TY - JOUR
T1 - Disproportionate hyperproinsulinemia, Β-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors Expression by human islets transplanted into athymic nude mice
T2 - Insights into nonimmune-mediated mechanisms of delayed islet graft failure
AU - Davalli, Alberto M.
AU - Perego, Lucia
AU - Bertuzzi, Federico
AU - Finzi, Giovanna
AU - La Rosa, Stefano
AU - Blau, Adam
AU - Placidi, Claudia
AU - Nano, Rita
AU - Gregorini, Luisa
AU - Perego, Carla
AU - Capella, Carlo
AU - Folli, Franco
PY - 2008/12/1
Y1 - 2008/12/1
N2 - To leam 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, immunohistochemi-cal, 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 (PCI) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted a-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 pl6 INK4, p21 WAF1, and p27 Kipl 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 p27 Kipl and p21 WAF1 that together may contribute to delayed graft failure.
AB - To leam 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, immunohistochemi-cal, 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 (PCI) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted a-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 pl6 INK4, p21 WAF1, and p27 Kipl 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 p27 Kipl and p21 WAF1 that together may contribute to delayed graft failure.
KW - Athymic nude mice
KW - Islet transplantation
KW - Prohormone convertase 2 (PC2)
KW - Proinsulin processing
KW - p27
KW - pl6 ; p21
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U2 - 10.3727/096368908787648137
DO - 10.3727/096368908787648137
M3 - Article
C2 - 19364070
AN - SCOPUS:62549143146
VL - 17
SP - 1323
EP - 1336
JO - Cell Transplantation
JF - Cell Transplantation
SN - 0963-6897
IS - 12
ER -