Disproportionate hyperproinsulinemia, beta-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.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_52AC35ADD879
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Disproportionate hyperproinsulinemia, beta-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.
Périodique
Cell Transplantation
Auteur(s)
Davalli A.M., Perego L., Bertuzzi F., Finzi G., La Rosa S., Blau A., Placidi C., Nano R., Gregorini L., Perego C., Capella C., Folli F.
ISSN
0963-6897 (Print)
ISSN-L
0963-6897
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
17
Numéro
12
Pages
1323-1336
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
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 beta-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 alpha-cells. Moreover, engrafted beta-cells did not show evidence of replication, and preapoptotic beta-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors p16(INK4), p21(WAF1), and p27(Kip1) 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 beta-cell restricted PC2 depletion, amyloid deposition and beta-cell death, and lack of beta-cell replication with nuclear translocation of p27(Kip1) and p21(WAF1) that together may contribute to delayed graft failure.
Mots-clé
Animals, Autopsy, Cell Cycle/physiology, Diabetes Mellitus, Experimental/surgery, Humans, Hyperinsulinism/etiology, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/enzymology, Islets of Langerhans/enzymology, Islets of Langerhans/pathology, Islets of Langerhans Transplantation/adverse effects, Islets of Langerhans Transplantation/pathology, Male, Mice, Mice, Nude, Pancreas/pathology, Proinsulin/blood, Proinsulin/secretion, Proprotein Convertase 2/deficiency, Reference Values, Transplantation, Heterologous/adverse effects, Treatment Failure
Pubmed
Web of science
Création de la notice
06/09/2016 14:32
Dernière modification de la notice
20/08/2019 14:08
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