笠原 尚哉

Abstract Intestinal adaptation does not necessarily recover absorptive capacity in short bowel syndrome (SBS), sometimes resulting in intestinal failure-associated liver disease (IFALD). Additionally, its therapeutic options remain limited. Polyamines (spermidine and spermine) are known as one of the autophagy inducers and play important roles in promoting the weaning process; however, their impact on intestinal adaptation is unknown. The aim of this study was to investigate the impact of polyamines ingestion on adaptation and hepatic lipid metabolism in SBS. We performed resection of two-thirds of the small intestine in male Lewis rats as an SBS model. They were allocated into three groups and fed different polyamine content diets (0%, 0.01%, 0.1%) for 30 days. Polyamines were confirmed to distribute to remnant intestine, whole blood, and liver. Villous height and number of Ki-67-positive cells in the crypt area increased with the high polyamine diet. Polyamines increased secretory IgA and mucin content in feces, and enhanced tissue Claudin-3 expression. In contrast, polyamines augmented albumin synthesis, mitochondrial DNA copy number, and ATP storage in the liver. Moreover, polyamines promoted autophagy flux and activated AMP-activated protein kinase with suppression of lipogenic gene expression. Polyamines ingestion may provide a new therapeutic option for SBS with IFALD.

Segmental grafts from living donors have advantages over grafts from deceased donors when used for small intestine transplantation. However, storage time for small intestine grafts can be extremely short and optimal graft preservation conditions for short-term storage remain undetermined. Secreted factors from mesenchymal stem cells (MSCs) that allow direct activation of preserved small intestine grafts. Freshly excised Luc-Tg LEW rat tissues were incubated in preservation solutions containing MSC-conditioned medium (MSC-CM). Preserved Luc-Tg rat-derived grafts were then transplanted to wild-type recipients, after which survival, injury score, and tight junction protein expression were examined. Luminance for each graft was determined using in vivo imaging. The findings indicated that 30-100 and 3-10 kDa fractions of MSC-CM have superior activating effects for small intestine preservation. Expression of the tight-junction proteins claudin-3, and zonula occludens-1 preserved for 24 h in University of Wisconsin (UW) solution containing MSC-CM with 50-100 kDa, as shown by immunostaining, also indicated effectiveness. Reflecting the improved graft preservation, MSC-CM preloading of grafts increased survival rate from 0% to 87%. This is the first report of successful transplantation of small intestine grafts preserved for more than 24 h using a rodent model to evaluate graft preservation conditions that mimic clinical conditions.

The success of islet transplantation in both basic research and clinical settings has proven that cell therapy has the potential to cure diabetes. Islets intended for transplantation are inevitably subjected to damage from a number of sources, including ischemic injury during removal and delivery of the donor pancreas, enzymatic digestion during islet isolation, and reperfusion injury after transplantation in the recipient. Here, we found that protein factors secreted by porcine adipose-tissue mesenchymal stem cells (AT-MSCs) were capable of activating preserved porcine islets. A conditioned medium was prepared from the supernatant obtained by culturing porcine AT-MSCs for 2 days in serum-free medium. Islets were preserved at 4°C in University of Wisconsin solution during transportation and then incubated at 37°C in RPMI-1620 medium with fractions of various molecular weights prepared from the conditioned medium. After treatment with certain fractions of the AT-MSC secretions, the intracellular ATP levels of the activated islets had increased to over 160% of their initial values after 4 days of incubation. Our novel system may be able to restore the condition of isolated islets after transportation or preservation and may help to improve the long-term outcome of islet transplantation.Abbreviations: AT-MSC, adipose-tissue mesenchymal stem cell; Cas-3, caspase-3; DAPI, 4,6-diamidino-2-phenylindole; DTZ, dithizone; ES cell, embryonic stem cell; FITC, fluorescein isothiocyanate; IEQ, islet equivalent; INS, insulin; iPS cell, induced pluripotent stem cell; Luc-Tg rat, luciferase-transgenic rat; PCNA, proliferating cell nuclear antigen; PDX1, pancreatic and duodenal homeobox protein-1; UW, University of Wisconsin; ZO1, zona occludens 1.

Polyamines are important to the survival and activation of organs and tissues via a homeostatic cell-metabolic process, and the polyamine content in cytoplasm decreases with aging. Decreases in cellular polyamine have been known to augment mutagenesis and cell death. Thus, supplementary polyamine in food is important to the prevention of aging. Here we show the anti-aging effects of oral intake of polyamine using luciferase-transgenic rats. Healthy rats, 10-12 weeks old, were given foods containing 0.01% and 0.1% (w/w) of polyamine, as compared a control food without polyamine, for 4 weeks. Using a bioimaging system, the photon intensities seen in the whole bodies and livers of rats consuming 0.1% of polyamine in food were stronger than those in rats consuming 0.01% and 0% of polyamine. However, there were no differences between groups in other characteristics, such as liver damage and body weight. In conclusion, we found that polyamine intake can activate cells throughout the whole body, providing an anti-aging effect.

A 48-year-old man underwent skin grafting from the left inguinal region to the left forearm one month previously. He noticed abdominal discomfort after discharge and was admitted to another hospital because of progression of abdominal pain and a decreased level of consciousness. An enhanced CT scan revealed extensive portal venous thrombosis. Lower gastrointestinal bleeding developed the following day, and he was transferred to our hospital and diagnosed with superior mesenteric venous thrombosis. Enhanced CT showed no intestinal necrosis. Anticoagulant therapy was started and the thrombosis had almost resolved 40 days later. However, after starting oral intake, the patient developed vomiting. Small bowel radiographs and 3D-CT showed significant proximal intestinal stenosis. Small bowel resection was performed on the 59th day after transfer. The pathological diagnosis was ischemic enteritis with venous thrombosis. The patient was discharged 20 days after intestinal resection and he has had no recurrence of symptoms. In this case, 3D-CT was useful to determine the range of intestinal stenosis and the required area of resection.