Yasuyuki Mizutani

Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) in culture are derived from BM stromal cells or skeletal stem cells. Whereas MSCs have been exploited in clinical medicine, the identification of MSC-specific markers has been limited. Here, we report that a cell surface and secreted protein, Meflin, is expressed in cultured MSCs, fibroblasts and pericytes, but not other types of cells including epithelial, endothelial and smooth muscle cells. In vivo, Meflin is expressed by immature osteoblasts and chondroblasts. In addition, Meflin is found on stromal cells distributed throughout the BM, and on pericytes and perivascular cells in multiple organs. Meflin maintains the undifferentiated state of cultured MSCs and is downregulated upon their differentiation, consistent with the observation that Meflin-deficient mice exhibit increased number of osteoblasts and accelerated bone development. In the bone and BM, Meflin is more highly expressed in primitive stromal cells that express platelet-derived growth factor receptor α and Sca-1 than the Sca-1-negative adipo-osteogenic progenitors, which create a niche for hematopoiesis. Those results are consistent with a decrease in the number of clonogenic colony-forming unit-fibroblasts within the BM of Meflin-deficient mice. These preliminary data suggest that Meflin is a potential marker for cultured MSCs and their source cells in vivo.

Validity of Capsule Endoscopy in Monitoring Therapeutic Interventions in Patients with Crohn’s Disease

Mucosal healing in Crohn’s disease (CD) can be evaluated by capsule endoscopy (CE). However, only a few studies have utilized CE to demonstrate the therapeutic effect of medical treatment. We sought to evaluate the validity of using CE to monitor the effect of medical treatment in patients with CD. One hundred (n = 100) patients with CD were enrolled. All patients had a gastrointestinal (GI) tract patency check prior to CE. Patients with baseline CE Lewis score (LS) ≤ 135 were included in the non-active CD group and ended the study. In those with LS > 135 (active CD group), additional treatment was administered, regardless of symptoms, as per the treating clinician’s advice. Patients of the active CD group underwent follow-up CE assessment 6 months later. Out of 92 patients with confirmed GI patency who underwent CE, 40 (43.4%) had CE findings of active inflammation. Of 29 patients with LS > 135 who received additional medications and underwent follow-up CE, improvement of the LS was noted in 23 (79.3%) patients. Eleven patients were asymptomatic but received additional medications; 8 (72.7%) had improvement of the LS. This study demonstrated that additional treatment even for patients with CD in clinical remission and active small-bowel inflammation on CE can reduce mucosal damage.

Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

Pathological observations show that cancer cells frequently invade the surrounding stroma in collective groups rather than through single cell migration. Here, we studied the role of the actin‐binding protein Girdin, a specific regulator of collective migration of neuroblasts in the brain, in collective cancer cell migration. We found that Girdin was essential for the collective migration of the skin cancer cell line A431 on collagen gels as well as their fibroblast‐led collective invasion in an organotypic culture model. We provide evidence that Girdin binds to β‐catenin that plays important roles in the Wnt signaling pathway and in E‐cadherin‐mediated cell‐cell adhesion. Girdin‐depleted cells displayed scattering and impaired E‐cadherin‐specific cell‐cell adhesion. Importantly, Girdin depletion led to impaired cytoskeletal association of the β‐catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization of cancer cell cohorts on collagen gels. Although the underlying mechanism is unclear, this observation is consistent with the established role of the actin cytoskeletal system and cell‐cell adhesion in the collective behavior of cells. Finally, we showed the correlation of the expression of Girdin with that of the components of the E‐cadherin complex and the differentiation of human skin cancer. Collectively, our results suggest that Girdin is an important modulator of the collective behavior of cancer cells.

Specific characteristics of hemorrhagic Meckel’s diverticulum at double-balloon endoscopy

Background and study aims Diagnosis of Meckel’s diverticulum (MD) before surgery may be challenging; double-balloon endoscopy (DBE) facilitates identification of MD in the setting of a gastrointestinal bleeding; however, MD can be found incidentally without this condition. The purpose of this research was to determine specific characteristic of hemorrhagic MD and incidental MD at DBE. Patients and methods Ectopic gastric mucosa enclosed in the MD and/or ulceration were defined as “major findings”; ring-like scar surrounding the MD was defined as “minor finding”. We retrospectively reviewed the medical records of patients affected by MD and analyzed the findings that significantly affected the characterization of MD. Results MD was diagnosed in 33 patients. The axis of the diverticulum was longer in hemorrhagic MD compared to incidental MD (P = 0.031). The amount of transfusion was significantly higher (P = 0.018) in the hemorrhagic MD group. Hemorrhagic MD was significantly more correlated with major findings (P = 0.01) and minor findings (P < 0.01). The specificity of major finding was 100 % while the sensitivity of major and/or minor findings was 96 %. Conclusions The combination of major and minor findings appears to improve the diagnostic ability of hemorrhagic MD avoiding unnecessary diverticulectomy.

An unusual cause of obscure gastrointestinal bleeding.

Question: A 53-year-old woman had been seeing a doctor regularly for liver cirrhosis. Her Child-Pugh score was 8 points and the ascites was well-controlled with diuretics. Her regular blood tests revealed progressive anemia, although she denied any event of melena, hematochezia, or bleeding elsewhere. Her hemoglobin level decreased from 9.0 to 4.5 mg/dL in 2 months and the examinations of gastrointestinal tract were suggested. Esophagogastroduodenoscopy revealed esophageal varices without bleeding stigmata and colonoscopy was normal. Because thebleedingwas thought to originate from the small bowel, sheunderwent capsule endoscopy (CE),which revealed the submucosal mass in the ileum (Figure A). She was referred to our hospital for the further investigations and a double-balloon endoscopy (DBE) with retrograde procedure was done. DBE demonstrated the same lesion as shown on CE (Figure B). This lesion seemed to be a submucosal tumor according to the formof the lesion on endoscopic images. It also had anulcer on the top part. The surroundingmucosa of the ulcer looked slightly redwhichwas a feature of inflammatory pathologic change (Figure A, B). Therefore,we considered this lesion as the cause of bleeding. Endoscopic ultrasonography (EUS)with the through-the-scope sonoprobewasperformed to identify theoriginof themass (FigureC). This EUSexamination showed the tumororiginating from the first to the third layer, corresponding with the mucosal and submucosal layers. In this case, endoscopic resection would be difficult because the lesion was very close to the muscle layer on EUS. We recommended the patient to receive surgical treatment. The surgical specimen (Figure D) demonstrated tumor involvement of the muscle layer (blue arrow). What is the diagnosis? Look on page 909 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.