|
| Status |
Public on Jun 02, 2010 |
| Title |
Protective unfolded protein response in human pancreatic beta cells transplanted into mice |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Islet transplantation exposes beta cells to mild hyperglycemia and to the abnormal environment of the transplant site. These conditions may affect beta cells and induce the expression of genes involved in beta cell damage. Gene expression profile of human beta cells exposed to mild hyperglycemia by transplantation into ICR-SCID mice was evaluated and compared with the gene profile of beta cells obtained from non-diabetic subjects. We found that the transplanted beta cells showed an unfolded protein response (UPR). There was upregulation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress. Among them, increased expression of genes coding XBP-1; the chaperone proteins PDIA4, Bip, and Grp94; and the ER degradation proteins EDEM1 and EDEM2. ERdj4 and DNA-JC3 were also upregulated. JUK had downregulated expression. The PERK and ATF-6 arms of the ER stress response had many downregulated genes in transplanted islets. The PERK's substrates, EIF2A and NRF2, showed markedly reduced expression, as downregulated was the expression of CReP. Other downregulated genes included HERP2, IRS-2, CHOP and C/EBP-beta. In the transplanted beta cells there was significantly decreased expression of ATF-6, as well as the downstream gene products CHOP and HERP2. There was increased expression of HRD1, which exerts an antiapoptotic effect by degrading unfolded proteins. In conclusion human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins.
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| Overall design |
Frozen sections were obtained from pancreases of non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 weeks. β cell enriched samples were obtained by laser capture microdissection. RNA was extracted, amplified and subjected to microarray analysis.
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| Contributor(s) |
Kennedy J, Katsuta H, Jung M, Marselli L, Goldfine AB, Balis UJ, Sgroi DC, Bonner-Weir S, Weir GC |
| Citation(s) |
20585452 |
| |
| Submission date |
Jun 02, 2010 |
| Last update date |
Mar 22, 2012 |
| Contact name |
Lorella Marselli |
| E-mail(s) |
[email protected]
|
| Phone |
+39 050 995135
|
| Fax |
+39 050 541521
|
| Organization name |
Harvard Medical School
|
| Department |
Joslin Diabetes Center and the Department of Medicine
|
| Lab |
Section on Islet Transplantation and Cell Biology
|
| Street address |
One Joslin Place
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL1352 |
[U133_X3P] Affymetrix Human X3P Array |
|
| Samples (13)
|
| GSM549530 |
beta-cells_non-diabetic condition_surgical specimen1 |
| GSM549531 |
beta-cells_non-diabetic condition_surgical specimen2 |
| GSM549532 |
beta-cells_non-diabetic condition_surgical specimen3 |
| GSM549533 |
beta-cells_non-diabetic condition_surgical specimen4 |
| GSM549534 |
beta-cells_non-diabetic condition_surgical specimen5 |
| GSM549535 |
beta-cells_non-diabetic condition_surgical specimen6 |
| GSM549536 |
beta-cells_non-diabetic condition_surgical specimen7 |
| GSM549537 |
transplanted beta-cells_hyperglycemic condition_donor1_sample_a |
| GSM549538 |
transplanted beta-cells_hyperglycemic condition_donor1_sample_b |
| GSM549539 |
transplanted beta-cells_hyperglycemic condition_donor1_sample_c |
| GSM549540 |
transplanted beta-cells_hyperglycemic condition_donor2_sample_a |
| GSM549541 |
transplanted beta-cells_hyperglycemic condition_donor2_sample_b |
| GSM549542 |
transplanted beta-cells_hyperglycemic condition_donor2_sample_c |
|
| Relations |
| BioProject |
PRJNA128915 |
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