In hematopoiesis,
cytokine levels modulate blood cell replacement, self-renewal of stem cells, and responses to disease. Feedback pathways regulating
cytokine levels and targets for therapeutic intervention remain to be determined. Amino boronic
dipeptides are orally bioavailable inhibitors of
dipeptidyl peptidases. Here we show that the high-affinity inhibitor
Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor cells in vivo and can accelerate neutrophil and erythrocyte regeneration in mouse models of
neutropenia and acute
anemia. Hematopoietic stimulation by
PT-100 correlated with increased
cytokine levels in vivo. In vitro,
PT-100 promoted the growth of primitive hematopoietic progenitor cells by increasing
granulocyte-colony-stimulating factor (
G-CSF),
interleukin-6 (IL-6), and
IL-11 production by bone marrow stromal cells. Two molecular targets of
PT-100 are expressed by stromal cells- CD26/DPP-IV and the closely related fibroblast activation
protein (FAP). Because
PT-100 was active in the absence of CD26, FAP appears to be the hematopoietic target for
PT-100. Interaction of
PT-100 with the catalytic site seems to be required because amino-terminal acetylation of
PT-100 abrogated
enzyme inhibition and hematopoietic stimulation.
PT-100 is a therapeutic candidate for the treatment of
neutropenia and
anemia. The data support increasing evidence that
dipeptidyl peptidases can regulate complex
biologic systems by the proteolysis of signaling
peptides.