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TRANSLATIONAL AND CLINICAL RESEARCH

Placental Growth Factor-1 Potentiates Hematopoietic Progenitor Cell Mobilization Induced by Granulocyte Colony-Stimulating Factor in Mice and Nonhuman Primates

^a"Cristina Gandini" Medical Oncology Unit, Istituto Nazionale Tumori, Milano, Italy;
^bChair of Medical Oncology, University of Milano, Milano, Italy;
^cDepartment of Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy;
^dHematology and Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Milano, Italy;
^eDompé S.p.A., Research and Development, L'Aquila, Italy;
^fDepartment of Pediatric Hematology-Oncology, Laboratory of Transplant Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Key Words. Stem cell mobilization • Stem cell transplantation • Placental growth factor • Granulocyte colony-stimulating factor

Correspondence: Carmelo Carlo-Stella, M.D., "C. Gandini" Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy. Telephone: +39 02 2390 2717; Fax: +39 02 2390 3461; e-mail: carmelo.carlostella{at}unimi.it

Received January 10, 2006; accepted for publication September 20, 2006.
First published online in STEM CELLS EXPRESS   September 28, 2006.



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 µg/kg per day) plus rhG-CSF (100 µg/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.