Type

Journal Article

Authors

Jochen H M Prehn
Maria M Byrne
Rolf Graf
Claes B Wollheim
Chantal M Boulanger
Manus W Ward
Heiko Düssmann
Seán M Kilbride
Angela M Farrelly
Mathurin Baquie
and 4 others

Subjects

Biochemistry

Topics
physiology pharmacology metabolism promoter regions genetic rats humans caspase 3 diabetes mellitus type 2 reverse transcriptase polymerase chain reaction animals apoptosis genetics hepatocyte nuclear factor 1 alpha mice cytology drug effects mice inbred c57bl enzyme linked immunosorbent assay mice transgenic insulinoma physiopathology insulin secreting cells caspases cell death

INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells. (2010)

Abstract In diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A-maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells. DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay. We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A-induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A-expressing cells, but not DN-HNF1A-expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V-positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A-induced cells by stimulating cell proliferation and increasing insulin gene expression. Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Maria M Byrne, Rolf Graf, Claes B Wollheim, Chantal M Boulanger, Manus W Ward, Heiko Düssmann, Seán M Kilbride, Angela M Farrelly, Mathurin Baquie and 4 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45