Local Sphingosine Kinase 1 Activity Improves Islet Transplantation.
Pancreatic islet transplantation is a promising clinical treatment for type 1 diabetes, but success is limited by extensive β-cell death in the immediate posttransplant period and impaired islet function in the longer term. Following transplantation, appropriate vascular remodeling is crucial to ensure the survival and function of engrafted islets. The sphingosine kinase (SK) pathway is an important regulator of vascular beds, but its role in the survival and function of transplanted islets is unknown. We observed that donor islets from mice deficient in SK1 (Sphk1knockout) contain a reduced number of resident intraislet vascular endothelial cells. Furthermore, we demonstrate that the main product of SK1, sphingosine-1-phosphate, controls the migration of intraislet endothelial cells in vitro. We reveal in vivo thatSphk1knockout islets have an impaired ability to cure diabetes compared with wild-type controls. Thus, SK1-deficient islets not only contain fewer resident vascular cells that participate in revascularization, but likely also a reduced ability to recruit new vessels into the transplanted islet. Together, our data suggest that SK1 is important for islet revascularization following transplantation and represents a novel clinical target for improving transplant outcomes.
Discipline of Medicine, The University of Adelaide, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia.
Darling
D
Rojas-Canales
Discipline of Medicine, The University of Adelaide, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia.
Daniella
D
Penko
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Kay K
KK
Myo Min
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Kate A
KA
Parham
Department of Human Physiology, Flinders University, Bedford Park, Australia.|Centre for Neuroscience, Flinders University, Bedford Park, Australia.
Heshan
H
Peiris
Department of Anatomy & Histology, Flinders University, Bedford Park, Australia.
Rainer V
RV
Haberberger
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Stuart M
SM
Pitson
Discipline of Medicine, The University of Adelaide, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia.
Chris
C
Drogemuller
Department of Human Physiology, Flinders University, Bedford Park, Australia.|Centre for Neuroscience, Flinders University, Bedford Park, Australia.|South Australian Health and Medical Research Institute, Adelaide, Australia.
Damien J
DJ
Keating
Garvan Medical Institute, Darlinghurst, Australia.
Shane T
ST
Grey
Discipline of Medicine, The University of Adelaide, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Services, Royal Adelaide Hospital, Adelaide, Australia.
Patrick T
PT
Coates
Discipline of Medicine, The University of Adelaide, Adelaide, Australia claudine.bonder@unisa.edu.au.|Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
Claudine S
CS
Bonder
Discipline of Medicine, The University of Adelaide, Adelaide, Australia claire.jessup@flinders.edu.au.|Centre for Neuroscience, Flinders University, Bedford Park, Australia.|Department of Anatomy & Histology, Flinders University, Bedford Park, Australia.
Claire F
CF
Jessup
D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D042783:Endothelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D007515:Islets of Langerhans / Q000098:blood supply*; D016381:Islets of Langerhans Transplantation; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019737:Transplants / Q000098:blood supply; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate