Mesenchymal stromal cell secretory factors induce sustained improvements in islet function pre- and post-transplantation

• Published in: Cytotherapy (Oxford, England) Vol. 20; no. 12; pp. 1427 - 1436
• Main Authors: Rackham, Chloe L, Amisten, Stefan, Persaud, Shanta J, King, Aileen J.F, Jones, Peter M
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.12.2018
• Subjects: Advanced Basic Science; diabetes; islet transplantation; mesenchymal stromal cells; Other; secretome; islet transplantation; secretome; diabetes; mesenchymal stromal cells
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2018.07.007

Abstract Background aims Mesenchymal stromal cells (MSCs) enhance islet function both in vitro and in vivo , at least in part by secreting ligands that activate islet G-protein coupled receptors (GPCRs). We assessed whether pre-treatment with a defined “cocktail” of MSC-secreted GPCR ligands enhances islet functional survival in vitro and improves the outcomes of islet transplantation in an experimental model of diabetes. Methods Isolated islets were cultured for 48 h with ANXA1, SDF-1 or C3a, alone or in combination. Glucose-stimulated insulin secretion (GSIS) and cytokine-induced apoptosis were measured immediately after the 48 h culture period and at 24 h or 72 h following removal of the ligands from the culture media. Islets were syngeneically transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice and blood glucose levels monitored for 28 days. Results Pre-culturing islets with a cocktail of ANXA1/SDF-1/C3a potentiated GSIS and protected islet cells from cytokine-induced apoptosis in vitro . These effects were maintained for up to 72 h after the removal of the factors from the culture medium, suggesting a sustained protection of islet graft functional survival during the immediate post-transplantation period. Islets pre-treated with the cocktail of MSC secretory factors were more effective in reducing blood glucose in diabetic mice, consistent with their improved functional survival in vivo. Discussion Pre-culturing islets with a cocktail of MSC secretory products offers a well-defined, cell-free approach to improve clinical islet transplantation outcomes while avoiding many of the safety, regulatory and logistical hurdles of incorporating MSCs into transplantation protocols.