Local Sphingosine Kinase 1 Activity Improves Islet Transplantation

Darling Rojas-Canales, Daniella Penko, Kaye Myo Min, Kate Parham, Galhenage Peiris, Rainer Haberberger, Stuart Pitson, Chris Drogemuller, Damien Keating, Shane Grey, P Coates, Claudine Bonder, Claire Jessup

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    Abstract

    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 (Sphk1 knockout) 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 that Sphk1 knockout 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.

    Original languageEnglish
    Pages (from-to)1301-1311
    Number of pages11
    JournalDiabetes
    Volume66
    Issue number5
    DOIs
    Publication statusE-pub ahead of print - 2017

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    Rojas-Canales, D., Penko, D., Myo Min, K., Parham, K., Peiris, G., Haberberger, R., Pitson, S., Drogemuller, C., Keating, D., Grey, S., Coates, P., Bonder, C., & Jessup, C. (2017). Local Sphingosine Kinase 1 Activity Improves Islet Transplantation. Diabetes, 66(5), 1301-1311. https://doi.org/10.2337/db16-0837