Placental growth factor attenuates suppression of erythroid colony formation by interferon

Abstract

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells and serum PlGF concentrations have been reported to distinguish sickle cell patients from healthy controls. We observed that CFU-E from homozygous sickle cell (SS) patients are less sensitive to inhibition by recombinant human (rh) γ interferon (IFN) than those from healthy controls, and the contribution of PlGF to this process was evaluated. At concentrations 10 -1000 pg/mL, PlGF neither inhibits nor enhances CFU-E colony formation, and there were no differences between the responses of SS patients or healthy controls. rhPlGF 100 pg/mL reversed the inhibitory effects of rhγIFN on CFU-E colony formation. rhPlGF significantly attenuated rhγIFN induction of Fas ligandin an erythroid cell line (HCD57). Both HCD57 cells and CD36+ human marrow cells express Flt-1, a receptor for PlGF. Neutralizing antibody against Flt-1 partially attenuated the IFN-protective effect of rhPlGF, although this effect was not statistically significant. In conclusion, increased PlGF concentrations in the marrow of SS patients may protect erythroid progenitors from cytokine-induced inhibition of colony formation, and may be a mechanism by which erythropoiesis in sickle cell disease is preserved despite concurrent inflammation.

Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor

“…Previously published results demonstrate clearly that PlGF is expressed highly in patients with SCD 21,38,39 and stimulates production of the potent vasoconstrictor ET-1 and other factors, [40][41][42][43][44][45][46] which is then associated in adults with SCD with echocardiographic indicators of elevated pulmonary artery pressure and in mice with histological evidence of pulmonary hypertension. 21,41 These prior results combined with our current data indicate for the first time a linkage between iron and expression of EKLF, PlGF, and ET-1 and clinical elevation of pulmonary artery pressure in humans with SCD with increased mortality.…”

Placental growth factor: What hematologists need to know

“…The most significant source of PlGF in the marrow appears to be the central marrow endothelial cells, protecting primitive HSCs within their vascular niche to a greater degree than marrow stromal cells 90 . Related research suggests that PlGF also attenuates inflammatory cytokine-suppressed erythropoiesis 94 and enhances platelet production via megakaryocyte maturation 95 , both of which may be of utility in the many patients with anemia and thrombocytopenia post-HCT. More studies are needed to validate these findings in transplant models and in clinical studies, as well as to elucidate the potential benefit of PlGF in normal hematopoiesis versus its role in inflammatory angiogenesis.…”