Pulse exposure of haematopoietic grafts to prostaglandin E2in vitro facilitates engraftment and recovery

Abstract

The aim of this study was to evaluate the effects of prostaglandin E(2) (PGE(2) ) on haematopoietic stem cell (HSC) function and determine its mechanism of action. HSC were exposed to PGE(2) for 2 h and effects on their homing, engraftment and self-renewal evaluated in vivo. Effects of PGE(2) on HSC cell cycle, CXCR4 expression and migration to SDF-1α were analysed in vitro. Apoptosis was evaluated by examination of survivin expression and active caspase-3 levels. Equivalent haematopoietic reconstitution was demonstrated using 4-fold fewer PGE(2) -treated cells compared to controls. Multilineage reconstitution was stable on secondary transplantation, indicating that PGE(2) affects long-term repopulating HSC (LT-HSC) and that enhanced chimaerism of PGE(2) -pulsed cells results from their initial treatment. PGE(2) increased CXCR4 expression on mouse and human HSC, increased their migration to SDF-1αin vitro and enhanced in vivo marrow homing 2-fold, which was blocked by a CXCR4 receptor antagonist. PGE(2) pulse exposure reduced apoptosis of mouse and human HSC, with increase in endogenous caspase inhibitor survivin, and concomitant decrease in active caspase-3. Two-fold more HSC entered the cell cycle and proliferated within 24 h after PGE(2) pulse exposure. These studies demonstrate that short-term PGE(2) exposure enhances HSC function and supports the concept of utility of PGE(2) as an ex vivo strategy to improve function of haematopoietic grafts, particularly those where HSC numbers are limited.