Short-Term Culture With the Caspase Inhibitor z-VAD.fmk Reduces Beta Cell Apoptosis in Transplanted Islets and Improves the Metabolic Outcome of the Graft

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Abstract:

In the initial days after transplantation islets are particularly vulnerable and show increased apoptosis and necrosis. We have studied the effects of caspase inhibition on this early beta cell death in syngeneically transplanted islets. Streptozotocin-diabetic C57BL/6 mice were transplanted with 150 syngeneic islets, an insufficient mass to restore normoglycemia, preincubated with or without the pan-caspase inhibitor z-VAD. fmk 2 h before transplantation. Beta cell apoptosis was increased in control islets on day 3 after transplantation (0.28 ± 0.02%) compared with freshly isolated islets (0.08 ± 0.02%, p < 0.001), and was partially reduced in transplanted islets preincubated with z-VAD.fmk 200 M (0.14 ± 0.02%, p = 0.003) or with z-VAD.fmk 500 M (0.17 ± 0.01%, p = 0.012), but not with a lower z-VAD.fmk (100 M) concentration. Diabetic mice transplanted with islets preincubated with z-VAD.fmk 500 M showed an improved metabolic evolution compared with control and z-VAD.fmk 200 M groups. The z-VAD.fmk 500 M group showed an overall lower blood glucose after transplantation (p = 0.02), and at the end of the study blood glucose values were reduced compared with transplantation day (15.7 ± 3.6 vs. 32.5 ± 0.5 mmol/L, p = 0.001). In contrast, blood glucose was not significantly changed in control and z-VAD.fmk 200 M groups. Four weeks after transplantation beta cell mass was higher in z-VAD.fmk 500 M group (0.15 ± 0.02 mg) than in the control group (0.10 ± 0.02 mg) (p = 0.043). In summary, the treatment of freshly isolated islets with the caspase inhibitor z-VAD.fmk reduced the subsequent apoptosis of the islets once they were transplanted and improved the outcome of the graft.

Keywords: Apoptosis; Beta cell mass; Caspase; Islet transplantation; z-VAD.fmk

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/000000005783983269

Affiliations: Laboratory of Diabetes and Experimental Endocrinology, Endocrine Unit, IDIBELL-Hospital Universitari de Bellvitge, University of Barcelona, Barcelona, Spain

Publication date: January 1, 2005

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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