Disproportionate Hyperproinsulinemia, β-Cell Restricted Prohormone Convertase 2 Deficiency, and Cell Cycle Inhibitors Expression by Human Islets Transplanted into Athymic Nude Mice: Insights into Nonimmune-Mediated Mechanisms of Delayed Islet Graft Failure

Cell Transplantation

Article

Luisa Gregorini¹  Adam Blau²  Franco Folli²  Alberto M. Davalli³  Lucia Perego³  Giovanna Finzi⁴  Claudia Placidi⁴  Stefano La Rosa⁴  Carlo Capella⁴  Federico Bertuzzi⁵  Rita Nano⁵  Carla Perego⁶ 

[1] Department of Internal Medicine, University of Milan, Milan, Italy;Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;Department of Medicine, Unit of Endocrinology and Metabolic Diseases, San Raffaele Hospital, Milan, Italy;Department of Pathology, University of Insubria and Ospedale di Circolo, Varese, Italy;Diabetes Department, Niguarda Hospital, Milan, Italy;Institute of General Physiology and Biological Chemistry, University of Milan, Milan, Italy;

关键词: Islet transplantation;    Proinsulin processing;    Prohormone convertase 2 (PC2);    p16;    p21;    p27;    Athymic nude mice;   

DOI  :  10.3727/096368908787648137

 received in 2007-04-20, accepted in 2008-07-11,  发布年份 2008

来源: Sage Journals

【 摘 要 】

To learn more about nonimmune-mediated islet graft failure, we transplanted different preparations (preps) of isolated human islets under the kidney capsule of streptozotocin (STZ)-diabetic nude mice. One month after the implantation of 1,000 or 2,000 islets, grafts were harvested for morphological, immunohistochemical, and ultrastructural analysis. Only a single islet prep cured the diabetes out of all the recipients, while the remaining preps showed only partial function after the implantation of 2,000 islets. Transplanted mice showed high circulating proinsulin levels but, with the exclusion of those bearing curative grafts, relatively low mature insulin levels. Engrafted β-cells showed positive carboxypeptidase E (CPE) and prohormone convertase 1 (PC1) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted α-cells. Moreover, engrafted β-cells did not show evidence of replication, and preapoptotic β-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors p16INK4, p21WAF1, and p27Kip1 were abundantly expressed in the islet grafts and showed a predominant nuclear localization. In conclusion, diabetic nude mice transplanted with human islets showed disproportionate hyperproinsulinemia and graft evidence of β-cell restricted PC2 depletion, amyloid deposition and β-cell death, and lack of β-cell replication with nuclear translocation of p27Kip1 and p21WAF1 that together may contribute to delayed graft failure.

【 授权许可】

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