The Experts below are selected from a list of 5721 Experts worldwide ranked by ideXlab platform
Kazuo Ohashi - One of the best experts on this subject based on the ideXlab platform.
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engineering liver tissues under the Kidney Capsule site provides therapeutic effects to hemophilia b mice
Cell Transplantation, 2010Co-Authors: Kazuo Ohashi, Kohei Tatsumi, Midori Shima, Rie Utoh, Soichi Takagi, Teruo OkanoAbstract:Recent advances in liver tissue engineering have encouraged further investigation into the evaluation of therapeutic benefits based on animal disease models. In the present study, liver tissues were engineered in coagulation factor IX knockout (FIX-KO) mice, a mouse model of hemophilia B, to determine if the tissue engineering approach would provide therapeutic benefits. Primary hepatocytes were isolated from the liver of wild-type mice and suspended in a mixture of culture medium and extracellular matrix components. The hepatocyte suspension was injected into the space under the bilateral Kidney Capsules of the FIX-KO mice to engineer liver tissues. The plasma FIX activities (FIX:C) of the untreated FIX-KO mice were undetectable at any time point. In contrast, the liver tissue engineered FIX-KO mice achieved 1.5-2.5% of plasma FIX activities (FIX:C) and this elevated FIX:C level persisted throughout the 90 day experimental period. Significant FIX mRNA expression levels were found in the engineered liver tissues at levels similar to the wild-type livers. The present study demonstrates that liver tissue engineering could provide therapeutic benefits in the treatment of hemophilia B.
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functional life long maintenance of engineered liver tissue in mice following transplantation under the Kidney Capsule
Journal of Tissue Engineering and Regenerative Medicine, 2010Co-Authors: Kazuo Ohashi, Fumikazu Koyama, Kohei Tatsumi, Midori Shima, Frank Park, Yoshiyuki Nakajima, Teruo OkanoAbstract:The ability to engineer biologically active cells and tissue matrices with long-term functional maintenance has been a principal focus for investigators in the field of hepatocyte transplantation and liver tissue engineering. The present study was designed to determine the efficacy and temporal persistence of functional engineered liver tissue following transplantation under the Kidney Capsule of a normal mouse. Hepatocytes were isolated from human alpha-1 antitrypsin (hA1AT) transgenic mouse livers. Hepatocytes were subsequently transplanted under the Kidney Capsule space in combination with extracellular matrix components (Matrigel) for engineering liver tissues. The primary outcome of interest was to assess the level of engineering liver tissue function over the experimental period, which was 450 days. Long-term survival by the engineered liver tissue was confirmed by measuring the serum level of hA1AT in the recipient mice throughout the experimental period. In addition, administration of chemical compounds at day 450 resulted in the ability of the engineered liver tissue to metabolize exogenously circulating compounds and induce drug-metabolizing enzyme production. Moreover, we were able to document that the engineered tissues could retain their native regenerative potential similar to that of naive livers. Overall, these results demonstrated that liver tissues could be engineered at a heterologous site while stably maintaining its functionality for nearly the life span of a normal mouse.
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transplantation of murine bone marrow stromal cells under the Kidney Capsule to secrete coagulation factor viii
Cell Transplantation, 2006Co-Authors: Alexandra Peister, Kazuo Ohashi, Frank ParkAbstract:Ectopic cell transplantation has been studied as an alternative to whole organ transplantation or as a method to produce secretable proteins for genetic disorders. In this study, bone marrow stroma...
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stability and repeat regeneration potential of the engineered liver tissues under the Kidney Capsule in mice
Cell Transplantation, 2005Co-Authors: Kazuo Ohashi, Mark A Kay, Takashi Yokoyama, Hiroyuki Kuge, Hiromichi Kanehiro, Michiyoshi Hisanaga, Yoshiyuki NakajimaAbstract:Liver tissue engineering using hepatocyte transplantation has been proposed as a therapeutic alternative to liver transplantation toward several liver diseases. We have previously reported that stable liver tissue with the potential for liver regeneration can be engineered at extrahepatic sites by transplanting mature hepatocytes into an extracellular matrix. The present study was aimed at assessing the liver tissue persistence after induced regeneration by hepatectomy and repeat regeneration potential induced by repeat hepatectomy. Mouse isolated hepatocytes mixed in EHS extracellular matrix gel were transplanted under both Kidney Capsules of isogenic mice. The hepatocyte survival persisted for over 25 weeks. In some of the mice, we confirmed that the grafted hepatocytes developed a thin layer of liver tissues under the Kidney Capsule, determined by specific characteristics of differentiated hepatocytes in cord structures between the capillaries. We then assessed the regenerative potential and persistence of the exogenous liver tissue. To induce liver regeneration, we performed a two-thirds hepatectomy at 70 days after hepatocyte transplantation. Three weeks after this procedure, the engineered liver tissues showed active regeneration, reaching serum marker protein levels of 261 +/- 42% of the prehepatectomy level. We found that the regenerated liver tissue was stably maintained for 100 days (length of the experiment). Repeat regeneration potential was established by performing a repeat hepatectomy (that had been two-thirds hepatectomized at day 70) 60 days after the initial hepatectomy. Again, the regenerated engineered liver tissues showed active regeneration as there was an approximately twofold increase in the serum marker protein levels. The present studies demonstrate that liver tissue, which was recognized as a part of the host naive liver in terms of the regeneration profile, could be engineered at a heterologous site that does not have access to the portal circulation.
Klaus H. Kaestner - One of the best experts on this subject based on the ideXlab platform.
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elevated mouse hepatic betatrophin expression does not increase human β cell replication in the transplant setting
Diabetes, 2014Co-Authors: Yang Jiao, Ali Naji, John Le Lay, Klaus H. KaestnerAbstract:The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing beta-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. However, at present the effects of betatrophin on human beta-cells are not known. Here we employ administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate beta-cell replication in mice, to test its effect on human beta-cells. While mouse beta-cells, both in their normal location in the pancreas or when transplanted under the Kidney Capsule, respond with a dramatic increase in beta-cell DNA replication, human beta-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic for human diabetes.
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elevated mouse hepatic betatrophin expression does not increase human β cell replication in the transplant setting
Diabetes, 2014Co-Authors: Yang Jiao, Ali Naji, John Le Lay, Klaus H. KaestnerAbstract:The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing β-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. At present, however, the effects of betatrophin on human β-cells are not known. Here we use administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate β-cell replication in mice, to test its effect on human β-cells. Although mouse β-cells, in their normal location in the pancreas or when transplanted under the Kidney Capsule, respond with a dramatic increase in β-cell DNA replication, human β-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic approach for treating human diabetes.
Teruo Okano - One of the best experts on this subject based on the ideXlab platform.
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engineering liver tissues under the Kidney Capsule site provides therapeutic effects to hemophilia b mice
Cell Transplantation, 2010Co-Authors: Kazuo Ohashi, Kohei Tatsumi, Midori Shima, Rie Utoh, Soichi Takagi, Teruo OkanoAbstract:Recent advances in liver tissue engineering have encouraged further investigation into the evaluation of therapeutic benefits based on animal disease models. In the present study, liver tissues were engineered in coagulation factor IX knockout (FIX-KO) mice, a mouse model of hemophilia B, to determine if the tissue engineering approach would provide therapeutic benefits. Primary hepatocytes were isolated from the liver of wild-type mice and suspended in a mixture of culture medium and extracellular matrix components. The hepatocyte suspension was injected into the space under the bilateral Kidney Capsules of the FIX-KO mice to engineer liver tissues. The plasma FIX activities (FIX:C) of the untreated FIX-KO mice were undetectable at any time point. In contrast, the liver tissue engineered FIX-KO mice achieved 1.5-2.5% of plasma FIX activities (FIX:C) and this elevated FIX:C level persisted throughout the 90 day experimental period. Significant FIX mRNA expression levels were found in the engineered liver tissues at levels similar to the wild-type livers. The present study demonstrates that liver tissue engineering could provide therapeutic benefits in the treatment of hemophilia B.
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functional life long maintenance of engineered liver tissue in mice following transplantation under the Kidney Capsule
Journal of Tissue Engineering and Regenerative Medicine, 2010Co-Authors: Kazuo Ohashi, Fumikazu Koyama, Kohei Tatsumi, Midori Shima, Frank Park, Yoshiyuki Nakajima, Teruo OkanoAbstract:The ability to engineer biologically active cells and tissue matrices with long-term functional maintenance has been a principal focus for investigators in the field of hepatocyte transplantation and liver tissue engineering. The present study was designed to determine the efficacy and temporal persistence of functional engineered liver tissue following transplantation under the Kidney Capsule of a normal mouse. Hepatocytes were isolated from human alpha-1 antitrypsin (hA1AT) transgenic mouse livers. Hepatocytes were subsequently transplanted under the Kidney Capsule space in combination with extracellular matrix components (Matrigel) for engineering liver tissues. The primary outcome of interest was to assess the level of engineering liver tissue function over the experimental period, which was 450 days. Long-term survival by the engineered liver tissue was confirmed by measuring the serum level of hA1AT in the recipient mice throughout the experimental period. In addition, administration of chemical compounds at day 450 resulted in the ability of the engineered liver tissue to metabolize exogenously circulating compounds and induce drug-metabolizing enzyme production. Moreover, we were able to document that the engineered tissues could retain their native regenerative potential similar to that of naive livers. Overall, these results demonstrated that liver tissues could be engineered at a heterologous site while stably maintaining its functionality for nearly the life span of a normal mouse.
Yang Jiao - One of the best experts on this subject based on the ideXlab platform.
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elevated mouse hepatic betatrophin expression does not increase human β cell replication in the transplant setting
Diabetes, 2014Co-Authors: Yang Jiao, Ali Naji, John Le Lay, Klaus H. KaestnerAbstract:The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing beta-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. However, at present the effects of betatrophin on human beta-cells are not known. Here we employ administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate beta-cell replication in mice, to test its effect on human beta-cells. While mouse beta-cells, both in their normal location in the pancreas or when transplanted under the Kidney Capsule, respond with a dramatic increase in beta-cell DNA replication, human beta-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic for human diabetes.
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elevated mouse hepatic betatrophin expression does not increase human β cell replication in the transplant setting
Diabetes, 2014Co-Authors: Yang Jiao, Ali Naji, John Le Lay, Klaus H. KaestnerAbstract:The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing β-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. At present, however, the effects of betatrophin on human β-cells are not known. Here we use administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate β-cell replication in mice, to test its effect on human β-cells. Although mouse β-cells, in their normal location in the pancreas or when transplanted under the Kidney Capsule, respond with a dramatic increase in β-cell DNA replication, human β-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic approach for treating human diabetes.
Gordon C Weir - One of the best experts on this subject based on the ideXlab platform.
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in vivo imaging of autologous islet grafts in the liver and under the Kidney Capsule in non human primates
Transplantation, 2009Co-Authors: Zdravka Medarova, David H Sachs, Gordon C Weir, Prashanth Vallabhajosyula, Aseda Tena, Natalia V Evgenov, Pamela Pantazopoulos, Vaja Tchipashvili, Anna MooreAbstract:Objective. As islet transplantation begins to show promise as a clinical method, there is a critical need for reliable, noninvasive techniques to monitor islet graft survival. Previous work in our laboratory has shown that human islets labeled with a superparamagnetic iron oxide contrast agent and transplanted into mice could be detected by magnetic resonance imaging (MRI). The potential translation of these findings to the clinical situation requires validation of our methodology in a non-human primate model, which we have now carried out in baboons (Papio hamadryas) and reported here. Research Design and Methods. For islet labeling, we adapted the Food and Drug Administration-approved superparamagnetic iron oxide contrast agent, Feridex, which is used clinically for liver imaging. After partial pancreatectomy, Feridex-labeled islets were prepared and autotransplanted underneath the renal Capsule and into the liver. Longitudinal in vivo MRI at days 1, 3, 8, 16, 23, and 30 after transplantation was performed to track the islet grafts. Results. The renal subcapsular islet graft was easily detectable on T2 * -weighted MR images as a pocket of signal loss disrupting the contour of the Kidney at the transplantation site. Islets transplanted in the liver appeared as distinct signal voids dispersed throughout the liver parenchyma. A semiautomated computational analysis of our MRI data established the feasibility of monitoring both the renal and intrahepatic grafts during the studied posttransplantation period. Conclusion. This study establishes a method for the noninvasive, longitudinal detection of pancreatic islets transplanted into non-human primates using a low-field clinical MRI system.
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islet transplantation under the Kidney Capsule corrects the defects in glycogen metabolism in both liver and muscle of streptozocin diabetic rats
Cell Transplantation, 2002Co-Authors: Margherita Matarazzo, M G Giardina, Vincenzo Guardasole, A M Davalli, Edward S Horton, Gordon C Weir, Luigi Sacca, Raffaele NapoliAbstract:Insulin-deficient rats are characterized by multiple defects in the pathway of glycogen synthesis and breakdown in both liver and skeletal muscle. The aim of this study was to clarify whether islet transplantation under the Kidney Capsule, which is associated with delivery of insulin into the peripheral circulation, is able to normalize glycogen metabolism in liver and muscle of streptozotocin-diabetic rats. Three groups of male Lewis rats were studied under fasting condition: controls, untreated diabetics, and islet transplanted diabetics. Glycogen content, glucose-6-phosphate concentration, and glycogen synthase activity were measured in both liver and skeletal muscle. Untreated diabetic rats were characterized by an increase in glycogen content of 178% and a reduction of glucose-6-phosphate level of 50%. Both glycogen and glucose-6-phosphate contents were restored to normal in transplanted diabetic rats. Active glycogen synthase (0.35 +/- 0.1 nmol/min/mg) and activity ratio (0.22 +/- 0.04) were significantly impaired compared with controls (0.99 +/- 0.2 nmol/min/mg and 0.43 +/- 0.06, respectively) and were normalized by islet transplantation. In the skeletal muscle, glycogen content was similar in the three groups of animals, whereas muscle glucose-6-phosphate level was reduced by 28% and glycogen synthase was in a less active state in the untreated diabetic rats. Both the glucose-6-phosphate concentration and the kinetic profile of glycogen synthase were normalized by islet transplantation. In conclusion, islet transplantation under the Kidney Capsule corrects the diabetes-induced abnormalities in glycogen and glucose-6-phosphate content and glycogen synthase activity in both liver and skeletal muscle.
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effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart
Diabetes, 2001Co-Authors: Luigi Laviola, Alberto M Davalli, Gordon C Weir, Raffaele Napoli, G Belsanti, Sebastio Perrini, R Giorgino, Francesco GiorginoAbstract:The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the Kidney Capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52 Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1–associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1 ) IRS-1, IRS-2, and p52 Shc are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3 ) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the Kidney Capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
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islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3 kinase activity in skeletal muscle and myocardium of streptozocin induced diabetic rats
Diabetes, 1999Co-Authors: Francesco Giorgino, A M Davalli, Edward S Horton, Gordon C Weir, Raffaele Napoli, Michael F Hirshman, F Logoluso, Luigi Laviola, Robert J SmithAbstract:Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the Kidney Capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the Kidney Capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.
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islet transplantation under the Kidney Capsule fully corrects the impaired skeletal muscle glucose transport system of streptozocin diabetic rats
Journal of Clinical Investigation, 1996Co-Authors: Raffaele Napoli, Alberto M Davalli, Gordon C Weir, Michael F Hirshman, Raimund Weitgasser, Edward S HortonAbstract:Chronic insulin therapy improves but does not restore impaired insulin-mediated muscle glucose uptake in human diabetes or muscle glucose uptake, transport, and transporter translocation in streptozocin diabetic rats. To determine whether this inability is due to inadequate insulin replacement, we studied fasted streptozocin-induced diabetic Lewis rats either untreated or after islet transplantation under the Kidney Capsule. Plasma glucose was increased in untreated diabetics and normalized by the islet transplantation (110 +/- 5, 452 +/- 9, and 102 +/- 3 mg/dl in controls, untreated diabetics, and transplanted diabetics, respectively). Plasma membrane and intracellular microsomal membrane vesicles were prepared from hindlimb skeletal muscle of basal and maximally insulin-stimulated rats. Islet transplantation normalized plasma membrane carrier-mediated glucose transport Vmax, plasma membrane glucose transporter content, and insulin-induced transporter translocation. There were no differences in transporter intrinsic activity (Vmax/Ro) among the three groups. Microsomal membrane GLUT4 content was reduced by 30% in untreated diabetic rats and normal in transplanted diabetics, whereas the insulin-induced changes in microsomal membrane GLUT4 content were quantitatively similar in the three groups. There were no differences in plasma membrane GLUT1 among the groups and between basal and insulin stimulated states. Microsomal membrane GLUT1 content was increased 60% in untreated diabetics and normalized by the transplantation. In conclusion, an adequate insulin delivery in the peripheral circulation, obtained by islet transplantation, fully restores the muscle glucose transport system to normal in streptozocin diabetic rats.
