319 individuals. The results showed that in all three study designs, the LAI group had fewer hospitalizations and relapses compared to the oral medication group, with no significant differences in almost all side effects between the two groups. This result is expected to influence many global guidelines that have not actively recommended the use of LAIs.

(Tashiro Kishimoto, 79th graduate, Department of Neuropsychiatry)