Protective unfolded protein response in human pancreatic beta cells transplanted into mice.
BACKGROUND
There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation.


RESULTS
Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated.


CONCLUSIONS
Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins.
Kennedy
Jeffrey
J
Section on Islet Cell Biology and Regenerative Medicine, Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
Katsuta
Hitoshi
H
Jung
Min-Ho
MH
Marselli
Lorella
L
Goldfine
Allison B
AB
Balis
Ulysses J
UJ
Sgroi
Dennis
D
Bonner-Weir
Susan
S
Weir
Gordon C
GC
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D011489:Protein Denaturation
D001786:Blood Glucose