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

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-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.

The underestimated role of basophils in Ph+ chronic myeloid leukaemia

“…The notion that basophils express substantial amounts of CD26 on their surface suggests that these cells may also be involved in SDF‐1 degradation and in the related migratory defect of CML LSC against this cytokine. Indeed, normal and CML stem cells express CXCR4, the receptor for SDF‐1; and disruption of SDF‐1 activity is considered to lead to stem cell mobilization 71, 72, 76, 77, 78. In this regard, it is worth noting that in patients with severe allergies where basophils may also increase, the numbers of circulating colony‐forming progenitor cells also increase 79.…”

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

“…Indeed, the kidney is where DPP-4 is expressed at the highest level per organ weight (13). Interestingly, DPP-4 has been associated with cell survival signaling and extracellular matrix remodelings (14)(15)(16).…”

Synthesis of granulocyte–macrophage colony-stimulating factor as homogeneous glycoforms and early comparisons with yeast cell-derived material

“…The glycan heterogeneity reflects a lack of specificity in CHO-cell posttranslational glycosylation. The degree of GM-CSF glycosylation has been reported to affect the in vivo properties of the glycoprotein (5,6); the aglycone may cause increased adverse side effects, perhaps due to its enhanced susceptibility to truncation pathways (7).…”