Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1–mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4−/− mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach.
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These studies were supported by US Health Service National Institutes of Health (NIH) grants R01 HL056416, R01 HL067284 and R01 HL112669 and a Center of Excellence in Hematology grant P01 DK090948 to H.E.B., and HL69669 and HL96305 to L.M.P. J.H. was supported as a doctoral candidate on NIH T32 DK07519 (to H.E.B.) and as a postdoc on NIH T32 HL07910 (to H.E.B.); H.A.O. was supported as a postdoc on NIH T32 DK07519; S.M.-G. was supported as a doctoral candidate on NIH R25 GM079657 (to H.E.B.); and T.B.C. was supported as a doctoral candidate on NIH T32 DK07519. S.L.R. was supported by NIH T32 CA111198 for parts of this study. We thank Y.-R. Zhou, The Feinstein Insitute for Medical Research, for the Cre+Cxcr4Fl/Fl mice.
H.E.B. is a founder of the CordUse family cord blood bank and a member of the Medical Scientific Advisory Board of CordUse.
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Broxmeyer, H., Hoggatt, J., O'Leary, H. et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med 18, 1786–1796 (2012). https://doi.org/10.1038/nm.2991
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