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First published online September 28, 2006
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2006-0020v1
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Submitted on January 10, 2006
Accepted on September 20, 2006

Translational and Clinical Research

PLACENTAL GROWTH FACTOR-1 POTENTIATES HEMATOPOIETIC PROGENITOR CELL MOBILIZATION INDUCED BY GRANULOCYTE COLONY-STIMULATING FACTOR IN MICE AND NONHUMAN PRIMATES

Carmelo Carlo-Stella 1*, Massimo Di Nicola 1, Paolo Longoni 1, Loredana Cleris 2, Cristiana Lavazza 1, Raffaella Milani 3, Marco Milanesi 1, Michele Magni 1, Virgilio Pace 4, Francesco Colotta 4, Maria A. Avanzini 5, Franca Formelli 2, Alessandro M. Gianni 1

1 "Cristina Gandini" Medical Oncology Unit, Istituto Nazionale Tumori, Milano, Italy
2 Department of Experimental Oncology, Istituto Nazionale Tumori, Milano, Italy
3 Hematology and Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Milano, Italy
4 Dompé S.p.A., R&D, L'Aquila, Italy
5 Department of Pediatric Hematology-Oncology, Laboratory of Transplant Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

* To whom correspondence should be addressed. E-mail: carmelo.carlostella{at}unimi.it.


  Abstract

The complex hematopoietic effects of Placental Growth Factor (PlGF) promted us to test in mice and nonhuman primates the mobilization of peripheral blood progenitor cells (PBPCs) elicited by recombinant mouse (rm)PlGF-2 and recombinant human (rh)PlGF-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 ml blood by 4- and 8-fold, respectively, as compared with rhG-CSF alone. rhPlGF-1 plus rhG-CSF significantly increased matrix metalloproteinase-9 (MMP-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/day) plus rhG-CSF (100 µg/kg/day) increased rhG-CSF-elicited mobilization of CFCs, HPP-CFCs and LTC-ICs per ml 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.

Key Words. Stem cell mobilization, stem cell transplantation, placental growth factor, granulocyte colony-stimulating factor




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