Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co‐transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co‐transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co‐transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP‐1 were selected as candidate crucial factors using the Bio‐Plex system, beneficial effects were partially counteracted by anti‐insulin receptor antibodies. In conclusion, this study demonstrated that islet co‐transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.
Background. Hepatocyte transplantation is expected to be an alternative therapy to liver transplantation; however, poor engraftment is a severe obstacle to be overcome. The adipose tissue-derived stem cells (ADSCs) are known to improve engraftment of transplanted pancreatic islets, which have many similarities to the hepatocytes. Therefore, we examined the effects and underlying mechanisms of ADSC cotransplantation on hepatocyte engraftment. Methods. Hepatocytes and ADSCs were cotransplanted into the renal subcapsular space and livers of syngeneic analbuminemic rats, and the serum albumin level was quantified to evaluate engraftment. Immunohistochemical staining and fluorescent staining to trace transplanted cells in the liver were also performed. To investigate the mechanisms, cocultured supernatants were analyzed by a multiplex assay and inhibition test using neutralizing antibodies for target factors. Results. Hepatocyte engraftment at both transplant sites was significantly improved by ADSC cotransplantation (P < 0.001, P < 0.001). In the renal subcapsular model, close proximity between hepatocytes and ADSCs was necessary to exert this effect. Unexpectedly, ≈50% of transplanted hepatocytes were attached by ADSCs in the liver. In an in vitro study, the hepatocyte function was significantly improved by ADSC coculture supernatant (P < 0.001). The multiplex assay and inhibition test demonstrated that hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6 may be key factors for the abovementioned effects of ADSCs. Conclusions. The present study revealed that ADSC cotransplantation can improve the engraftment of transplanted hepatocytes. This effect may be based on crucial factors, such as hepatocyte growth factor, vascular endothelial growth factor, and interleukin-6, which are secreted by ADSCs.
Background Endoscopic and PTB interventions are common nonsurgical interventions for biliary anastomotic strictures that occur after liver transplantation. When these nonsurgical interventions fail, surgical re‐anastomosis is considered; however, this is quite invasive and can cause additional injury that may lead to graft loss. We report a case in which conventional nonsurgical interventions failed, but a new method that involve the use of a transseptal needle—a device to create a transseptal left‐heart access during cardiac catheter interventions—was successfully used in recanalization of the hepaticojejunal anastomotic obstruction. Case A 21‐year‐old man, who had received living‐donor liver transplantation for biliary atresia at the age of 23 months presented with recurrent cholangitis and liver dysfunction due to a biliary anastomotic stricture of the hepaticojejunostomy. Therapeutic interventions for biliary stricture, including the PTB approach, double‐balloon enteroscopic approach, and rendezvous approach failed. We then performed needle puncture of the anastomotic obstruction using a transseptal needle and succeeded in recanalizing the complete anastomotic obstruction. To perform the procedures safely, we evaluated the organ and needle positions using biplane fluoroscopy and placed a balloon in the afferent jejunal limb as a target for puncture. The 12 Fr catheter via the biliary route was removed 7 months after the procedure, without using a catheter, there was no recurrent stricture or cholangitis for 26 months. Conclusion Using a transseptal needle to manage hepaticojejunal anastomotic obstruction can reduce the number of patients who need surgical re‐anastomosis.
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