Kentaro Matsubara

Mesenchymal stem cells support hepatocyte function in engineered liver grafts

Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft.

Surgical and Endovascular Procedures for Treating Isolated Iliac Artery Aneurysms: Ten-year Experience

Characteristics of atherosclerotic isolated iliac artery aneurysms (IAAs) and various strategies for their treatment were assessed retrospectively. The computerized medical records of 18 patients who underwent surgical or endovascular treatment of an IAA during the 10 years from April 1993 to March 2003 at our university hospital were reviewed to obtain information on patient demographics, risk factors, type of IAA treatment, and outcome. Additional data were obtained by mail and telephone. Patients with an IAA were compared with 168 patients treated for an abdominal aortic aneurysm (AAA) also at our institution. Early in the series of isolated IAA repairs, patients underwent prosthetic graft interposition (n = 7) or thromboexclusion (n = 4). Subsequently, patients had either endovascular thromboembolization (n = 4) or endovascular thromboembolization with femorofemoral crossover bypass (n = 3). No perioperative deaths occurred in the series. Deep venous thrombosis developed postoperatively in one patient; there were no other serious complications. The cumulative patency rate for the implanted interposition grafts during the mean observation time of 5.5 years was 100%. No endoleakage was observed after the endovascular procedures. In the long-term, five patients died of causes unrelated to the IAA treatment. A statistical analysis revealed no significant differences between the IAA group and the AAA group with respect to atherosclerotic risk factors. In conclusion, open surgical procedures to repair isolated IAAs generally have a good outcome, although the risk of injury to adjacent iliac veins remains. Endovascular treatments appear to have some advantages, but studies including long-term follow-up are needed to assess the efficacy and durability of prosthetic grafts used for these procedures.

Evolution of Computed Tomographic Characteristics of Spontaneous Isolated Superior Mesenteric Artery Dissection During Conservative Management

BACKGROUND Spontaneous isolated superior mesenteric artery (SMA) dissection is a rare condition, and its clinical and angiographic courses are poorly defined. We aimed to monitor the morphological characteristics of spontaneous isolated SMA dissection using computed tomography (CT) over 2 years of follow-up, including the recovery process via vascular remodeling, and identify the factors that affect vascular remodeling using univariate analysis. METHODSANDRESULTS We retrospectively reviewed the medical records and morphological findings of 59 consecutive patients with spontaneous isolated SMA dissection between October 2007 and July 2014, which included 36 symptomatic and 23 asymptomatic patients. Surgical intervention with open laparotomy was required in 3 patients during the follow-up period; 41 patients who received conservative treatment were followed up over 2 years with regular CT. Complete remodeling was achieved in 16 of 25 symptomatic patients who were treated conservatively (64.0%). A patent false lumen and aneurysmal formation on an initial CT scan were identified as negative factors that affected remodeling in patients with spontaneous isolated SMA dissection. CONCLUSIONS Conservative management of spontaneous isolated SMA dissection is associated with a good prognosis, both clinically and morphologically. Surgical intervention is only required in patients with severe intestinal ischemia or rapid aneurysmal enlargement. (Circ J 2016; 80: 1452-1459).

Liver-Regenerative Transplantation: Regrow and Reset.

Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end‐stage liver disease. Only one‐third of those on the liver transplant waiting list will be transplanted, and the demand for livers is projected to increase 23% in the next 20 years. Consequently, organ availability is an absolute constraint on the number of liver transplants that can be performed. Regenerative therapies aim to enhance liver tissue repair and regeneration by any means available (cell repopulation, tissue engineering, biomaterials, proteins, small molecules, and genes). Recent experimental work suggests that liver repopulation and engineered liver tissue are best suited to the task if an unlimited availability of functional induced pluripotent stem (iPS)–derived liver cells can be achieved. The derivation of iPS cells by reprogramming cell fate has opened up new lines of investigation, for instance, the generation of iPS‐derived xenogeneic organs or the possibility of simply inducing the liver to reprogram its own hepatocyte function after injury. We reviewed current knowledge about liver repopulation, generation of engineered livers and reprogramming of liver function. We also discussed the numerous barriers that have to be overcome for clinical implementation.

Living Donor Liver Transplantation For Biliary Atresia Complicated By Situs Inversus: Technical Highlights

Living‐donor liver transplantation (LDLT) has become an established technique to treat children with end‐stage liver disease. Biliary atresia (BA), one of the most common indications for liver transplantation in children, can be associated with situs inversus (SI). In the past, the presence of SI has been considered to be an absolute contraindication for liver transplantation because of the technical difficulties. Recently, some reports of successful diseased‐donor liver transplantation in patients with BA complicated by SI have been published; however, few reports of that with LDLT exist. The technical difficulties involved with LDLT for such cases have not been described. Herein, we present 4 successful cases of LDLT for BA with SI. Complex anomalies associated with SI, such as a hepatic artery arising from the supraceliac aorta, a preduodenal portal vein, and absence of the retrohepatic inferior vena cava, increase the technical difficulties involved with the operation. Additional caution is required in LDLT because a living‐donor graft has short vessels and the availability of vascular grafts from the donor is limited. In conclusion, LDLT for BA complicated by SI can be managed successfully with technical modifications and scrupulous attention. This series represents the largest reported group of patients with BA complicated by SI who underwent a successful LDLT procedure. (Liver Transpl 2005;11:1444–1447.)

Increased plasma levels of high mobility group box 1 in patients with acute liver failure

Background: High-mobility group box 1 (HMGB1) is a monocyte-derived late-acting inflammatory mediator, which is released in conditions such as shock, tissue injury and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in patients with acute liver failure (ALF). Patients and Methods: We determined the plasma levels of HMGB1 and aspartate aminotransferase (AST) in 7 healthy volunteers (HVs), 40 patients with liver cirrhosis (LC), 37 patients with chronic hepatitis (CH), 18 patients with severe acute hepatitis (AH), and 14 patients with fulminant hepatitis (FH). The 14 patients with FH were divided into two subgroups depending upon the history of plasma exchange (PE) before their plasma sample collection. The hepatic levels of HMGB1 were measured in tissue samples from 3 patients with FH who underwent living-donor liver transplantation and from 3 healthy living donors. Hepatic tissue samples were also subjected to immunohistochemical examination for HMGB1. Results: The plasma levels of HMGB1 (ng/ml) were higher in patients with liver diseases, especially in FH patients with no history of PE, than in HVs (0.3 ± 0.3 in HVs, 4.0 ± 2.0 in LC, 5.2 ± 2.6 in CH, 8.6 ± 4.8 in severe AH, 7.8 ± 2.7 in FH with a history of PE, and 12.5 ± 2.6 in FH with no history of PE, p < 0.05 in each comparison). There was a strong and statistically significant relationship between the mean plasma HMGB1 level and the logarithm of the mean AST level (R = 0.900, p < 0.05). The hepatic tissue levels of HMGB1 (ng/mg tissue protein) were lower in patients with FH than in healthy donors (539 ± 116 in FH vs. 874 ± 81 in healthy donors, p < 0.05). Immunohistochemical staining for HMGB1 was strong and clear in the nuclei of hepatocytes in liver sections from healthy donors, but little staining in either nuclei or cytoplasm was evident in specimens from patients with FH. Conclusion: We confirmed that plasma HMGB1 levels were increased in patients with ALF. Based on a comparison between HMGB1 contents in normal and ALF livers, it is very likely that HMGB1 is released from injured liver tissue.

Successful endovascular treatment of hemosuccus pancreaticus due to splenic artery aneurysm associated with segmental arterial mediolysis

Hemosuccus pancreaticus, which is generally due to the rupture of a splenic artery aneursym into the pancreatic duct, is a rare cause of intermittent upper gastrointestinal hemorrhage. Segmental arterial mediolysis (SAM) is a rare arteriopathy. We report a 53-year-old man with hemosuccus pancreaticus due to a splenic artery aneurysm associated with SAM. The patient, who also had a celiac artery aneurysm affected by SAM, was successfully treated by both coil embolization and aortic stent grafting for complete coverage of the celiac artery. SAM is a very rare cause of hemosuccus pancreaticus, and endovascular treatment may be favorable for hemosuccus pancreaticus.

Multiple Aneurysms of the Splenic Artery Caused by Fibromuscular Dysplasia

Splenic artery aneurysms (SAAs) are relatively rare. Moreover, there has been only one previous report of fibromuscular dysplasia (FMD) affecting the splenic artery alone. We describe a 64-year-old man with long, segmental, large, and multiple SAAs in whom the splenic artery branched from the aorta. The patient underwent endoaneurysmorrhaphy and splenectomy, with ligation in the proximal segment of the splenic artery. Histopathological analyses of resected specimens showed characteristics compatible with FMD. To our knowledge, long, segmental, large, and multiple SAAs caused by FMD have not previously been reported.

Surgical technique for allogeneic uterus transplantation in macaques

No study has reported an animal model of uterus transplantation (UTx) using cynomolgus macaques. We aimed to establish a surgical technique of allogeneic UTx assuming the recovery of a uterus from a deceased donor in cynomolgus macaques. Four allogeneic UTxs were performed in female cynomolgus macaques. Donor surgeries comprised en bloc recovery of organs with iliac vessels on both sides, and/or abdominal aorta/vena cava after sufficient perfusion from one femoral artery or external iliac artery. Before perfusion, 150 mL of whole blood was obtained from the donor for subsequent blood transfusion to the recipient. Four uterine grafts were orthotopically transplanted to recipients. End-to-side anastomosis was performed to the iliac vessels on one side in case 1 and iliac vessels on both sides in case 2; aorto-aorto/cavo-caval anastomosis was performed in cases 3 and 4. Arterial blood flow of the uterine grafts was determined by intraoperative indocyanine green (ICG) angiography. ICG angiography results showed sufficient blood flow to all uterine grafts, and anaemia did not progress. Under appropriate immune suppression, all recipients survived for more than 90 days post-transplantation, without any surgical complications. We describe a surgical technique for allogeneic UTx in cynomolgus macaques.

Cyclosporine A-based immunotherapy in adult living donor liver transplantation: accurate and improved therapeutic drug monitoring by 4-hr intravenous infusion.

Background. A paucity of data exists for evaluating therapeutic drug monitoring in association with clinical outcomes of cyclosporine A (CYA) treatment in living donor liver transplantation (LDLT). Methods. A retrospective cohort analysis was conducted on 50 consecutive adult patients who underwent LDLT between 2001 and 2009 to investigate the feasibility and efficacy of 4-hr continuous intravenous infusion of CYA-based immunotherapy (4-hr CYA-IV, n=27) and compare the pharmacokinetic profile and short-term prognoses with an oral microemulsion formulation of CYA (CYA-ME, n=23). Results. All patients in the 4-hr CYA-IV group reached target CYA peak by day 3 compared with only 22% in the CYA-ME group (P<0.001). Adjustability to achieve the target range was easier in the 4-hr CYA-IV group compared with the CYA-ME group (P=0.017). Acute cellular rejection rate was lower in the 4-hr CYA-IV group (0%) compared with the CYA-ME group (17%, P=0.038). A subset analysis of the CYA-ME group revealed that CYA exposure was affected by external bile output (P=0.006). Patients in the CYA-ME group showed increased risk of switch to tacrolimus (35%) compared with the 4-hr CYA-IV group (7%, P=0.030). Toxicities and mortality rates were equivalent. The optimal initial dose of oral CYA at conversion from the 4-hr CYA-IV was considered to be 3-fold greater than that of the intravenous dose. Conclusions. In LDLT, our 4-hr CYA-IV immunosuppression protocol was superior to CYA-ME oral dosing and allowed accurate therapeutic drug monitoring with excellent patient compliance.