Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis

Hal E. Broxmeyer, Jonathan Hoggatt, Heather A. O'leary, Charlie Mantel, Brahmananda R. Chitteti, Scott Cooper, Steven Messina-Graham, Giao Hangoc, Sherif Farag, Sara L. Rohrabaugh, Xuan Ou, Jennifer Speth, Louis M. Pelus, Edward F. Srour, Timothy B. Campbell

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

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-1a - 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.

Original languageEnglish (US)
Pages (from-to)1786-1796
Number of pages11
JournalNature Medicine
Volume18
Issue number12
DOIs
StatePublished - Dec 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Broxmeyer, H. E., Hoggatt, J., O'leary, H. A., Mantel, C., Chitteti, B. R., Cooper, S., Messina-Graham, S., Hangoc, G., Farag, S., Rohrabaugh, S. L., Ou, X., Speth, J., Pelus, L. M., Srour, E. F., & Campbell, T. B. (2012). Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nature Medicine, 18(12), 1786-1796. https://doi.org/10.1038/nm.2991