1. Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice.
- Author
-
Pepper AR, Bruni A, Pawlick R, Wink J, Rafiei Y, Gala-Lopez B, Bral M, Abualhassan N, Kin T, and Shapiro AMJ
- Subjects
- Animals, Biomarkers blood, Blood Glucose metabolism, Cell Survival drug effects, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 chemically induced, Enzyme Activation, Heterografts, Humans, Islets of Langerhans enzymology, Islets of Langerhans pathology, Male, Mice, Inbred C57BL, Signal Transduction drug effects, Streptozocin, Time Factors, Tissue Culture Techniques, Amino Acid Chloromethyl Ketones pharmacology, Apoptosis drug effects, Caspase 3 metabolism, Caspase Inhibitors pharmacology, Diabetes Mellitus, Experimental surgery, Diabetes Mellitus, Type 1 surgery, Graft Survival drug effects, Islets of Langerhans drug effects, Islets of Langerhans surgery, Islets of Langerhans Transplantation methods
- Abstract
Background: Islet transplantation is an effective therapy in type 1 diabetes and recalcitrant hypoglycemia. However, there is an ongoing need to circumvent islet loss posttransplant. We explore herein the potential of the pan-caspase inhibitor F573 to mitigate early apoptosis-mediated islet death within portal and extrahepatic portal sites in mice., Methods: Mouse or human islets were cultured in standard media ±100 μM F573 and subsequently assessed for viability and apoptosis via terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation. Diabetic mice were transplanted with syngeneic islets placed under the kidney capsule (KC) or into the subcutaneous deviceless (DL) site at a marginal islet dose (150 islets), or into the portal vein (PV) at a full dose (500 islets). Human islets were transplanted under the KC of diabetic immunodeficient mice at a marginal dose (500 islet equivalents). Islets were cultured in the presence of F573, and F573 was administered subcutaneously on days 0 to 5 posttransplant. Control mice were transplanted with nontreated islets and were injected with saline. Graft function was measured by nonfasting blood glucose and glucose tolerance testing., Results: F573 markedly reduced human and mouse islet apoptosis after in vitro culture (P < 0.05 and P < 0.05, respectively). Furthermore, F573 improved human islet function when transplanted under the KC (P < 0.05); whereas F573 did not enhance murine islet marginal KC transplants. Conversely, F573 significantly improved mouse islet engraftment in the PV and DL site (P < 0.05 and P < 0.05, respectively)., Conclusions: The pan-caspase inhibitor F573 markedly reduces human and mouse islet apoptosis and improves engraftment most effectively in the portal and DL subcutaneous sites.
- Published
- 2017
- Full Text
- View/download PDF