Placental growth factor-1 potentiates hematopoietic progenitor cell mobilization induced by granulocyte colony-stimulating factor in mice and nonhuman primates.
The complex hematopoietic effects of placental growth factor (PlGF) prompted us to test in mice and nonhuman primates the mobilization of peripheral blood progenitor cells (PBPCs) elicited by recombinant mouse PlGF-2 (rmPlGF-2) and recombinant human PlGF-1 (rhPlGF-1). PBPC mobilization was evaluated by assaying colony-forming cells (CFCs), high-proliferative potential-CFCs (HPP-CFCs), and long-term culture-initiating cells (LTC-ICs). In mice, both rmPlGF-2 and rhPlGF-1 used as single agents failed to mobilize PBPCs, whereas the combination of rhPlGF-1 and granulocyte colony-stimulating factor (rhG-CSF) increased CFCs and LTC-ICs per milliliter of blood by four- and eightfold, respectively, as compared with rhG-CSF alone. rhPlGF-1 plus rhG-CSF significantly increased matrix metalloproteinase-9 plasma levels over rhG-CSF alone, suggesting a mechanistic explanation for rhPlGF-1/rhG-CSF synergism. In rhesus monkeys, rhPlGF-1 alone had no mobilization effect, whereas rhPlGF-1 (260 microg/kg per day) plus rhG-CSF (100 microg/kg per day) increased rhG-CSF-elicited mobilization of CFCs, HPP-CFCs, and LTC-ICs per milliliter of blood by 5-, 7-, and 15-fold, respectively. No specific toxicity was associated with the administration of rhPlGF-1 alone or in combination. In conclusion, our data demonstrate that rhPlGF-1 significantly increases rhG-CSF-elicited hematopoietic mobilization and provide a preclinical rationale for evaluating rhPlGF-1 in the clinical setting.
Carlo-Stella
Carmelo
C
C. Gandini Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy. carmelo.carlostella@unimi.it
Di Nicola
Massimo
M
Longoni
Paolo
P
Cleris
Loredana
L
Lavazza
Cristiana
C
Milani
Raffaella
R
Milanesi
Marco
M
Magni
Michele
M
Pace
Virgilio
V
Colotta
Francesco
F
Avanzini
Maria A
MA
Formelli
Franca
F
Gianni
Alessandro M
AM
D000818:Animals; D003114:Colony-Forming Units Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010920:Placenta / Q000502:physiology*; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000502:physiology*; D011323:Primates; D011994:Recombinant Proteins / Q000494:pharmacology
D006133:Growth Substances; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000072483:Placenta Growth Factor; D020780:Matrix Metalloproteinase 9