Vascularized islet-cell transplantation in miniature swine. I. Preparation of vascularized islet kidneys

Kumagai, Naoya; O’Neil, John J.; Barth, Rolf N.; LaMattina, John C.; Utsugi, Ryu; Moran, Shannon; Yamamoto, Shin; Vagefi, Parsia A.; Kitamura, Hiroshi; Kamano, Chisako; Sachs, David H.; Yamada, Kazuhiko

doi:10.1097/00007890-200211150-00005

Cited by 30 publications

(43 citation statements)

References 22 publications

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“…28 It was suggested that this site allowed rapid establishment of a vascular network that contributed to long-term cell survival. However, hepatocytes alone, grafted under the kidney capsule, have not shown persistent survival.…”

Section: Discussionmentioning

confidence: 99%

Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases

et al. 2005

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Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. However, when we transplanted hepatocytes with the extracellular matrix components extracted from Engelbreth-Holm-Swarm cells, hepatocytes survived for at least 140 days and formed small liver tissues. Liver engineering in hemophilia A mice reconstituted 5% to 10% of normal clotting activity, enough to reduce the bleeding time and have a therapeutic benefit. Conversely, the subcutaneous space did not support the persistent survival of hepatocytes with Engelbreth-Holm-Swarm gel matrix. We hypothesized that establishing a local vascular network at the transplantation site would reduce graft loss. To test this idea, we provided a potent angiogenic agent before hepatocyte transplantation into the subcutaneous space. With this procedure, persistent survival was achieved for the length of the experiment (120 days). To establish that these engineered liver tissues also retained their native regeneration potential in vivo, we induced two different modes of proliferative stimulus to the naïve liver and confirmed that hepatocytes within the extrahepatic tissues regenerated with activity similar to that of naïve liver. In conclusion, our studies indicate that liver tissues can be engineered and maintained at extrahepatic sites, retain their capacity for regeneration in vivo, and used to successfully treat genetic disorders. (HEPATOLOGY 2005; 41:132-140.)

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Section: Discussionmentioning

confidence: 99%

Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases

et al. 2005

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“…22 At 3 months after the transplantation, tumors with the same histological features as the original thymomas in lck-pX rats occupied the transplanted thymus in the recipient kidney, indicating that thymomas can also develop at heterotopic sites if there is a thymic tissue.…”

Section: Malignant Transformation Of Thymoma In Rats T Tsuji Et Almentioning

confidence: 93%

“…The subcapsular space of the kidney may be a suitable site for tumor aggression where vascularization into the grafted tissues is easily introduced. 22 Actually, when tumor cells from the renal cell carcinoma were injected into subcutaneous, intraperitoneum, intravein or beneath the renal capsule of nude mice, a remarkable metastasis was observed only in cases where the cells were inoculated into the subcapsular space of the kidney. 24 In line with this, the thymomas could develop and become malignant with aggressive growth in the subcapusular space of the kidney, although development of a tumor was never found when original thymomas were transplanted into the retroperitoneal subserosal space (unpublished data).…”

Section: Malignant Transformation Of Thymoma In Rats T Tsuji Et Almentioning

confidence: 99%

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats

Tsuji

Ikeda

Tsuchikawa

et al. 2005

Laboratory Investigation

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Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation. Laboratory Investigation (2005) 85, 851-861.

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“…Extension of the concept of composite organ transplantation to islets-kidneys A schematic of the preparation and testing of vascularized islet-kidneys (IK) in miniature swine [25] is shown in Fig. 2.…”

Section: Induction Of Tolerance To Renal Allografts In Miniature Swinementioning

confidence: 99%

“…Islet-kidneys (IK) were prepared by use of a paramedian or flank abdominal incision to expose the kidney, and injecting islets beneath the renal capsule using a 20G angiocatheter [25]. As for the previous thymic grafts, islets were allowed to heal for about 2 months prior to the intended date of allogeneic transplantation of the composite organ.…”

Section: Induction Of Tolerance To Renal Allografts In Miniature Swinementioning

confidence: 99%

Vascularized composite islet-kidney transplantation in a miniature swine model

Vallabhajosyula

Griesemer

Yamada

et al. 2007

Cell Biochem Biophys

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Previous work from this laboratory has demonstrated that transplantation of allogeneic thymic tissue as part of a composite vascularized graft is far more successful in terms of both engraftment and long-term survival than transplantation of thymic tissue or cells alone. We have subsequently extended this concept to transplantation of allogeneic islets, comparing survival of islet cell suspensions to that of vascularized composite islet-kidneys (IK), prepared by injection of autologous islets underneath the renal capsule 2-3 months prior to allogeneic transplantation of the composite organ. We have utilized partially inbred miniature swine with defined MHC loci as the experimental large animals for this study, permitting reproducible transplantation across specific MHC barriers. Composite IK have been transplanted successfully across minor and full MHC mismatch barriers, using treatment regimens previously demonstrated to induce long-term tolerance of kidney allografts across these barriers. IK allografts containing > or =5000 islet equivalents (IE)/kg recipient body weight were found capable of reversing surgically induced diabetes, while injection of comparable numbers of purified islets via the portal vein or under the renal capsule did not. Studies are also being directed toward preparation of autologous "thymo-isletkidneys" (TIK), for potential use as xenografts, in which the thymic component is intended to induce tolerance and the islets to reverse diabetic hyperglycemia. The use of both types of composite organ transplants may eventually be applicable to the treatment of type I diabetic patients suffering from end-stage diabetic nephropathy.

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Vascularized islet-cell transplantation in miniature swine. I. Preparation of vascularized islet kidneys

Cited by 30 publications

References 22 publications

Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases

Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases

Malignant transformation of thymoma in recipient rats by heterotopic thymus transplantation from HTLV-I transgenic rats

Vascularized composite islet-kidney transplantation in a miniature swine model

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