title: Engraftment Site and Effectiveness of the Pan-Caspase Inhibitor F573 to Improve Engraftment in Mouse and Human Islet Transplantation in Mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  The pan-caspase inhibitor F573 markedly reduces human and mouse islet apoptosis and improves engraftment most effectively in the portal and DL subcutaneous sites.
authors.affiliation: 1 Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada. 2 Department of Surgery, University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pepper
authors.forename: Antonio
authors.initials: A
authors.lastname: Bruni
authors.forename: Rena
authors.initials: R
authors.lastname: Pawlick
authors.forename: John
authors.initials: J
authors.lastname: Wink
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rafiei
authors.forename: Boris
authors.initials: B
authors.lastname: Gala-Lopez
authors.forename: Mariusz
authors.initials: M
authors.lastname: Bral
authors.forename: Nasser
authors.initials: N
authors.lastname: Abualhassan
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kin
authors.forename: A M James
authors.initials: AMJ
authors.lastname: Shapiro
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000601:surgery*; D004789:Enzyme Activation; D006085:Graft Survival / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015415:Biomarkers; D001786:Blood Glucose; D061945:Caspase Inhibitors; C484771:benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone; D013311:Streptozocin; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3