Abstract
The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials.Key messagesPretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs.Vildagliptin enhances in vitro migration of pretreated HSPCs.Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs.Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.
Highlights
The merit of hematopoietic cell transplantation (HCT) is undisputed [1]
We show that recipient mice benefitted most from a sequential regimen, in which hematopoietic stem and progenitor cells (HSPCs) were first incubated in the presence of treprostinil and forskolin and the recipient animals subsequently treated with vildagliptin
The DPP4-inhibitor sitagliptin was previously shown to enhance engraftment of HSPCs, which had been preincubated in the presence of dimethylated PGE2 [9]
Summary
The merit of hematopoietic cell transplantation (HCT) is undisputed [1]. Umbilical cord blood (CB) is an accessible source of hematopoietic stem and progenitor cells (HSPCs) for HCT [2]. The small number of HSPCs in single units of umbilical CB preparations is a major limitation: depending on the extent of immunological mismatch, the dose of nucleated cells must exceed 2.5 × 107/kg to 5 × 107/kg to achieve 50% 1-year overall survival after myeloablative transplantation [3]. This cell dose cannot be readily achieved with single CB units. Stromal cell-derived factor-1 (SDF-1/CXCL12), the cognate ligand of CXCR4, is a chemoattractant for HSPCs [10] and is degraded by DPP4/ CD26 [11]
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