Inhibition of DPP4/CD26 and dmPGE2 treatment enhances engraftment of mouse bone marrow hematopoietic stem cells

Abstract

Enhancing the engraftment of hematopoietic stem cells (HSC) is especially important when times to engraftment are prolonged due either to limiting numbers of HSC in the donor graft or to intrinsic slower engrafting time of the tissue sources of HSC. Both inhibition of Dipeptidylpeptidase (DPP) 4/CD26 and treatment of cells with 16,16 dimethyl prostaglandin E2 (dmPGE2) have been shown to enhance hematopoietic stem cell engraftment in murine transplantation models and have been evaluated in clinical settings for their influence on engraftment of cord blood cells, a tissue source of HSC known to manifest an extended time to engraftment of donor cells compared to that of bone marrow (BM) and mobilized peripheral blood for hematopoietic cell transplantation (HCT). Herein, we present new experimental data, using a CD45+ head-to head congenic model of donor mouse BM cells for engraftment of lethally-irradiated mice, demonstrating that similar levels of enhanced engraftment are detected by pulsing donor BM cells with Diprotin A, a DPP4 inhibitor, or with dmPGE2 prior to infusion, or by pretreating recipient mice with sitagliptin, also a DPP4 inhibitor, by oral gavage. Moreover, the combined effects of pretreating the donor BM cells with dmPGE2 in context of pretreating the recipient mice with sitagliptin after administration of a lethal dose of radiation resulted in significantly enhanced competitively repopulating HCT compared to either treatment alone. This information is highly relevant to the goal of enhancing engraftment in human clinical HCT.